Stimuli-Responsive Nano-Architecture Drug-Delivery Systems to Solid

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Stimuli-Responsive Nano-Architectures Drug Delivery Systems to Solid Tumor Micromilieu: Past, Present and Future Perspectives Hossam Samir El-Sawy, Ahmed Al-Abd, Tarek Ahmed, Khalid M. El-Say, and Vladimir P. Torchilin ACS Nano, Just Accepted Manuscript • Publication Date (Web): 17 Oct 2018 Downloaded from http://pubs.acs.org on October 17, 2018

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Stimuli-Responsive Nano-Architectures Drug Delivery Systems to Solid Tumor Micromilieu: Past, Present and Future Perspectives Hossam S. El-Sawy1, Ahmed M. Al-Abd2,3, Tarek A. Ahmed4,5, Khalid M. El-Say4,5, Vladimir P. Torchilin6,*

1

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt 2

Department of Pharmaceutical Sciences, College of Pharmacy, Medical Gulf University, Ajman, United Arab Emirates. 3

4

Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt.

Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia 5

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

6

Department of Pharmaceutical Sciences Center for Pharmaceutical Biotechnology and

Nanomedicine Northeastern University 140 The Fenway, Room 211/214, 360 Huntington Ave. Boston, Massachusetts 02115, USA

Corresponding author: Vladimir P. Torchilin Department of Pharmaceutical Sciences Center for Pharmaceutical Biotechnology and Nanomedicine Northeastern University 140 The Fenway, Room 211/214, 360 Huntington Ave. Boston, Massachusetts 02115, USA e-mail: [email protected]

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Abstract The microenvironment characteristics of solid tumors, renowned as barriers that harshly impeded many drug delivery approaches, were precisely studied, investigated, categorized, divided and subdivided into a complex diverse of barriers. These categories were further studied with a particular perspective, which makes all barriers found in solid tumors micromilieu turned into different types of stimuli, and considered as triggers that can increase and hasten drug release targeting efficacy. This review is gathering the data concerning the nature of solid tumors micromilieu, the past directions focused on treatment of such tumors, the recent efforts employed for engineering smart nano-architectures with the utilization of the specified stimuli categories, the possibility of combining more than one stimuli for much more targeting enhancement, examples of the approved nano-architectures that already translated clinically as well as the obstacles faced by these nano-structures, and lastly overview the possible future implementations of smart chemical engineering for designing more efficient drug delivery/theranostic systems and for making nano-systems with much higher level of specificity and penetrability features. Keywords: solid tumor micromilieu, nano-architectures engineering, cancer cell targeting, stimuli/trigger responsive mechanisms, smart nano drug delivery systems, liposomes, polymeric nanoparticles, smart theranostics.


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Over the past seven decades, cumulative scientific evidences are rising and denoting pharmacokinetic obstacles as a major underlying reason for solid tumor treatment failure.1 Researchers are getting more specific and dissecting pharmacokinetics into several sublevels; whole body pharmacokinetics, intratumoral pharmacokinetics and cellular pharmacokinetics.2 Amongst, whole body pharmacokinetics could be readily overcome by many simple techniques such as optimizing the route of drug administration (intravenous administration, intra-thecal administration, intra-arterial chemoembolization …etc.).3 Cellular pharmacokinetics represents affordable challenge which could be tackled by several permeation enhancers (such as Pglycoprotein inhibitors, cell membrane mobilizers and proton pump inhibitors).4–6 However, intratumoral pharmacokinetics represents core hurdle for drug delivery and requires extensive research efforts to get the anticancer chemotherapeutic agent to every single micromilieu of solid tumor micro-regions.7 Not only delivering the anticancer agent to every bucket within the solid tumor, but also it must be delivered in a cytotoxic concentration.2,8 Exposure of tumor cells to sub-cytotoxic concentration of anticancer drug recruits tumor resistance rather than just treatment failure.9,10 Yet, the challenge of drug delivery within solid tumor micromilieu is attributed mainly to the complicated biology of the intratumoral microenvironment.1,7 SPECIAL CHARACTERISTICS OF SOLID TUMOR MICROENVIRONMENT Perforated endothelium and enhanced permeation and retention (EPR) effect Blood capillaries within human bodies can be classified according to their endothelial lining and basement membrane into three types; continuous, fenestrated, and perforated.11,12 Intratumoral blood capillaries are found to be highly perforated with wide open pores between their endothelial cells which are resting on discontinuous basement membrane.13 This phenomenon led to preferential filtration/permeation and accumulation of any macromolecular 3 ACS Paragon Plus Environment

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material (size range of 10-100 nm) within tumor tissue; it is called enhanced permeation and retention phenomenon (EPR).14 In 1986, Maeda and coworkers showed the preferential accumulation of macromolecules within tumor micro-regions.15 This led to very optimistic expectations in the field of intratumoral drug delivery; however, nothing significant was observed clinically.16 Despite the clear experimental evidence of EPR-related macromolecular accumulation within tumor regions, huge doubt about its clinical influence in clinical settings.17,18 It is worth mentioning that, the correlation between EPR effect in animal cancer models and human cancer patients is very weak.19,20 The huge discrepancies between experimental and clinical aspects of solid tumors were more than clear and influential in terms of EPR. Tumor growth rates are markedly different in experimental compared to clinical settings; 0.5 gm xenograft tumor mass (common subcutaneous tumor size) in mouse would be equivalent to 1-2 kg solid tumor in human body.21,22 Besides size, xenograft or orthotopic solid tumor animal models are very different from human neoplasia in terms of extracellular matrix complexity and micro-environmental traits.23–25 After more than three decades of optimism and hopes regarding the influence of EPR effect in solid tumor targeting, It might be possible to conclude that EPR effect is suitable for rodent tumors rather than human solid malignancies.25 On another aspect, patient derived tumor animal models (PDX model) are partly constituting a step up in simulating human tumor.26 Yet, EPR effect is even different between different animal tumor models (orthotopic versus xenograft models).27,28 Beside the extracellular accumulation of macromolecules due to EPR effect, endothelial transcytosis might be responsible in macromolecular extravasation. In both cases, EPR-aided extravasation and endothelial transcytosis, drug molecules are restricted to tumor periphery rather than homogenously distributed within solid tumor mass.29–31 In other words, EPR is not the end of the story; it is the


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start of great struggle. After EPR takes place, the anticancer drug must penetrate/distribute homogeneously through very hostile micro-regions in terms of crowded tumor cells; excessive extracellular matrix (ECM); high level of matrix metalloproteinases (MMP’s); high interstitial fluid pressure (IFP); hypoxia and acidosis (figure 1).7 Each characteristic of these will be discussed in details in the coming sections.


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Figure 1. Schematic diagram showing the complicated biology of the intratumoral microenvironment. Abbreviations: ECM; excessive extracellular matrix, EPR; enhanced permeation and retention effect, IFP; interstitial fluid pressure. 6 ACS Paragon Plus Environment

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Tumor parenchymal cell crowdness The enormous uncontrolled cell proliferation of most of the tumor types results in undifferentiated mass of malignant cells. Actually, this characteristic is the origin of naming cancer as “tumor” or malignant mass.32 Normal dividing cells including rapidly proliferating cell types (such as gastric mucosa, spermatogonia, hair follicles, and blood cells) undergo full cycle of division within approximately 28 days or longer. On the other hand, tumor cells divide into two daughter cells within 36 h on average; some tumor cells can divide even faster.33,34 Cell proliferation rate of tumor cells exceeds their excessive requirement of angiogenesis resulting in cells far from their own source of nutrition and oxygen supply. Some tumor cells might be as far as more than 10 rows of cells from the nearest functioning capillary.13,35–37 It is worth mentioning that any normal cell is not more distant than two rows of cells from their nearest capillary.38 Tumor cell crowdness, per se, results in significant intratumoral cellular heterogeneity due to gradient nutritional and oxygen distribution across the tumor mass.39 The direct influence of tumor crowdness to intratumoral drug delivery might not be as weight-full as other intratumoral micro-environmental peculiarities (discussed in the next sections).40 However, the tumor crowdness could be considered the primary reason for the vast majority of the rest of solid tumor micro-environmental characteristics.41 Tumor cell crowdness over weigh the angiogenesis machinery and results in intratumoral hypoxia.12,42 Besides, higher numbers of tumor cells consume more oxygen and glucose as energy units and produce more lactic acid which in turn increase the intratumoral hypoxia and acidosis.43 Crowded cells constitute static physical pressure on the prematurely formed intratumoral capillary as well as lymphatic drainage system and result in stagnant blood flow, excessive hypoxia and elevated IFP.44–47


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Elevated tumor packing density results in narrower inter-cellular spaces and negatively influences diffusivity of drugs penetrating tumor tissue via para-cellular diffusion.44 On the other hand, tumor cells proximal to functioning capillary uptake huge amount circulating drugs in a sink-like behavior.40 This in turn results in much less remaining amount of the drug to penetrate to deeper micromilieu via trans-cellular diffusion as well.48 Besides, it was found that tumor cells proximal to functioning capillaries overexpressed many efflux proteins such as Pglycoprotein.49,50 Yet, trapped drug molecules within tumor peripheral cells will be ended up fluxed back to blood stream rather than distributed to the deep tumor micromilieu. In general, elevated intratumoral cell packing density directly and indirectly decreases intratumoral drug distribution, nonetheless, deeper micromilieu.39,41 Jessie-Au and co-workers carried out significant effort to enhance the intratumoral drug distribution by resolving this obstacle via tumor priming and pre-treatment protocols.51–55 Intratumoral poor vascularity/avascularity We need to dissociate “low intratumoral vascularity” from “high intratumoral vascular density”. Vascularity describes functioning vascular network; while vascular density refers to the occurrence of blood vessels.12 Due to the increased demand to oxygen and nutrient within tumor micro-regions, tumor cells secrete several pro-angiogenic growth factors (such as VEGF, FGF, PDGF…etc.) and express their counterpart receptors (such as VEGFR’s, FGFR’s, PDGFR …etc.).56 These growth factors and their receptors result in excessive intratumoral neoangiogenesis. However, it is repeatedly reported that these freshly formed intratumoral blood vessels are pre-mature, tortuous, chaotic, not properly anastomosing and ultimately not functioning.13


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These reciprocal characters (high intratumoral vascular density and poor intratumoral blood flow) aggravate several intratumoral micro-environmental characteristics and add more obstacles against intratumoral drug delivery.57 Poor intratumoral vascular capillary anastomosis results in fluid accumulation; elevated IFP; slower intratumoral blood flow; excessive hypoxia and excessive intratumoral acidosis.46 Intratumoral angiogenesis was targeted by many aspects. Classic approach of antiangiogenic drugs was via abolishing these weak pre-mature intratumoral blood vessels leaving tumor cells to die silently.58 Technically, it was not like planned to theoretically; it was also due to delivery obstacles. Anti-angiogenic agents are designed solely to target pre-mature capillaries which are far from the tumor periphery and the functioning blood vessels.59,60 Other approach is called vascular normalization; it depends on delivering low doses of anti-angiogenic agents to slow down the rush of angiogenesis and give the intratumoral blood vessel time to mature. Yet, this approach significantly enhances the delivery of other classic anticancer agents and facilitates the intratumoral delivery of cytotoxic agents.61–63 Kerbel and co-workers as well as Rakesh Jain and co-workers carried out significant body of research in the area of metronomic therapy and intratumoral vascular normalization.61,64–72 Blocked lymphatic drainage Lymphatic tree could be considered as the biological drainage system; it takes away macromolecules, such as peptides, cytokines and antibodies from the different body tissues to blood stream.44,73 In tumor tissue, lymphatic drainage system is partially to completely blocked and non-functioning. This blockage might be attributed to the high pro-angiogenic balance within tumor tissue and its subsequent uncontrolled angiogenesis.44,46 In another point of view, it might be attributed to the static pressure exerted by tumor parenchyma crowdness.48 In either 9 ACS Paragon Plus Environment

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case, blocked lymphatic drainage leads to fluid and macromolecule retention and subsequent elevated osmotic IFP.74 Yet, elevated osmotic pressure will recruit more fluid retention and induce more static pressure on lymphatic and other intratumoral vasculature leading to more lymphatic blockage. In most circumstances, strategies taken to resolve intratumoral angiogenesis problem would help in improving lymphatic drainage.1,2,7 Excessive extracellular matrix (ECM) proteins/ ECM remodeling enzymes ECM proteins can be classified into two major categories; filament-like ECM proteins (such

as

collagen,

fibronectin,

laminin

…etc.)

and

cement-like

ECM

(such

as,

glycosaminoglycans and hyaluronic acid). Both types of ECM are essential for maintaining the anatomical 3D shape of tissues and organs beside some other molecular signaling functions.75–77 Tumor associated fibroblast and even tumor cells are superiorly active in synthesizing ECM and ECM remodeling enzymes (such as decorin, collagenase, hyaluronidase, elastase and other MMP’s) to accommodate the rapidly growing nature of solid tumor. ECM remodeling enzymes are crucial in tumor cell invasion, extravasation and remote metastasis.78,79 Direct relationship was noticed between the excessive amount of ECM and intratumoral drug penetration/distribution. This was mainly attributed to the influence of ECM accumulation to the intratumoral IFP.80,81 ECM remodeling enzymes such as collagenase, hyaluronidase and decorin significantly enhanced intratumoral distribution of anticancer drugs, drug delivery systems and even aden-oncolytic viruses.82–87 However, the accelerated remote tissue metastasis is an expected dangerous side effect of using these ECM degrading enzymes.88–90 Intratumoral hypoxia Hypoxia is one of the direct outcomes of poor intratumoral vascularity. Hypoxia is aggravated by increasing distance from the nearest functioning blood vessel.39,41 Tumor 10 ACS Paragon Plus Environment

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parenchymal cell crowdness contributes to intratumoral hypoxia by decreasing solutes and fluid diffusivity and by increasing the cellular demand for oxygen. Central necrosis is among the striking signs of intratumoral hypoxia; and it inspired the whole idea of using anti-angiogenic drugs for cancer treatment.91–93 Tumor cell survival under hypoxic and even anoxic condition is very interesting for cancer biology. Intratumoral pO2 can reach to as low levels as 0.1 mmHg.41,94 This phenomenon is even more interesting when coupled with Warburg effect. Tumor cells merely utilize glucose to produce energy via glycolysis; oxygen-dependent tricarboxylic acid cycle (Krebs cycle) is known to be not functioning in tumor cells.95 In other words, tumor cells are genetically trained to survive without oxygen. Tumor cells switch on several gene families/molecular pathways, such as HIF-α and downstream gene family; autophagy pathway, anti-apoptotic pathway and several pro-angiogenic growth factors to survive hypoxic condition.41,96–100 Hypoxia when coupled with tumoral Warburg effect is the main underlying reason for intratumoral acidosis. Glycolysis end product, lactic acid, accumulates within the deep intratumoral micro-regions in the absence of proper intratumoral diffusivity and significantly decreases the pH. Hypoxia dependent pro-angiogenic gene activation significantly participates in the excessive uncontrolled intratumoral angiogenesis and blood vessel pre-maturity.49,101 This in turn increases the tortuousness of intratumoral capillary bed and elevates the IFP. Besides, hypoxia also increases the expression of micro-environmental remodeling enzymes such as several MMP’s to facilitate oxygen and nutrient delivery to the deep intratumoral micromilieu.69,98,99 Hypoxia, per se, does not constitute intratumoral delivery barrier. On contrary, complete family of agents called bio-reductive cytotoxic drugs which utilize intratumoral hypoxia are in


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different levels of preclinical to clinical use. Bio-reductive agents such as mitomycin-C, tirapazamin, AQ4N, are activated to their cytotoxic active metabolites under low oxygen tension.102–104 The real challenge for these agents is to deliver them to the deep hypoxic microregion itself. On the other hand, some agents are inactivated under reductive or hypoxic conditions such as anthracycline cytotoxic drugs.105 In summary, hypoxia is not a delivery barrier rather than it is a challenge for any drug delivery system to deliver a bio-reductive agent to this territory. Intratumoral acidosis Warburg effect and subsequently lactic acid accumulation are the direct reasons for intratumoral acidosis.95 Besides, poor diffusivity and slow waste product wash out from tumor tissues are other underlying reasons for intratumoral acidosis.94 Despite the very acidic extracellular compartment of solid tumor (pH can be as low as pH 3), the intracellular pH of tumor cells is maintained with the ambient physiological pH (pH 7.4).41,106 This is attributed to the overexpression of H+-pump receptors on the cellular membrane as well as on the intracellular lysosomal membranes of tumor cells. This results in efficient efflux of acidic H+ to the extracellular compartment or sequestering these H+ within the lysosomal vacuoles of the tumor cells.107–109 Acidic intratumoral pH is optimum for the activity of several ECM remodeling enzymes such as MMP’s. In addition, acidic degradation of ECM proteins results in smaller molecular weight peptides and subsequently increases the interstitial fluid osmotic pressure.110–112 Finally, elevated IFP decreases oxygen diffusivity and delivery to deep intratumoral micromilieu which aggravates the Warburg effect resulting in more intratumoral acidosis.


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Similarly, intratumoral acidosis per se does not constitute any solid tumor penetration barrier. Consequences to this trait such as elevated IFP might be the real drug delivery obstacle. Also the over activation of MMP’s might form very hostile and deactivating microenvironment to protein based anticancer drugs such as monoclonal antibodies.113,114 In addition, many anticancer drugs could be inactivated (at least partially) in acidic pH such as, doxorubicin, bleomycin, vinblastin, paclitaxel, methotrexate, mitoxantrone and topotecan.115 On the other hand, some anticancer drugs could be more active in acidic pH such as, chlorambucil, mephalan, cyclophosphamide, mitomycin-C, cisplatin, 5-fluorouracil and camptothecin.116,117 Yet, intratumoral acidosis is not restricted to the deep and hard to reach tumoral micromilieu. In summary, acidic intratumoral microenvironment represents very useful tool for targeted and smart drug delivery strategies compared to other intratumoral biological characteristics.118 Interstitial fluid pressure (IFP) In our opinion, elevation of the intratumoral IFP is the major underlying reason for the failure of the vast majority of solid tumor treatment as well as drug delivery systems.2,7 There must be pressure gradient between the arterial and venous shunts of the capillary bed to guarantee normal blood flow and oxygen/nutrients transfer.119 IFP could be as high as 50-100 mmHg within the deep intratumoral regions.94 Yet, this value is more than 5 fold the highest capillary blood pressure and is very close to the blood pressure within the aortic artery.120 Accordingly, fluid diffusion direction within tumor tissue is expected to be out ward rather than an uptake from blood stream. This is the biggest challenge for drug delivery to solid tumors.121 Indeed, elevated intratumoral IFP could be considered the central reason for drug delivery failure into tumor tissue. Interestingly, the majority of the biological and biophysical obstacles to intratumoral drug delivery would ultimately lead to elevated IFP.122 Increased cellular packing 13 ACS Paragon Plus Environment

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density of tumor cells; abnormal intratumoral vascularity; blocked lymphatic drainage; and excessive production of ECM materials would lead to increased IFP within deep tumor microregions (figure 2).123 Other factors such as excessive tissue remodeling by MMP’s and intratumoral acidosis/hypoxia would indirectly result in elevated intratumoral IFP.124,125 In summary, intratumoral IFP could be considered as direct functional surrogate marker for the degree of intratumoral drug delivery.

Figure 2. Schematic illustration displaying the ‘all roads lead to IFP elevation’ concept. The biological and biophysical complexities of the intratumoral micromilieu would ultimately lead to elevated IFP, which would further result in drugs and nanocarriers poor penetration. This concept emphasizes the elevated IFP as a major challenge facing nanomedicine application for solid tumor treatment. Abbreviations: ECM; excessive 14 ACS Paragon Plus Environment

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extracellular matrix, EPR; enhanced permeation and retention effect, IFP; interstitial fluid pressure, MMP; matrix metalloproteinases.


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Attributed to its central role in intratumoral drug delivery, wide range of strategies to decrease or alleviate intratumoral IFP is being adopted. Jain and coworkers are from the pioneers in targeting IFP as a tool to enhance intratumoral delivery and entrapment of anticancer drugs.42,47,61,62,73,99,126–136 Among these counteracting strategies is vascular normalization,127 ECM dissolving agents,1,86,87,137 metronomic treatment,7,138 and even decreasing tumoral packing density by tumor priming/pre-treatment protocols.53–55 BRIEF HISTORY OF DRUG TARGETING TO SOLID TUMORS Passive targeting Intratumoral passive targeting is meant herein by the ability of anticancer drug to accumulate within tumor tissue due to physical, chemical and/or biological properties of the drug and/or the tumor tissue. Since the understanding for EPR effect, wide open intratumoral vasculature is considered the most promising biological feature in favor of drug accumulation within tumor tissue. On the other aspect, any macromolecular carrier with a size in the range from 100 nm to 1 µm diameter will preferentially deposit within tumor tissues attributed to their perforated vasculature.94

Metal based nanoparticles such as gold nanorods accumulated

significantly within tumor tissues based on their particle size and EPR effect alone.139 Another biophysical phenomenon, proton-sponge effect, facilitates cellular uptake of positively charged particles.140 Cell membrane is known to be negatively charged due to the phospholipids bi-layer. Yet, positively charged molecules such as lipofectamine and similar compounds are preferentially attracted to cell membrane and possess greater chance of endocytosis.141 Since the very early invention of drug delivery systems (DDSs), poly-amines are among the most favored surface decorations which in turn facilitate cellular internalization.


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Active targeting On contrary to passive targeting, active targeting solely utilizes biological features of tumor cells/tumor tissue to enhance drug concentration within the intratumoral micro-regions. However, the very early step for active targeting is passive accumulation within solid tumor periphery via EPR effect.27 Several receptors, ligands or extracellular protein motifs are either expressed only on tumor cells/tumor tissue or highly expressed in tumor tissue compared to normal tissue.142 Antibodies or similar ligands which bind specifically to these molecules are used to decorate many drug delivery systems in order to enhance their homing to tumor tissues. Monoclonal antibodies (mAb) against molecules such as, HER2 (trastuzumab),143 EGFR (cetuximab),144 transferring receptors (OX26 or R17217),145 PSA (J591)146 and CD20 (rituximab)147 are commonly used decorating agent for active tumor tissue targeting. Due to the smaller size of Fab fragment (compared to mAb) and its easier technology for conjugation, Fab fragments are used to decorate many DDSs for active tumor targeting.142 Anti-CD19 Fab fragment is used to decorate DDS used to treat B-cell lymphoma;123 humanized anti-HER2 Fab fragment is used for the treatment of breast cancer.148 Unlike antibodies, aptamer is a stable double strand RNA or DNA random sequence arises from incomplete digestion of high RNA or DNA content samples. Attributed to the 3D configuration and ligand affinity of different aptamers, specific sequence aptamers are selected and multiplied chemically without the need for biological system.149 Aptamers are more stable than antibodies (in terms of pH, heat and organic solvent stability) and possess higher ligand affinity. Besides, aptamer is smaller in size and less immunogenic compared to antibodies.150 Aptamers specific to tumor restricted/overexpressed ligands or receptors are used to decorate DDSs for enhanced intratumoral delivery.151 Aptamers against EGFR (A10 RNA aptamers),


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nucleolin (AS1411) and MUC1 can be used for several types of tumor targeting DDSs.152–154 Ligand based targeting of DDS is another active targeting strategy which utilizes these ligands as decorating moieties. Receptors for folic acid,155 RGD peptide156 and transferrin are overexpressed on tumor cells.157 DDSs-conjugated with any of these ligands enhance intratumoral accumulation of the carried anticancer load as well as improve their cellular internalization.142 Vascular transcytosis is a recently discovered pathway that differs from EPR effect and other endocytic uptake mechanisms. It permits uptake of small drug molecules, monoclonal antibodies and nanoparticles at the tumor site during co-administration of the cyclic tumorpenetrating peptide iRGD. The pathway is initiated by the interaction between iRGD and the neuropilin-1 (NRP-1) receptor which plays an important role in tumor angiogenesis.158–162 Sugahara et al., studied the effect of administration iRGD as a combination treatment with some anti-cancer drugs, such as paclitaxel, doxorubicin and trastuzumab, to mice bearing human tumor xenografts. They reported 12-fold accumulation and deeper penetration into the human breast tumors from Nanoparticle albumin-bound (Nab)-paclitaxel (Abraxane®; ABX) intravenously injected with iRGD than from ABX administered alone.160 The same results were also obtained with Doxorubicin (DOX). Better penetration and accumulation of the chemotherapeutic agent by more than 7-fold in the tumor cells was observed from DOX co-injected with iRGD than DOX given alone. Finally, trastuzumab, a chemotherapeutic monoclonal antibody in clinical use for the management of breast cancer, showed the same effects. Co-administration of iRGD resulted in enhanced accumulation of trastuzumab in the tumors by 40 fold due to enhanced access and binding of the antibody to the tumor cells. Liu et al. demonstrated the role of transcytosis in the enhancement of survival and marked decrease in metastasis of pancreatic ductal adenocarcinoma


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following administration of silicasome-based chemotherapy that comprises lipid bilayer-coated mesoporous silica nanoparticles.163 In general, active targeting might enhance the very early step of intratumoral drug delivery (EPR-effect) and the very last step of cellular internalization. Yet, the milestone obstacle of intratumoral distribution of drug-loaded DDSs is not solved. TYPES OF STIMULI USED TO TRIGGER DRUG RELEASE Different types of stimuli have been reported to trigger the release of drug to solid tumor, which can be classified into two groups; either endo or exo-triggers stimuli (figure 3).

Figure 3. Diagrammatic classification of nano smart DDSs and different stimuli triggers that can be potentially utilized.


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Endo-triggers stimuli pH-responsive pH is one of the most frequently used inducements that has been employed to control drug delivery either in specific organs (such as the vagina or the gastrointestinal tract) or in the intracellular organs (such as lysosomes or endosomes), as well as the drug release when environmental changes are accompanied with pathological conditions, such as cancer or inflammation.164,165 The pH of some organs such as the stomach (pH≈ 2) and the intestinal (pH≈ 7) may be used to trigger the drug release from different formulations. For example, Eudragit S100 has been utilized to develop nanoparticles coated with citrus pectin and used for colon specific targeting of 5-Fluorouracil.166 Delicate pH changes in specific disease sites, such as inflammation, ischemia, and in tumor tissues, even in some organelles, like endosomes and lysosomes can trigger the drug release from the designed carriers. The pH-responsive nanocarriers category is one of the typical examples that targeting solid tumor.167 In normal condition, the pH of the extracellular tissue and blood is usually maintained at around 7.4 and this value is decreased to around 7.0 in various solid tumors due to the high rate of glycolysis.168,169 The low pH value in the extracellular tumor matrix can be utilized as a specific stimulus in controlled DDSs. Moreover, this pH difference can also be found in some organelles, such as endosomes and lysosomes, in which the pH value is lower than other intracellular organelles with the pH range from 4.5 to 5.5. Accordingly, the difference in pH may be considered as a key design rationale for the development of advanced DDSs.164,169 Two main strategies are employed, first; the use of polymers (polyacids or polybases) that are characterized by ionizable groups which undergo conformational and/or solubility changes upon environmental pH change, second; the design of polymeric systems that have acid-sensitive 20 ACS Paragon Plus Environment

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bonds whose cleavage permits the release of molecules attached to the polymer backbone, change of the polymer charge or the exposure of targeting ligands. Many anticancer drug delivery systems have been formulated to deliver or release their drug content utilizing the process of the slight pH value difference that is existing between healthy tissues (~7.4) and the extracellular environment of solid tumors (6.5–7.2). This pH difference is directly related to irregular angiogenesis in the fast-growing tumor tissues, which causes a rapid decrease in both oxygen and nutrients. Thus, a shift toward glycolytic metabolism process will occur and lead to production of acidic metabolites in the tumor interstitium. Therefore, efficient pH-sensitive drug delivery systems must possess a sharp response to a small change in the pH of the tumor extracellular microenvironment. For example, the release of the tumor necrosis factor alpha (TNFα) from chitosan in the local acidic environment of tumor tissues due to swelling of the polymer induced on amino-group protonation (pKa ~6.3).165,170 Sudden disassembly of PEG– poly(β-amino ester) micelles at pH 6.4–6.8 triggered the leakage of campthotecin entrapped in the polymeric micelles.171 Self-assembling piperidine- and imidazole-modified PEG–poly(βamino ester) micelles loaded with human serum albumin was prepared and exhibited a pH-tuning conversion from neutral to positive charge when the pH was changed from 7.8 to 6.2.172 Promotion of cell internalization of cell-penetrating peptides (CPP) display at the surface of nanocarriers, was also achieved due to pH change. Polyhistidine-based micelles containing 15% by weight doxorubicin have the strong capability to translocate the prepared micelle into cells at a slightly acidic tumor extracellular pH,which enable the internalization, disintegration in early endosomal pH of tumor cells and so quickly releasing of doxorubicin.173 The pH-sensitive PEGylated liposomes, modified with cell-penetrating TAT peptide and the cancer cell-specific mAb 2C5, enhanced Doxil cytotoxicity and carrier internalization by tumor cells. The


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immunoliposomal nanocarrier also exhibited the potential for intracellular drug delivery after exposure to lowered pH environment.174 Other targeting strategies involved the design of doxorubicin based functionalized lipid vesicles with pH-triggered heterogeneous membranes that demonstrate tunable surface structure. These functionalized vesicles hide targeting ligands from their surface during their circulation in the blood stream, and expose these ligands only when they gradually penetrate deeper into the tumor interstitium, where they burst release their doxorubicin content after endocytosis at the endosomal pH 5.5-5.0

175

. Cell internalization can

also be promoted by means of a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulates DDS, which are capable of reversing the prepared nanoparticles surface charge from negative to positive at tumor extracellular pH of about 6.8, to facilitate cell internalization.176 It is noteworthy to mention that, despite the pH stimulus is widely used in smart DDS, yet it needs to be combined with other stimuli, such as temperature or redox to achieve extremely precise and specific drug release at the targeted tumor sites. Hypoxia-responsive Despite the amazing progress in science and technology, still cancer is a very complex, multi-step process with mechanisms largely unknown. Hypoxia is considered as one of the most important factors contributing to malignancy and cancer progression. Inadequate and abnormal microvasculature occur in the whole tumor tissue once the cancer cells start to grow.177 Accordingly, hypoxia occurs which is considered as a major problem in cancer therapy due to its roles in tumorigenesis and resistance to therapy.178 However, hypoxia can be considered as an attractive therapeutic target, particularly in the context of radiotherapy for some tumor types as non-small cell lung cancer.179 Many techniques were developed to target and deliver many genetic, chemotherapeutic and radio-therapeutic agents to solid tumors depending on hypoxia as 22 ACS Paragon Plus Environment

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a prominent cancerous factor.178 Tumor microenvironment-responsive nano DDSs are gaining much attention in the field of biomedical sciences. Hypoxia-responsive DDS is considered as the more appealing in cancer chemotherapy.180,181 Many examples for hypoxia-responsive smart DDSs have developed and demonstrated their usefulness in cancer treatment. Ahmad et al., prepared hypoxia-responsive doxorubicin loaded polymeric micelles from methoxy poly (ethylene glycol)-block-poly (glutamic acid)-graft-6-(2-nitroimidazole) hexyl amine (mPEG-bPLG-g-NID) that exhibited faster release in the tumor cells hypoxic condition when compared to normoxic conditions (physiological condition).181 In another study, Kulkarni et al. formulated a hypoxia-responsive self-assembly polymersomes from di-block copolymer of polylactic acidazobenzene-polyethylene glycol in an aqueous medium. Under normoxic conditions, the prepared polymersomes did not release any encapsulated contents for 50 minutes, while 90% of the encapsulated dye was released in the same time interval under hypoxia.182 In addition, it was reported that the hypoxia-responsive ionizable liposomes delivered small interference RNA (siRNA) anticancer drugs, which selectively improved the cellular uptake of siRNA under hypoxic and low-pH conditions, to treat glioma.183 Moreover, hypoxia-responsive lipid-based nanoparticles were synthesized and conjugated with a peptide-lipid iRGD (a tumor‑penetrating peptide) which exhibited better penetration to the hypoxic regions of the tumors. The developed nanoparticles underwent reduction, lipid membrane destabilization, and release of the encapsulated gemcitabine under low oxygen partial pressure which resulted in reduction of the viability of pancreatic cancer cells to 35% under hypoxic conditions.184 Different preparations of hypoxia-responsive nanoparticles (HR-NPs) were designed and studied for their effect in cancer treatment. Doxorubicin was effectively encapsulated into HR-NPs that released their drug content in a controlled manner under normoxic condition, while the doxorubicin release rate was


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noticeably increased under the hypoxic condition. It was found from in vitro cytotoxicity study that the drug-loaded HR-NPs showed higher cytotoxicity to hypoxic cells when compared to normoxic cells. Also, HR-NPs were selectively accumulated at the hypoxic tumor tissues and exhibited high anti-tumor activity as revealed by the in vivo biodistribution study.185 Moreover, an amphiphilic self-assembled nanoparticle made from a combination of, azobenzene, combretastatin A-4 and irinotecan investigated inhibition in the migration, invasion and mammospheres formation capacity of cancer stem cells and endothelial cells without the interference on the normal cell.186 Overall, the HR-NPs are considered a promising smart DDS that might have a potential in the treatment of hypoxia-associated diseases, particularly solid tumors. Enzyme-responsive (MMP’s-responsive and Non-MMP’s ECM re-modelling) Many enzymes with

disrupted regulation were clearly observed within the

pathophysiological changes of tumor progression. From this prospective, a targeting strategy was designed to formulate nanostructured drug delivery systems which can release their loaded cargo depending on the sensitivity for certain abnormally overexpressed enzyme. MMP’s, a family of zinc-dependent endopeptidases enzymes, are known to be involved and overexpressed in many stages of human cancers which have multiple functions in all stages of cancer development: from initiation to outgrowth of clinically relevant metastases and also in apoptosis and angiogenesis.187–189 Many MMP-sensitive substrates have been designed and exhibited stimulus responsiveness toward these enzymes when used in drug delivery and imaging

systems.187,190

Zhu

et

al.,

developed

a

surface-functionalized

smart

liposomal nanocarrier consists of PEG-lipid conjugates that have been modified with a tumor cell-specific antinucleosome monoclonal antibody (mAb 2C5). Authors reported that the 24 ACS Paragon Plus Environment

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nanocarriers system was used as MMP2-sensitive linker which provided selectivity at the tumor site and enhanced the targetability and internalization in cancer cells.191 In this approach, the cytotoxic effects conferred by the encapsulated drug cannot be initiated unless MMP2 first cleaves the linker to remove the blocker and expose this membrane-penetrating peptide.191,192 In another work, multifunctional poly(ethylene glycol)- blocked-poly(L-lysine) Biotin 6maleimido- caproic acid (Biotin-PEG-b-PLL(Mal)-peptide) polymeric micelles loaded with doxorubicin were prepared which were able to improve cancer cell uptake through the receptormediated endocytosis, respond to excessive secretion of protease MMP2 from cancer cell, and so release the anticancer drug and induce apoptosis in a targeted manner.193 Another interesting study made use of the overexpression of the MMP9 enzyme in the extracellular matrix of tumor tissues, which act as a trigger to chemically modulate the drug delivery from the drug loaded nanocarrier. In this study, MMP9 cleavable, collagen mimetic lipopeptide was synthesized and conjugated with PEG to form a smart nano-sized vesicles which were stable in physiological conditions and in human serum. In the presence of elevated level of glutathione, the PEG groups are removed by reduction, leading to exposure of the lipopeptides to MMP9, which resulted in release of the anticancer, gemcitabine, content due to disruption of the lipid bilayer. Intravenous administration of the gemcitabine-encapsulated nanovesicles resulted in reduction in tumor growth in the xenograft model of athymic, female nude mice.194 In addition, other non MMPs enzymes, like cathepsin B, were also noticed to be normally overexpressed in cancer cells.195 On this basis, dendrimer-methoxy poly(ethylene glycol) doxorubicin (DOX) conjugates were synthesized using a cathepsin B-cleavable peptide for antitumor drug targeting. The system enhanced the anticancer activity when compared with doxorubicin in an in vivo CT26 tumor xenograft model. The prepared smart nanoparticulate


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system was found to be relatively concentrated in the tumor cells and exhibited stronger fluorescence intensity when compared to other body sites, while doxorubicin showed strong fluorescence intensity in the various organs, indicating that the formulated nanoparticles have cathepsin B sensitivity.195 Phospholipase A2 (PLA2) is gaining much interest as a therapeutic target, as it is known to be up regulated in tumors.196 A smart liposomal drug delivery system, which is enzymatically activated by secretory PLA2, containing masked antitumor ether lipids (AELs) as pro-drugs, was developed by Andresen et al.197 They synthesized (R)-1-O-hexadecyl2-palmitoyl-sn- glycero-3-phosphocholine (1-O-DPPC), which offered many advantages. It was not only capable of forming liposomes, but also was able to carry water soluble pro-drugs which could be activated by the activating enzyme PLA2 (pro AELs). Authors reported that pro AELs were successfully activated by PLA2 enzymes and effectively converted to chemotherapeutic agents. Moreover, the cellular uptake of drugs encapsulated in the liposomes was enhanced which could be attributed to the generated AELs and fatty acid hydrolysis products. Additionally, limited side effects, such as hemolysis, were also reported because PLA2 expression specifically in tumor cells localized the activation of pro AELs.197 Besides the aforementioned examples of enzymes manipulated for enzymatic-responsive DDSs, many other enzymes overexpression in tumor cells were studied and employed as well.198 Nevertheless, making use of up regulated enzymes in cancer cells with targeting components of the ECM in order to enable the penetration of standard chemotherapeutic agents is a promising way to prevent the life-threatening spread of cancer.199 Temperature-responsive Smart DDS based on temperature stimuli-responsive mechanism was first proposed in the late 1970s using thermosensitive liposomes. Recently, this has been widely explored in cancer 26 ACS Paragon Plus Environment

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treatment.200 The process is usually controlled by a nonlinear sharp change in the properties of at least one component of the nanocarrier system, following a variation in the surrounding temperature which triggers the drug release. Smart thermosensitive DDSs rely on rapid delivery of the loaded drug when the temperature changes from the normal body temperature (~37 °C) to a locally heated tumor (~40–42 °C).165 Mostly, thermosensitive DDSs are liposomes, polymer nanoparticles or micelles made usually from poly (N-isopropyl acrylamide) polymer, that exhibit a lower critical solution temperature. Based on their use in many clinical trials, thermosensitive liposomes (TSLs) are considered the most advanced thermo-responsive nanosystems. Their mechanism involves conformational changes in the lipid bilayers attributed to phase transition of the lipid constituents, which could be applied in vivo using temperature-controlled water sacks, miniature annular-phased array microwave applicators or radiofrequency oscillators. Now, hyperthermia or radiofrequency ablation responsive liposomes loaded with doxorubicin, (ThermoDox®, Celsion Corporation), are being examined in phase II trials for management of breast cancer and colorectal liver metastasis, and the successfulness has extended to reach phase III trials in the treatment of hepatocellular carcinoma.165 The high demand in development of the pharmaceutical technology allows for improvement in the thermosensitive liposomal formulation, which has released their drug content shortly after the onset of hyperthermia (~40– 45 °C).201 Alternatively, recent generations of thermosensitive liposomes have been emerged. Leucine zipper peptide–liposome hybrids and thermo-responsive bubble-generating liposomal systems are common examples. The former combine the advantages of traditional thermosensitive liposomes with the dissociative, unfolding properties of a temperature-sensitive peptide,202 while the later depend on generation of carbon dioxide bubbles through decomposition of ammonium bicarbonate at mild hyperthermia (~42 °C) which leads to creation


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of permeable defects in the lipid bilayer that cause rapid release of their chemotherapeutic agent such as doxorubicin,203 and also improved ultrasound imaging of tissues. Functionalized thermosensitive liposomes have also been developed, utilizing certain ligands, and have been used for specific targeting of human epidermal growth factor receptor 2 antibody for treatment of breast cancer.204 Some polymers have been studied for their potential use in the development of thermosensitive polymeric drug nanocarriers. Poly (N-isopropyl acrylamide) polymer is the widely used building block for this type of smart nanocarrier systems.205 Other polymeric materials,

such

as

poly(γ-2-(2-(2-methoxyethoxy)-ethoxy)ethoxy-ε-caprolactone)-b-poly(γ-

octyloxy-ε-caprolactone), have revealed noticeable transition temperatures at low hyperthermia (40 °C) which allow improved drug release.206 Modifications in the nature and composition of the thermosensitive copolymers that permit transition temperatures near to body temperature may be useful in this type of DDS for local (either subcutaneous, or intra- or peritumoural) administration. Also, local hyperthermia has been utilized as a stimulus to trigger the assembly of diblock-copolymer elastin-like polypeptides which permitted arginine residues to be presented at the periphery of the resulting micelles. This process resulted in an increase in the HeLa-cell uptake by more than 8-fold.207 Interestingly, cold shock or cryotherapy which refers to temperature responsiveness due to a temperature decrease has been reported. In this case, a reversible swelling or de-swelling of the thermosensitive based polymeric NPs led to free diffusion of the encapsulated drugs as a result of increased porosity. As a common example for this process is the successful delivery of siRNA from Pluronic F127–polyethyleneimine based nanocapsules into the cytosol, which resulted in silencing of a target messenger RNA.208 Generally, development of temperature sensitive DDS is challenging and necessitates selection of a polymer that is safe and sensitive to slight temperature changes around normal


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body temperature (37 °C). Thermosensitive liposomes are the most common among thermoresponsive nanocarriers and are in advanced stages of clinical trials. Redox-responsive The concentration of glutathione (GSH) in cancer cells is higher than its corresponding level in the blood and normal tissues by 100 to 1000 and 100-fold, respectively.209 GSH is an important antioxidant that can inhibit the damage of the cellular components induced by reactive oxygen species (ROS). It acts as electron donor (reducing agent) due to the thiol groups. Consequently, development of smart nanoparticles responsive to GSH can be considered as a promising approach for targeting delivery of anticancer drugs. Moreover, high concentration (10100- fold) of ROS in some inflammatory tissues and colon cancer has been also reported.164 ROS-responsive smart DDS has demonstrated specificity and accuracy as a targeted drug release therapy. These smart DDS is designed to release the therapeutic agents only in specific sites that produce excessive oxygen derived chemical species (ROS) such as hydrogen peroxide (H2O2), hydroxyl radicals (HO·), singlet oxygen (1 O2) and superoxide (O2-).210 ROS can be generated from endogenous or exogenous sources. The former includes mitochondrial metabolism or nicotinamide adenine dinucleotide phosphate enzyme catalyzed reactions while, the later comprises exposure to UV light or xenobiotic compounds.211 Different types of ROS-responsive DDS have been explored in drug delivery applications, including those containing thioether, selenium/tellurium, thioketal, boronic ester, peroxalate ester, polyproline, polysaccharide, and aminoacrylate. Reductively degradable micelles containing disulphide (-S-S-) link(s) within the hydrophobic backbone, in the shell, or in the core of the polymeric micelle have illustrated rapid micelle disassembly and specific intracellular release of the loaded drugs.165 Orally administered 29 ACS Paragon Plus Environment

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ROS sensitive thioketal-based NPs were able to specifically delivery TNFα–siRNA to the intestinal inflammation sites and so provide efficient therapeutic levels of gene silencing.212 Other redox-sensitive DDSs that have been studied for their potential effects include; disulphide crosslinked nanogels, quinone-lipid conjugate liposomes and dendrimer containing thiolcleavable bonds.165 Thioethers are characterized by their ability to exhibit phase transition from the hydrophobic to the hydrophilic states under oxidative environmental condition.213 An amphiphilic diblock copolymer of propylene sulfide and N,N dimethylacrylamide was utilized to develop polymeric micelle drug nanocarrier that was found to be highly responsive to H2O2. Oxidation of the thioether-containing polymer led to solubility change with subsequent dissociation of the nanocarrier and release of the payload.214 Selenium (Se) and tellurium (Te) containing compounds were exploited as redoxresponsive drug delivery systems. The mechanism of action of the organoselenium and organotellurium compounds involves oxidation from divalent to tetravalent states, the effect which may lead to phase transition from hydrophobic to hydrophilic and making them attractive ROS scavengers.215 The amphiphilic block copolymer (PEG‐PUSe‐PEG) that has a hydrophobic monoselenide‐containing block polymer and two hydrophilic blocks of PEG was synthesized by Xu and Zhang, and utilized in the development of self-assembles polymeric micelles.216 The developed polymeric micelles demonstrated successful delivery of the anticancer DOX. The same research group reported development of Se‐containing poly(ethylene oxide‐b‐acrylic acid) block copolymers that is characterized by its reversible self‐assembly and disassembly properties upon subject to repeated cycles of ROS or Vitamin C exposure.217


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Boronic ester constitutes redox rsesponsive DDSs that are sensitive to H2O2 at physiological pH and temperature. Arylboronic acid pinacol esters are common example that produce phenol and pinacol borate once oxidized by H2O2.218 Some water soluble polysaccharides are chemically modified at their hydroxyl groups with arylboronic ester groups to become organic soluble and thus facilitate payload encapsulation. These chemically modified polysaccharides are converted back to the water soluble parent form, upon exposure to ROS species and oxidation of boronic esters, the effect that results in release of the payloads. β‐ cyclodextrin conjugated with boronic ester has been utilized to develop biocompatible NPs that have been loaded with a hydrophobic docetaxel, an antimitotic chemotherapy drug. The docetaxel loaded NPs exhibited much higher antitumor efficiency with little effect to body weight, indicating their therapeutic advantage and safety as in vivo DDS.219 Recently, thioketal linkers have been utilized to develop ROS sensitive DDSs that deliver certain chemotherapeutic agents to cancer cells. They are readily cleaved by ROS oxidants to produce ketones and thiols.220 Certain genes have been delivered to prostate cancer cells following complexation between a cationic poly amino thioketal and negatively charged DNA.221 High levels of ROS in cancer cells result in cleavage of the thioketal linkers with subsequent efficient intracellular release of DNA and substantial higher gene transfection. Other types of ROS-responsive DDSs such as aminoacrylate,222 peroxalate ester,223 and polyproline224 were also explored in drug delivery applications. The major mechanism of drug release from these DDSs can be attributed to phase solubility change induced carrier disassembly, bond cleavage induced carrier degradation and cleavage of the carrier-drug linker. Exo-triggers stimuli Light-responsive 31 ACS Paragon Plus Environment

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Smart DDSs based on external stimuli, such as light, offer many advantages over those rely on internal stimuli due to easy of handling and precise control of the time and location of treatment. Many light-responsive smart delivery systems release their drug content upon excitation by ultraviolet or visible light but they have limited application especially in vivo owing to the inadequate tissue penetration that required to dissociate the chemical bonds for drug delivery.165,225,226 To overcome this, near-infrared light with a wavelength in the range 650-900 nm may be used.226 Also, the two-photon absorption (TPA) technique has been recently used, which depend on excitation of a molecule from its ground state to a higher energy state by using two concurrently absorbed photons of identical or different frequencies. The technique needs a pulsed laser source which has a high-energy density to focus small areas to acquire effective instant energy and finds wide applications in biomedical imaging such as in two-photon confocal fluorescence microscope.226–228 The above-mentioned concept has been used to formulate smart photosensitive DDSs based on specially fabricated molecules with strong TPA that are NIRresponsive. Interestingly, photoactivatable micelles were synthesized using an amphiphilic block copolymer

containing

either

2-nitrobenzyl

moiety

or

7-diethylamino-4-

(hydroxymethyl)coumarin for hydrophobic drugs delivery. Upon exposure to two-photon NIR laser irradiation, the prepared photosensitive micelles disrupted and released the encapsulated drug from the hydrophobic core of micelle into aqueous solution.229,230 More recently, smart nanoparticles were prepared from the anticancer drug doxorubicin and photothermal conjugated polymer using a NIR laser-responsive amphiphilic copolymer as the encapsulation matrix.231 The prepared nanoparticles can efficiently change laser energy into thermal energy for photothermal therapy in which the hydrophobic polymeric matrix that contains several 2-diazo-1,2naphthoquinones moieties can be changed into a hydrophilic one upon NIR two-photon laser


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irradiation, which consequently leads to fast drug release. Moreover, the thermal energy produced was reported to produce a synergistic inhibition effect on the treated cells. In another study, 7-amino-coumarin derivative, a two-photon-responsive moiety, was exploited as a NIRresponsive cross-linker for covalent loading of the anticancer drug chlorambucil in the pores of mesoporous silica nanoparticles.232 Results revealed that chlorambucil was released upon twophoton NIR excitation at 800 nm that led to killing of the treated cells. Zink and coworkers successfully synthesized NIR-responsive mesoporous silica nanoparticles with pores caged with the β-cyclodextrin via a disulfide bond linker.233 A photo transducer molecule, which acts as a reducing agent at its excited state, was covalently linked to the surface of the prepared nanoparticles. The authors confirmed that the photo transducer would reduce the disulfide bonds upon two photon excitation which resulted in detachment of the β-cyclodextrin and release of the loaded drug.226 It could be concluded that two-photon-responsive is a promising strategy for controllable delivery of anticancer drugs since it is characterized by deeper tissue penetration, low scattering losses, and high spatial/temporal resolutions of the applied pulsed NIR laser. However, the technique suffers from some disadvantages since it needs a light source of focal pulsed laser with high-energy density to treat small focused areas, and thus the technique is not an ideal candidate for in vivo controllable drug release. Most of two-photon-responsive based nano DDSs are therefore still at the proof-of-concept in vitro study stage. Magnetic-responsive Iron oxide nanoparticles especially those with nanocrystalline magnetite (Fe3O4) cores characterized by a great potential for use in oncological medicine. The reasons for their wide applicability are attributed to their biocompatibility, biodegradability, easy of synthesis, and 33 ACS Paragon Plus Environment

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simplicity procedure for modification and functionalization for specific applications.234 Spherical magnetite NPs with diameters approximately less than 20 nm will also exhibit a superparamagnetic behavior, a property that could be used to enhance contrast in magnetic resonance imaging (MRI).235 Usually, the process of size reduction characterized by enhanced pharmacokinetics, tissue distribution and cellular permeation.236 Magnetic nanoparticles (MNPs) of small size and hence large specific surface area are able to easily reach the desired location and so, MNPs are considered a potential drug delivery system with an application that cannot be ignored. When an externally applied magnetic field is used during treatment with MNPs, many drugs may be targeted to the desired specific site in vivo.237 Many antibodies and chemotherapeutic drugs have been loaded into MNPs and are exploited in treatment of many pathological conditions. In cancer treatment, MNPs are generally used in different ways: chemotherapy; magnetic hyperthermia (MHT), photodynamic therapy (PDT), and photothermal therapy (PTT).237 Superparamagnetic iron oxide nanoparticle conjugates are consisted of a magnetite core and a biocompatible coating substance. The core providing inherent contrast for MRI while the coating substance be responsible for ample functional groups for conjugation of additional tumor targeting and therapeutic moieties.234 Many anti-cancer drugs have been combined with superparamagnetic iron oxide nanoparticle such as temozolomide (TMZ),238 doxorubicin,239 paclitaxel,240 and 5-fluorouracil.234,241 Many challenges should be considered to render MNPs suitable for clinical use in the near future. These include; improving their drug loading capacity, and increasing their specificity and affinity to target cancer cells. Ultrasound-responsive The ultrasound technique is well known for its diagnostic applications. Recently, it is extensively used in therapeutic purposes such as imaging-guided drug and gene delivery to different tissue 34 ACS Paragon Plus Environment

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types since ultrasound is generally available, relatively inexpensive and portable, and characterized by its ability to focus into a target area non-invasively with high rate of precision. The technique of ultrasound-guided delivery of therapeutic agents has gained great attention since it permits delivery of drugs into targeted areas, such as a tumor cells, while minimizing systemic dose and toxicity. Moreover, ultrasound-guided drug delivery is a promising way to efficiently treat certain types of cancer that are anatomically accessible for ultrasound such as liver tumors.242 Utilizing a process called sonoporation, ultrasound- microbubble mediated cavitation produces transient or permanent pores in the blood vessels walls and can significantly improve extravascular delivery of therapeutic agents in the region of interest.242,243 Microbubbles which are hollow particles that contain gas, are applied as an ultrasound contrast agent since they possess acoustic characteristics different from plasma.243 Calcium carbonate minerals produce carbon dioxide in acidic conditions but are insoluble in neutral pH. Furthermore, the pH value of intracellular compartments such as endosomes and lysosomes are (5-6) and (4-5), respectively. When calcium carbonate mineral is being internalized via endocytosis by tumor cells, it is almost completely decomposed to carbon dioxide at pH 5.244 Hence, encapsulating fine-grained calcium carbonate inside a rabies virus glycoprotein (RVG) modified Poly(D,L-lactide-co-glycolide) (PLG) nanocomplex via W/O/W double emulsion method, can create gas-generating polymer nanoparticles (GNPs) and these GNPs are expected to induce necrotic cell death by releasing gas bubbles under ultrasound trigger. Injected into tumor-bearing mice intravenously, carbon dioxide generated from GNPs can effectively reduce the tumor size upon ultrasound applied extracorporeally.245 Additionally, it could reach deeper sites into the body than light-trigger (except for NIR-responsive) and the sonoporation phenomenon could act on the cell membrane to facilitate therapeutic molecules entrance into cells and, to some extent, could reverse the


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multi-drug resistance of tumor cells.246 Mechanisms beyond the ultrasound-based cell uptake enhancement were widely studied. Under low acoustic pressures, cell endocytosis is enhanced, since higher acoustic pressures favor uptake via membrane pores.247 Hence, it is important to understand whether loading nanoparticles into microbubbles or when they are physically mixed with the microbubbles can enhance the delivery across cellular membrane. In order to complete this task, two different nanoparticles types were used. One type is fluorescent polystyrene nanospheres, it was chosen as model nanoparticles as they are highly fluorescent. Another one is fluorescently labeled mRNA-lipoplexes, served as therapeutically nanoparticles and there are two options whether combine microbubble with nanoparticles or not. The results of the in vitro experiments elucidated that ultrasound can improve the intracellular delivery of large nanoparticles like mRNA- lipoplexes only when these were loaded into microbubbles and the ‘co-administration mode’ may only be useful when using small drug molecules, since they can readily cross the membrane pores generated by cavitation.248 Other responsive Glucose-responsive This type associated with bio-responsive release, can greatly enhance the efficacy of many drugs as it can completely decrease medications side effects. Nevertheless, design and synthesis of bio-responsive nanoparticle is more challenging since local bio-environment varies depending on cell/organ. In particular, glucose-responsive drug delivery systems have great potential in treatment of cancer.249 Insulin and insulin-like growth factor (IGF)-1 receptors are overexpressed in certain types of cancer, and therefore, glucose-responsive targeting/delivery systems may have better therapeutic performance.250 Some attempts have been made to develop glucose-responsive gate in mesoporous silica platform. In a previous study, a magnetic 36 ACS Paragon Plus Environment

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mesoporous silica (MMS)-based drug delivery nanocarriers (that can release a drug in a target specific cell via glucose-responsive gate) were designed and functionalized with phenylboronic acid and folate. The studied drug was loaded inside the pores where the pores were closed from outside by dextran via binding with phenylboronic acid. In the presence of glucose, the dextrangated pores are opened for drug release since glucose competes binding with phenylboronic acid. The release of tolbutamide and camptothecin from MMS had been achieved at beta cells and cancer cells, respectively, where the release of both drugs was depending on bulk glucose concentration and exhibited glucose concentration dependent cytotoxicity. Therapeutic benefits of functional MMS could be extended to treat diabetes and cancers with more efficient therapy.251 Electro-responsive External stimulus-responsive DDSs offer controlled drug release for chronic conditions that necessitate daily administration or precise doses of medication.252 Ultrasound, light, and magnetic based DDSs require the use of large or specialized equipment. On the other hand, electric stimulus-responsive DDSs depend on electric stimulus which is easy to generate. These systems have been successfully utilized to activate the release of molecules via conducting polymeric bulk materials or implantable electronic delivery devices.253 Nanofibers of poly(3,4ethylenedioxythiophene)-coated poly(L-lactide) or poly- (lactide-co-glycolide) loaded with dexamethasone have been developed in which following degradation of poly(L-lactide) or poly(lactide-co-glycolide), the obtained conducting polymer nanotubes provide precise control of dexamethasone release.254 Development of electrically responsive nanoporous membrane, loaded with fluorescently labeled protein as a model drug, based on polypyrrole, has been reported. Owing to a fast switching time which was less than 10 s and high flux of the drugs, this DDS 37 ACS Paragon Plus Environment

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could be used for emergency treatment of angina pectoris, migraine hormone-related disease and metabolic syndrome, all of which require acute and on-demand drug delivery.255 In summary, this approach is a facile and minimally invasive technique for potential medical applications. External temperature trigger-responsive Endo trigger temperature sensitive stimuli utilizes the concept that the temperature of the tumors and tissues suffering from inflammation conditions is higher than normal tissues. However, the temperature difference is still not sufficient for many smart thermosensitive DDSs to deliver their drug load. Accordingly, an external heating source to accurately control the temperature difference between normal and tumor tissues is required. Examples of external temperature trigger sources are laser, magnetic field, ultrasound and water bath.164,209,256 As previously described, lipid-based nanoparticles especially liposomes that based on lipids with the suitable gel-to-liquid phase transition temperature were utilized for this purpose. DUAL AND MULTI-RESPONSIVE The dual and/or multiple trigger responsive nanoparticulates that can be triggered by a mixture of two or more stimuli, have been recently established for more controlled and improved drug release pattern. Such triggers can be mixed and utilized as a suitable combined-stimuli for smart-responsive DDSs, like magnetic field/pH, temperature/redox, temperature/enzyme, dual/multiple

dissimilar

pH,

temperature/pH,

redox/pH,

magnetic

field/temperature,

pH/temperature/magnetic, pH/redox/magnetic and pH/temperature/redox.257 Markedly, the responses of these triggers combinations can happen either in a simultaneous way at target sites or in a chronological mode starting from nanoparticulate elaboration, nanoparticulate transferring passageways, ending at cellular partitions. These dual and multiple triggered responsive nanoparticulates were revealed an extraordinary regulation over drug release and delivery 38 ACS Paragon Plus Environment

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resulting in higher anti-cancer efficacy on in vitro and/or in vivo levels (figure 4), besides the significant potential for targeted cancer therapy owing to their drug delivery of site-specific feature.

Figure 4. Diagrammatic differentiation between conventional and single/dual/multiresponsive smart DDSs. Temperature/pH-responsive As a dual-responsive smart DDSs, pH and temperature-triggered nanoparticulates are from the most investigated dual-sensitive nano smart DDSs. Various polymers of pH and temperaturetriggered property are fabricated by combining a pH-sensitive moieties like weak acids along with thermo-sensitive polymers as poly(N-iso- propylacrylamide) (PNIPAAm), which result in a smart designed copolymers with pH-dependent lower critical solution temperature (LCST) 39 ACS Paragon Plus Environment

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properties. This phase transition adjustment by little pH alteration has facilitated improvement of tumor pH-triggered drug release systems. In a previous work, the core-shell nanoparticulates of a pH/temperature-triggered property were designed, elaborated and proved to be stable under normal physiological conditions while distorted with the release of their contents spontaneously after reaching an acidic milieu.258 Also, it was proved that DOX release from nanoparticles (degradable poly(b-amino ester) dendrimers with pH/temperature-triggered photo-luminescent features) was very low at physiological temperature and pH but considerably augmented at pH range between 4 and 5.259 A different group of researchers succeeded in developing a thermal/pH dual-triggered nanoparticles fabricated from deoxycholic acid and poly(ionic liquid-coNIPAAm). The in vitro release profile was examined under different conditions and revealed that 80% of DOX was released over two days at acidic pH and elevated temperature owing to nanoparticulates distortion and breakdown, while in the same time interval the released DOX was only 30% under normal physiological conditions.260 Hollow nanogels were also represented as a pH/temperature dual triggered-responsive smart nano DDSs, which were elaborated from methacryloylethyl acrylate polymeric derivative imbedded with PNIPAAm or mixture of mPEG and PNIPAAm at room temperature and pH 3.0 with the utilization of radical polymerization crosslinking approach.261 Positive results, as rapid drug release from nanogels loaded with DOX at pH 5.0 and higher cytotoxic activity compared with free DOX, were noted and ascertained. Redox/pH-responsive Redox and pH are two of the most interesting intrinsic triggers, as both of them are naturally existed with certain dysfunction inside many pathological locates, such as in all types of cancer.257 pH/redox dual-responsive nanoparticulates have been fabricated to support a variety of approaches, such as nanoparticulates development and/or deformation in aqueous 40 ACS Paragon Plus Environment

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environments via pH alteration, optimization of nanoparticulates in vivo stability by utilizing disulfide cross-linkage advantage, activation of the drug release from nanocarriers or improvement of their tumor cellular uptake, enhancement of drug release targeting in the lysosomal and/or endogenous compartments of a particular cells, and attainment of fast release of drugs into nucleus and/or cytoplasm. Promising models are polymersomes of pH/redox dualtriggered nanoparticulates, which were elaborated from paired di-block hydrophilic copolymers by just rising their solution pH to reach the physiological pH. And so, an effective proteins loading under trivial conditions can be afforded with these dual-sensitive nanoparticulates.262 Furthermore, a substantial protein release was noted at either acidic pH 6.0 or at physiological pH 7.4 but with 10 mM dithiothreitol (DTT), to attain a reductive condition, while the protein release under normal physiological conditions was not exceeded 20% along whole eight hours. In another promising work, another type of pH/redox dual-responsive nanoparticulates were developed from some graft copolymers as well as poly(2-(pyridin-2- yldisulfanyl)ethyl acrylate)g-PEG/cRGD (PDS-g- PEG/cRGD).263 The in vitro release experiments revealed that the DOX release rate from these smart polymeric nanoparticles was little and insignificant at physiological pH 7.4, compared with the significantly boosted release at acidic pH of 5.5 and/or in the existence of reduction factor by using a 10 mM concentration of reducing glutathione (GSH). Interestingly, these DOX-loaded dual-responsive nanoparticulates were exhibited a greater anticancer cytotoxicity effect in colon cancer cell lines than the free unloaded DOX. Magnetic/pH-responsive Another trigger that utilized with the intrinsic pH trigger is the extrinsic magnetic trigger. Few years ago, several pH/magnetic dual-stimuli nanoparticulates have been advanced for pHresponsive drug release approach combined with magnetic thermotherapy, targeting, and 41 ACS Paragon Plus Environment

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diagnostics. In a previous work, a researcher was succeeded in developing a pH-triggered charge-reversal peptide/magnetic composites nanoparticulates, which exhibited an elevated hyperthermia activity and magnetization with the influence of exterior AC magnetic field (AMF), besides the great DOX entrapment capacity at pH 7.4 and prompt DOX release at pH in the acidic range (4 – 5).264 Furthermore, DOX-daul pH/magnetic nanoparticulates under AMF influence in HeLa cells displayed more cytotoxic activity than the separate treatments, indicating their prospective promising use as chemotherapy/magnetic hyperthermia smart dual/multiple triggered DDSs.257,264 Redox/temperature-responsive Redox/thermal dual-responsive nanoparticulates were also widely investigated as one of the potential smart DDSs for solid tumor micro-milieu targeting approaches. One elaboration procedure was utilized for these smart nanoparticles fabrication, which was prepared from poly(PEG-MA-co-Boc- Cystamine-MA) copolymers with making the temperature of their solution as well as the normal physiological/body temperature.265 These nanoparticles were able to keep their stability at body temperature along a duration of one week while distorted and deformed after 10 mM DTT addition in only half an hour. Another research group were designed a core-shell dual-stimuli nanoparticulates consisted of a thermo-responsive PNIPAAm shell and a reductive-triggered hyper-branched poly(- amido amine) core.266 Upon twofold elevation of solution temperature from room temperature, the particles size decreased by 25% of their initial size, besides the pyrene release was stimulated by the DTT addition. Double pH-responsive Poor intracellular drug release and weak tumor cellular uptake are two main issues can be responsible for compromising the anti-cancer efficiency of many nanoparticles-drugs composites 42 ACS Paragon Plus Environment

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DDSs. So, researchers went to the approach of designing a dual pH-triggered polymer-drug nano-combinations to conquer such issues. Self-assembled nanoparticles DDSs renowned as dual pH-sensitive polymer-DOX conjugate (PPC-Hyd-DOX-DA) are good examples of this approach, which were PEG shielded with bearing a surface negative charge at physiological pH.176,257 After incubation at pH 6.8, the surface charge was reversed because of the acid-triggered cleavage of bond that was formed between the amide and 3- dimethylmaleic anhydride (DMMA), which in turn significantly led to maximizing tumor cell internalization. With further pH decrease till reaching 5.0, the DOX release was triggered due to a second cleavage of hydrazone acid-labile bonds. These pH/pH-triggered nanoparticulates have confirmed the enhancement of the progression inhibition of drug resistant cancer stem cells.176 Light/temperature-responsive Light would be considered as a particularly interesting extrinsic trigger for stimulation the drug release from responsive smart DDSs owing to its distinctive sequential, longitudinal, simple and affordable control. Zhao et al. elaborated light/thermo-dual-triggered micelles from PEO-bpoly(ethoxytri(ethylene glycol) acrylate-co-o-nitrobenzyl acrylate) block co-polymers basically by elevating the temperature of solution above the LCST of these co-polymers.267 Consequently, the designed micelles were promptly disrupted to release their payload after exposure to UV radiation which resulted in o-nitrobenzyl group cleavage and then LCST elevating for at least 11 °C. Another photo/thermo-dual-responsive micelles were attained based on PEO-bpoly(azobenzene-containing methacrylate-co-NIPAAm) block co-polymer.268 The micellar hydrodynamic radius were 45% decreased below its initial radius length after 30 °C temperature elevation above room temperature, while the payload release was prompted as a result of temperature decrease. 43 ACS Paragon Plus Environment

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Redox/enzymatic-responsive One of the very interesting dual-responsive nanoparticles DDSs is redox/enzymatic dualstimuli DDSs for cancer therapy and targeting applications. GSH/ MMP2 dual stimuli-responsive polymeric mixed micelles (MM) were the dual-responsive nanocarriers designed for the miRNA34a (internal tumor suppressor) co-delivery along with DOX into tumor cells.269 The main objective for the formulation of this particular dual-responsive category was to overcome harsh challenges facing RNAi delivery to target tissues with the making use of the synergistic effect of DOX co-delivery for both resistant and sensitive cancer cells.270 Targeting objective was confirmed by the higher cytotoxicity efficacy of the dual-triggered DDSs in MMP2overexpressing HT1080 cells, three times more than its cytotoxicity in the low MMP2expressing MCF7 cells, emphasizing the potential role of these dual-responsive smart DDSs in conquering the in vivo microenvironment of many solid tumors. Multiple-responsive Besides the dual-triggered nanoparticulates smart DDSs, many multiple-responsive nanoparticulates have lately been advanced. One of the many previous works was focused on the design of a triple-triggered-responsive nanoparticulates, which were fabricated from a block copolymer consisting of a thermo-responsive PNIPAAm hydrophilic block, linked with an acidresponsive tetrahydropyran-protected 2-hydroxyethyl methacrylate (THP-protected HEMA) hydrophobic block by using a redox-responsive disulfide linker.271 These nanoparticulates were excellent temperature/pH/redox-responsive smart nano DDSs. Firstly, by elevating the temperature over its LCST, nanoparticulates precipitation would take place owing to the hydrophilic shell transformation into a water insoluble precipitates. Secondly, the pH decrease led to nanoparticulates dissolution as the hydrophobic core turned into hydrophilic one. Thirdly, 44 ACS Paragon Plus Environment

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the detachment of one block co-polymer into separable homo-polymers was the result of assembly disruption in a reducing environment. The Nile Red release from these nanoparticulates was found to be a sluggish incomplete release over a relatively long time period in case of either the existence of 3.2mM GSH at physiological pH, or only an acidic pH of 5.0 acquired without a reducing milieu. On the other hand, the dye release pattern was considerably enhanced and much more complete by joining the both triggers together at the same time (i.e. acidic pH of 5.0 with the existence of 3.2 mM GSH). Another advantage of these multi-triggered nanoparticulates which is their capability to improve the hydrophobic moieties release kinetics. A group of multi-triggered nanogels of different structures and grades of crosslinking have been elaborated from the mini-emulsion co-polymerization of multiple monomers with a crosslinker such

as

bis(2-acryloyloxyethyl)

disulfide

(BADS),

which

yielded

an

outstanding

pH/temperature/redox-responsive nanogels.272 As predicted, paclitaxel (PTX) release was impressively augmented by the combinational influence of both DTT-stimulated disruption and acid-stimulated hydrolysis. The PTX-loaded nanogels displayed a high cytotoxicity effect on MCF-7 cell lines, whereas the intact drug-unloaded nanogels were completely non-toxic, which assuring their potentiality for utilization as nanocarriers for anticancer drugs of hydrophobic nature. SMART NANO DDSS The most renowned smart nano DDSs platforms Smart polymeric nanoparticles The polymeric nanomaterials which bearing the capability of responding to single/multiple extrinsic chemical and/or physical triggers are widely renowned as trigger-


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responsive or smart polymeric nanoparticles. In the last fifty years, the polymeric structures with responsiveness

ability

to

various

exo-triggers,

were

employed

to

regulate

many

pharmacologically-active ingredients release pattern. Consequently, they governed a highly vital function in the advancement of nanomedicine.273,274 With strength oscillation of the manipulated trigger applied to the designed polymeric systems, the physico-chemical properties transformation of these structures will take place and the drug release rate can be smartly regulated. According to responsiveness capacity, two main types of smart polymeric fabrications are raised: single trigger and dual or multi triggers-responsive polymeric materials257,275,276 as formerly mentioned in the previous section. Single triggers that prompt molecular amendable adaptation, hydrolytic cleavage or protonation in the polymeric nanomaterials, can be classified as endogenous and/or exogenous triggers. In general, there are two approaches to govern drug release from polymeric nanoparticles in the cancer proximity. First is that the nano-polymeric carriers can be triggered, depending on pH variability, to release their loads when reaching cancerous vicinities with slightly acidic pH values. The second scenario is that polymer surface charge might be altered for targeted cells internalization purposes. The pH-triggered smart polymeric nanoparticles have been prominently advanced, resulting in a governable release at the tumor locations.277 Though, pH variability triggered delivery systems for a more rapidly drug release could be insufficient. Consequently, polymeric nanoparticles of switchable surface charge were utilized to improve cancer drug delivery, particularly for nucleic acid moieties or drug-resistant cells. The charge alteration of nanocarriers surface can be employed to augment cellular uptake by taking the advantage of the reinforced interaction between cellular membrane and polymer nanoparticles.278 Furthermore, many polymeric self-structured assembles were designed and formulated for smartly controlled delivery of drugs as like as dendritic polymers,


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polymersomes, polymeric gels and nanoparticles micelles.279,280 In addition, pH-responsive polymeric systems were also utilized for cancerous masses imaging. The fluorescent ultra pHsensitive (UPS) nanoprobes were elaborated particularly for imaging and diagnostic applications.281,282 These nanoprobes were remained inactive as long they still circulating throughout the blood stream, until they approached a tumor site where pH was altered, they strongly activated as much as 300 times owing to tumors acidic pH nature either at extracellular cancerous region or in tumors recently formed blood vessels (neovasculature). Therefore, the fluorescence imaging, by using UPS nanoprobes, will be afforded with a vastly high resolution tumors demarcation for attaining a thorough cancer removal throughout surgical resections. Another promising application for smart polymeric nanoparticles advancement, is the corporation of disulfide bond in nanoparticles fabrication. It is well renowned that thiol-disulfide bond exchange can be triggered by intracellular GSH. Mainly, two approaches can be used for disulfide bonds incorporation in polymeric structures; firstly is the disulfide bond adjustment at specific sites within the long polymeric chains, and secondly is the utilization of disulfide bonds to be a cross-linkers inside complex polymeric networks.283,284 By employing this feature, polymers containing disulfide bond can be crumbled and disintegrated in a way that the entrapped drugs can be released promptly from smart polymeric nanoparticles when endotriggered by GSH.285 Many other smart polymeric nanoparticles were exploited with other endotriggers and exo-triggers like light, glucose, temperature …etc. Moreover, various polymers of natural origin can also be utilized as governed smart DDSs, like cyclodextrin and chitosan.164 In general, polymeric nanoparticles are the utmost investigated carriers with proven well-controlled release pattern for application in the clinical stage. While many of them are already inspected


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and studied on the preclinical level, they can be well utilized as a smart drug nanocarriers and as pronounced promising applications in diagnosis and cancerous imaging. Smart lipid based DDSs From the very beginning of the pharmaceutical nanocarriers, lipid based vesicles utilization for drug delivery was well established. Owing to their biocompatibility, effectiveness, nonimmunogenicity, ability of boosting anticancer drugs solubility and their high capacity to entrap an extensive range of therapeutics, these nano-sized vesicular of a bi-layered structures have developed and widely held as an outstanding DDSs.286–288 Additionally, the ligand-mediated liposomes with active or passive targeting are proofed to enhance cancer selectivity with practically reduced side effects resulting from off-target issues.289 Current determinations have focused on the improvement of liposomes with multifunctional purpose as a single delivery system that target particular type of cells or intracellular organelles.290 Besides, liposomes can be considered for many smart approaches and scenarios like the fabrication of therapeutics and magnetic resonance imaging (MRI) contrast agents co-delivery systems.164,201 From recent clinical applications, smart liposomes enhancement is currently a point of focus in nanomedicine, which can be simply triggered by several stimuli.291–293 Liposomal complex fabrication with different potential components can further encourage the smart liposomes development. The magnetic liposomal formulations, for example, were donated with multifunctional features (like surface effect, vessel effect, easy recovery property, biocompatibility, and targeting effect) after being elaborated with magnetic nanoparticles (MNPs) and allowed to be introduced under magnetic field exposure. Researchers in a previous work designed a magnetic liposomes that can target folate receptor sites.256 Another smart delivery approach to enhance chemotherapy therapeutic index has been developed for targeted doxorubicin delivery. MCF-7-targeted Doxil 48 ACS Paragon Plus Environment

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liposomes led to superior cancer reduction and more rapidly antitumor activity onset than nontargeted treatments formulations. Mice treated with Doxil did not display any hepatotoxicity sign and maintained overall health.286 To emphasize, smart liposomal fabrication was really progressed with the extent to believe that these smart DDSs will soon get a tremendous impact and great success in the clinical application and tumor targeting particularly. Organic-inorganic hybrid materials The materials of inorganic and organic joined features that can respond to a trigger after combination were referred as organic-inorganic hybrid smart biomaterials. The combined materials are simply assembled as a result of involving polymer or organic moieties with nanometallic or nano-oxides particulates such as titanium dioxide and silica.294,295 Mesoporous silica nanoparticles (MSNPs) as an example of smart DDSs have concerned with great focus in the last ten years.295,296 However, even these silica complexes are employed as a smart drug delivery system with greater biocompatibility, MSNPs pharmacodynamics and pharmacokinetics profiles should be more appraised. In addition, gold nanoparticles (AuNPs), including nanorods, composite nanostructures, nanocages, and nanoshells, have been extensively advanced as photothermal therapy (PTT) agents.297 On the other hand, AuNPs, as inorganic nanoparticles, cannot be degraded or metabolized internally but, instead, will be accumulated gradually in the body compartments after systemic administration. Hence, by surface organic functional groups alteration, such problem can be resolved. Researchers have elaborated a variety of liposomal formulations compounded with AuNPs. It was found that the liposomal complexes encourage stable AuNPs dispersions formation in simulation with biological conditions.298 In addition, many dendrimers were also utilized to smartly entrap AuNPs within their structure and can be used for PTT, as poly(ethylene glycol) (PEG)-attached poly(amidoamine) (PAMAM), and 49 ACS Paragon Plus Environment

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outcomes confirmed that these AuNPs dendrimers were of high cytotoxic action versus human cervical cancer cells (HeLa) after exposure to irradiation of visible light.299 Another drug delivery system was developed which linked DOX amended onto the AuNPs surface by using PEG as linking spacer with acid-labile feature, and outcomes were evidenced that multi drug resistance in cancer cells was vastly overwhelmed.300 Since MNPs can be used under extrinsic alternating magnetic field (AMF) effect, they were manipulated in various diagnostics and therapeutics applications. To significantly rise delivery efficiency and diminish side effects, MNPs can be elaborated and assembled with other multiple triggers in a manner that the magnetic complexes will be advanced as a smart synergistic DDSs. For instance, when superparamagnetic iron oxide nanoparticulates (SPIO -Fe3O4) were implanted within the microbubbles surface, the SPIO micro-bubbles combinations will be able to be utilized as contrast agents for MRI and ultrasound dual smart imaging, and to be employed instantly by the moderate ultrasound irradiation. With controlling extrinsic ultrasound frequency, these nanoparticulates can reach their targeted cells noninvasively and efficiently.301,302 One more vital role of MNPs when SPIO nanoparticles were utilized as MRI contrast agent, which is theranostic applications. Also, SPIO can be elaborated as nanocarrier to deliver anti-tumor moieties to their target locates under extrinsic magnetic field influence. The combination of SPIO hyperthermia and the magnetic field triggered release of chemical drug are strategic for cancer treatment.303 On the other hand, challenges are quiet ahead to rise both therapy efficiency and imaging in one particular SPIO platform. Another efficient magnetic nano-crystals (MNCs) were magnificently advanced in a theranostics-mediated strategy by MRI and AMF utilization in hyperthermic therapy.304 Regardless of these hybrids rapid advancement, the all-in-one strategy in these combinations has several issues to be amended, like toxicity, high cost of manufacture, the


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intrinsic low sensitivity and non-biodegradable property. The existing developing phase of combined smart drug delivery systems for theranostics are walking their initial steps so far. Exosomes As a response for intrinsic or extrinsic trigger, a membrane nanovesicles will be resulted and secreted by particular cells, which are frequently identified as exosomes. The exosome application is promptly advanced as biomaterials DDSs. For instance, exosomes may be targeted at a particular type of tissues, while preserving their own biological activities, at the same time.164,305 Therefore, exosomes seem to role an essential part in various disease progressions, most curiously cancers and inflammation. As a main intercellular linking mediators and cellular niche regulators, exosomes applications have been developed. One application is that many drugs can be encapsulated within the exosomes as a tailored drugs smart carriers. Owing to the exosomes release from different host cells kinds, they can display diverse targeting mechanisms and biological effects. In addition, exosomes are of highest biocompatibility and lowermost cytotoxicity.306 Exosomes restructure procedures such as saponin permeabilization or both sonication and extrusion, are capable of resulting in a higher sustained release, more catalase protection versus proteases catalysis and greater entrapment efficacy. Consequently, exosomes are capable of functioning as a multipurpose approach for neurodegenerative and inflammatory diseases treatment.307 Similarly, exosomes are able to be utilized in chemotherapeutics delivery like DOX delivery to tumor sites and tissues. A group of researchers has succeeded to yield exosomes from mouse immature dendritic cells (imDCs), followed by merging of exosomal membrane protein (Lamp2b) with αv integrin-specific peptide (internalizing-RGD/iRGD peptide; a tumor penetrating peptide) and finally, via electroporation, DOX were entrapped sufficiently into the refined exosomes that produced from imDCs.306,308 iRGD exosomes have 51 ACS Paragon Plus Environment

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confirmed an extremely competent targeting. The tumor growth was supressed vastly without any evident toxicity, which made exosomes utilization in tumor targeting an encouraging tactic for many challenging clinical applications. On the other hand, as a developing area, the exosomes application as a DDS is yet not generally discovered, as various challenges still in advance and facing these nanovesicles. An example of these main challenges is the ability of exosomes to preserve their own biological features throughout the encapsulation process of therapeutics. Even though the exosomes production scale is able to be performed with the utilization of human stem cells oncogenic immortalization,306,309 it is vital to accomplish a manufacture scale production characterized by the required perfect reproducibility with using the suitable exosomes type. Furthermore, another significant challenges facing recent exosomes research like data classification, data collection, and establishing appropriate correlated tests and assessment procedures, which are crucial concerns and must be more focused for successful application in clinical field. Barriers and obstacles for smart nano DDSs clinical applications Several DDSs of stimuli-responsive type are yet remaining at clinical phase, like ThermoDox™,310 Opaxio,311 NanoTherm®,312 and AuroShell.313 Over the years, many approved pharmaceutical formulations have been sufficiently assessed and intensely improved. One substantial feature of these clinical nanocarriers depends on the simple formulations. Examples of the approved nanotherapeutics are mentioned in the next section. On the other hand, the majority of designed smart drug delivery systems were of a sophisticated assemblies and complex elaborations, in order to acquire smart features, and such issue is challenging for scaleup to manufacture scale. Hence, the simplicity of the design is one of the crucial factors for an effective conversion of drug carriers into these smart DDSs. In addition, implementing a lot of 52 ACS Paragon Plus Environment

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improvement and optimization experimentations are required to make a successful transformation for every smart DDS from stage of preclinical investigational models to the level of approved clinical practice. Particularly, intrinsic triggers (like enzyme concentration and pH gradient) are truly hard to govern because of the great inter-variability between different patients. Although exo-trigger responsive smart DDSs are much more promising for clinical implementation and also much more able to be governed, major enhancements considered to be essential for resolving difficulties correlated to DDSs-penetration depth capacity and incidence of normal tissue injury.164,165 A clinically convenient pharmaceutical products are expected to retain the characteristics of verifiability, scale-up probability, and reproducibility. Thus, further considerations must be taken for the advancement of improved methodologies that can accurately govern the elaboration procedure, for the aim of producing nanocarriers with necessary properties, manufacture scale-up feasibility and high batch-to-batch reproducibility. The standard production approaches and procedures can lastly hasten the conversion of smart DDSs from lab to bed. However, there are a lot of obstacles facing smart DDSs from bench to bed as reported in numerous review articles,314,315 and some of these potential obstacles have been termed as following. As known, the route of administration of many nanotherapeutics is mostly the intravenous parenteral route. In spite of the nano smart DDSs capability for elongating drugs half-life, these nanocarriers will front a sequence of biological complex barriers that significantly hinder targeting to the required specific sites. The majority of nanoplatforms will not be successful in clinics if the biological barriers are not be overcame by the nanocarriers.316 Biological barriers like the mononuclear phagocyte system (MPS), opsonization, cellular internalization, drug efflux pumps, escaping from lysosomal and endosomal compartments as well as the high intratumoral


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pressure will not only limit the nanocarriers accumulation and targeting, but also hinder the treatment plan results.317 Besides the significant challenges exhibited by each particular biological barrier, further issues such as disease progression, disease types and administration routes should be taken into consideration while designing the smart DDS because of complexity variation of these barriers in vivo. Another obstacle is clearly shown with the pharmaceutical development principles which are renowned in terms of effectiveness, safety, patient compliance and quality controllability. The issues of safety and toxicity are still a main concern and necessitates the smart DDSs to satisfy these needs. There are several concerns must be well considered, including the nanocarriers safety and their metabolites, biocompatibility and biodegradability. For any prospective recently designed drugs, the safety assessments as subacute toxicity, acute toxicity, carcinogenicity, biocompatibility, immunotoxicology, developmental toxicity, blood vessel irritation studies, and genotoxicity are mandatory. Besides, the pharmacokinetics and pharmacodynamics of prospective drug candidates should be considered and well investigated. Furthermore, stimuli-responsive DDSs are possibly more vulnerable for inter subject performance variation, in comparison with conventional DDSs, hence arising a reproducibility issues in efficacy and safety. Researchers still require to give more focus and pay attention to this topic from the market perspectives. Taking into consideration another major issues for nanomedicine clinical application and translation which include the governability of nanomaterials’ physicochemical properties, production scale-up possibility, as well as batch-to-batch reproducibility. Methodology verification must be established for smart DDSs, like stability, linearity, repeatability, precision, and specificity. Consequently, product analysis and reproducibility are the strategic obstacles for


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production scale-up manufacture of smart drug delivery systems and Good Manufacturing Practice (GMP)-compliant. So, all these issues encounter trigger-sensitive DDSs advancement in clinical applications and must be resolved to warrant effective clinical translation. To conclude, in order to make nanotechnology be combined effectively with pharmaceutical industry, it is essential to construct a well-established and real regulatory structure to accept and approve any further prospective nanomedicine products. Though the FDA and European Medicines Agency (EMA) have approved many nanomedicines, structures for the nano-based medical products regulation are still not available.318 The only authorized regulation that can be itemized for manufacturing nanomedicine was done by FDA in 2014 and limited to the guidance stated; “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology”. In spite of the nanomaterials scope is well-described in the guidance, it is still away from sufficiency regarding manufacturing pharmaceutical nano-products.319 Regulations are not only vital for describing nanomedicine products concept, but also substantial for nanomedicine quality control and characterization, as well as the approval process and clinical trials. Likewise, standard procedures will hasten the smart DDSs translation and research. Although countless work on nanomedicine characterizations and standardization investigates have been done by FDA and the National Cancer Institute (NCI), it is yet a long way to generate protocols and standardized descriptions to portray nanomedicines for clinics. Clinically approved smart nano DDSs Over the last decades, many smart DDSs have been arisen and industrialized.314 Till now, various nanocarriers have been agreed for use in clinic, like nano-suspension, micelles, liposomes, nanocapsule and polymer nanoparticles. Lipusu (Liposomal PTX), Abraxane (Nanoparticulate albumin/PTX) and Doxil (Liposomal DOX) are examples of nanomedicines 55 ACS Paragon Plus Environment

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that clinically approved.316 The nanomedicine utilized as photodynamics therapy, Visudyne, was the only trigger-responsive type nanomedicine that approved by FDA. The smart DDSs research works and literatures are impressively growing. Although the information regarding the performance of nano DDSs in vivo still inadequate, all previous research outcomes were greatly elucidated the successful role of nano DDSs in the clinics. Examples were summarized in Table 1.


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Table 1. Examples of approved commercial and/or in clinical trials state products of nanoplatform for solid tumor micromilieu remediation.

Nanoplatform type/drug

Mode of action

Treatment objective(s)

Doxil®

PEGylated liposomal doxorubicin

Passive targeting

Ovarian cancer, AIDS-related Kaposi’s sarcoma, breast cancer, myeloma

In market

FDA (1995) EMA (1996)

291,315,316,320–324

Onivyde®

Irinotecan liposome injection

Passive targeting

Metastatic adenocarcinoma of the pancreas

In market

FDA (2015)

325,326

Lipusu®

Liposomal paclitaxel

Passive targeting

Ovarian cancer, non-small cell lung cancer and solid tumors

In market

China FDA (2006)

209,290,319,327,328

Myocet®

Non-PEGylated liposomal doxorubicin

Passive targeting

Metastatic breast cancer

In market

EMEA (2000)

319,329,330

Mepact®

Liposomal Mifamurtide

Passive targeting

Osteosarcoma

In market

EMA (2009)

319,321,331

DaunoXome®

Liposomal daunorubicin

Passive targeting

Kaposi's sarcoma

In market

FDA (1996)

291,323,332

DepoCyt®

Liposomal cytarabine

Passive targeting

Lymphomatous meningitis

In market

FDA (2007)

321,333

Eligard®

Polymeric nanoparticles of Leuprolide acetate

Passive targeting, prolonged release

Prostate cancer

In market

FDA (2002)

333,334

2B3-101 (2-BBB)

Glutathione pegylated liposomal doxorubicin

Active targeting

Brain malignancies due to breast cancer metastases

Phase II

FDA orphan drug designation (2010)

319,335

Abraxane®

Nanoparticle albumin-bound

Active targeting;

Metastatic breast cancer as well as

In market

FDA (2005 - 2013)

321,324,336

Product

Status


Approval date

Reference

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Visudyne®

paclitaxel

preferential intratumoral accumulation of paclitaxel (induced endothelial transcytosis)

other solid tumors, including non-small-cell lung cancer, ovarian cancer, and malignant melanoma

Non-PEGylated liposomal verteporfin

UV light (exo-trigger)

Choroidal neovascularization symptoms

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EMA (2008)

In market

Phase II trial for cutaneous metastases of breast cancer. Clinical trial information: NCT02939274.

FDA (2000)

337,338

FDA pending approval

338

OpaxioTM

Enzymeactivated polymeric NP ( Paclitaxel poligumex)

Tumor enzyme (endotrigger)

Non-Small Cell Lung Cancer, Ovarian Cancer, Glioblastoma Multiforme, Head and Neck Cancer

Approved orphan drug for glioblastoma multiforme (Phase III)

FDA (2012)

311,315,322,324

NanoTherm®

Magnetic sensitive iron oxide NPs coated with aminosaline

Magnetic (exo-trigger)

Glioblastoma, prostate cancer, eosphageal cancer, pancreatic cancer

Phase I/II

EMA (2010)

312,323,324

ThermoDox®

Thermosensitive liposomes for tumor specific release of doxorubicin

Temperature (exo-trigger)

Breast cancer, primary liver cancer

Phase III in liver cancer, Phase II in chest wall recurrence of cancer, colorectal liver metastases, lung cancer and bone metastases

FDA Approval for phase III (2014)

164,165,310,315

AuroShell®

Thermosensitive gold nanoshell for solid tumor hyperthermia

Near infrared radiation (exo-trigger)

Intracranial tumors

Phase I solid tumors

FDA (2008)

164,312,313


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PROSPECTIVE DIRECTIONS FOR TARGETING SOLID TUMOR MICROMILIEU Intracellular targeting At the target sites, smart DDSs may require to cross or dodge the cell membrane barrier to provide their cargo into particular organelles. To avoid lysosomal degradation of smart DDSs after their internalization within the target cells, many approaches and strategies have been suggested and described.209,339 These strategies were such as the capability of utilizing cell penetrating agents along with moieties able to disrupt the lysosomal membrane, like poreforming proteins and fusogenic lipids.290,340 Cell-penetrating moieties are capable of performing and facilitating nanoparticles cellular internalization.209,341 A plasmid encoding green fluorescence protein (pGFP) and HIV TAT peptide (TATp)–liposomes Complexes were utilized for successful Lewis lung carcinoma tumor cells in vivo transfection in mice, as well as for several normal cells and tumor in vitro transfection.191,209,342,343 Octa-arginine-modified, DOX or bleomycin loaded liposomes were also confirmed high tumor growth inhibition and strong intracellular penetration in murine replicas.344,345 It is also vital to protect these moieties combined with DDSs till reaching their sites of intracellular targets. So, shielding the cell-penetrating function should be performed, to improve drug delivery within cells, by using a PEG coating for example, till the DDS is internalized and then PEG coating is unsettled and disrupted under endogenous particular environment.209 A highly competent tumor cells transfection in vivo was experienced with the pegylated TATpmodified pGFP-loaded liposomal formulation which is shielded with PEG coating that will be detached spontaneously at lowered pH conditions. This tactic potentiality was validated in mice bearing xenografts of ovarian cancer by utilizing a liposomal formulation that uncovered a concealed cell-penetrating peptide (TATp) upon PEG elimination under tumor endogenous low 60 ACS Paragon Plus Environment

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pH micro-milieu.174,346 From the nanoplatform DDSs, specific smart DDSs were fabricated utilizing ε-caprolactone-based degradable co-polymers and the co-polymer functional group was utilized to add in siRNA or DOX. In addition, the integrin-specific peptide for tumor targeting along with the cell-penetrating TATp were used to further modify these micelles. Outcomes proved that the labelled fluorescent micelles were successfully internalized within cells and the drug delivery to the cell nuclei was boosted, giving an improved cytotoxicity activity in a tumor model mouse.316 Moreover, the drug-loaded DDSs can be delivered directly to the targeted organelle instead of just cellular internalization, which could optimize the required effect and minimize any off-target side effects. This entails emerging smart DDSs that combine targeting ability along with organelle recognition and longevity. Several approaches such as the lipophilic cation rhodamine incorporation into smart DDSs for mitochondrial targeting have been described,347,348 utilizing the fact that mitochondrial dysfunction was related to several disorders, as well as tumors.349 Another smart DDSs amended with octadecyl-rhodamine B and utilized for cell lysosomes targeting.350 Another successful research work outcomes confirmed the reduction of tumor growth in mice by using the cytotoxic ceramides which have been reached cancer cells lysosomes with utilizing transferrin-adjusted liposomes.351 Multimodal (Theranostics) smart targeting Multifunctional smart DDSs have been fabricated for multimodal imaging, which could resolve many difficulties related to singular imaging modalities, like inadequate resolution or sensitivity.347 Hence, many DDSs that combine positron emission tomography (PET) or computed tomography with optical imaging, or combine computed tomography with PET have been established. These combinations can provide a greater resolution and can be constructed 61 ACS Paragon Plus Environment

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from conventional DDSs, like micelles or liposomes, or they can utilize nanoparticles template with contrast characteristics (like quantum dots, iron oxide or gold nanoparticles), which could be also amended with contrast agents for other imaging modalities. Accordingly, iron-oxideconstructed nanoparticulates were adapted utilizing a dye of near- infrared sensitivity with click chemistry to yield a smart dual near-infrared- MRI contrast agent.352 Pegylated liposomes carrying gadoteridol (a MRI agent containing Gd), along with iohexol (an agent for computed tomography imaging) were found to have a long circulation feature and simultaneous improvement of magnetic resonance and computed tomography signals in rabbits and mice.353 Also, the multimodal Gd-loaded dendrimers combined with gold nanoparticles were achieved a dual-mode MRI-computed tomography imaging in mice and rats.354 Additionally, a great breakthrough was reported from a radionuclide addition with the multimodal smart DDSs which allows the imaging system to turn into a therapeutic. Moreover, poly-chelating amphiphilic polymers utilization can enable many reporter metal atoms attachment which can be integrated on nanocarrier surface, resulting in a noticeable elevation in image-signal strength and the amount of reporter metal atoms bound per particle.209,355 With a cancer-specific mAb-based DDSs, outcomes revealed that it is possible to target tumors in mouse models with prompt activity and tumor specificity and could also act as efficient contrast agents for tumors MRI.356 Theranostics, A comparatively very recent advancement in relation to multimodal smart DDSs which renowned as the simultaneous utilization of DDSs for diagnosis or imaging purposes accompanied by therapeutic usage. With contrast reporter agents’ usage, theranostics provide a prompt monitoring for both DDSs accumulation in target sites and their biodistribution. Theranostics frequently utilize micelles, liposomes, iron oxide nanoparticulates


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and dendrimers as the carrier constituent of smart DDSs, while heavy metal atoms (like 111

99m

Tc,

In, Gd and Mn) as MRI metallic contrast agents.357 Liposomes loaded with both the

apomorphine and quantum dots had improved uptake into the mice brains by 2.4 times as well as fluorescent brain imaging were supported.358 Also, pegylated liposomes carrying doxorubicin and fabricated with contrast moieties and a tumor- specific antibody had elevated cytotoxic activity in vivo, long-circulating property and their approach to target sites could be tracked using MRI.359 Iron-oxide-based as a theranostic nanoparticles DDSs, had combined MRI and magnetic drug targeting. SPIONs (MRI imaging agents) are often combined with PEG for longevity along with pharmaceutical agents.209,237 Chlorotoxin-iron oxide complex nanoparticles were able to deliver an MRI contrast agent and methotrexate to cancer sites in mice bearing 9L glioma xenografts.360 Another theranostic smart DDS was elaborated by a translocation peptide and a near-infrared imaging agent covalent attachment to magnetic nanoparticles carrying siRNA, which was utilized for monitoring the activity of siRNA in tumor models and for multimodal tumor imaging.361 Moreover, protoporphyrin IX, the hydrophobic photosensitizer, was encapsulated within the pH-sensitive PEG–poly(β- amino ester)block co-polymer micelles for photodynamic therapy and tumor imaging simultaneously, in mice models.243,362 Liposomes of antibody-mediated targeting approach, loaded with doxorubicin and iron oxide for pancreatic tumors in mice were confirmed an enhancement in both the tumor magnetic resonance signal and the antitumor cytotoxic activity in comparison with the conventional non antibody-mediated liposomes.363 One other major advantage raised from the combination of a contrast agent and a chemotherapeutic drug, (both were loaded on one smart DDS), is enabling the advance of personalized nanotherapeutic strategies owing to the nanocarrier accumulation efficacy in the


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tumor which can support in the determination of therapeutic agent correct dose for each specific tumor treatment.364


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CONCLUSIONS The information presented above allows making several important conclusions. 1. Tumor microenvironment demonstrates several important features, such as very high degree of heterogeneity; the presence of certain areas of the compromised (“leaky”) endothelium allowing for the EPR effect, together with very poorly vascularized areas preventing the free tissue entry of drugs and/or drug delivery systems; an overdeveloped extracellular matrix and increased expression of EMC-specific enzymes; a pronounced hypoxia in some areas within the tumor; a noticeable acidosis of the tumor tissues with a significant pH gradient from the periphery of the tumor to the tumor core; redox potential within the tumor tissue and especially inside tumor cells different from that in normal cells and tissues; significantly increased interstitial pressure (especially in solid tumors); 2. While some of those features significantly hinder the efficacy of the intratumoral drug delivery (interstitial pressure, poor vascularization), the others can facilitate drug delivery (perforated endothelium) or be considered as tumor-specific intrinsic stimuli which can be used to assist intratumoral drug delivery or drug release from the delivery systems if these systems are engineered in a way allowing these system to respond to those stimuli in a desired way (acidosis, hypoxia, overexpression of tumor-specific enzymes, redox-potential); 3. In addition to the listed intrinsic stimuli, several; external stimuli can be applied to tumor tissue from the outside of the patient’s body also capable to act on drugs and drug delivery systems in a desirable way, for example, by activating prodrugs or promoting drug release from the delivery systems or facilitation intracellular drug penetration (magnetic field, light, heat, ultrasound);


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4. As of today, a broad variety of drug delivery systems is engineered and described, which are stimuli-sensitive, i.e. capable to react towards both, intrinsic and external stimuli (and even respond to more than one stimulus simultaneously) in a desirable way by activating the drug molecules, releasing incorporating drug(s), and/or acquiring the ability to specifically interact/bind cancer cells and be internalized or being able to penetrate inside those facilitating and enhancing drug therapeutic action. Such “smart” delivery systems are based on various materials – organic polymers, lipids, different hybrids, exosomes, self-assembling components – and many of those are quite simple to prepare and scale up; 5. Despite multiple publications and much elaborated bench science in this exciting area, its clinical transition is still in its infancy with just a few systems currently entering clinical trials or clinical application. Taken into account a clearly demonstrated therapeutic anti-cancer potential of such systems and their ability to be fine-tuned, one can be sure that in not a very distant future we will witness a dramatic increase in their transition from the bench to the bed, and this transition will positively change the whole landscape of cancer therapy and personalized medicine. COMPETING INTERESTS STATEMENT The authors declare no competing financial or any other interest.


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VOCABULARY Enhanced permeability and retention (EPR) effect, The feature caused by the increased vascular permeability of abnormal blood vessel architecture, which macromolecules and nanoparticles can pass through and accumulate in areas of inflammation including tumors; Warburg effect, the energy that produced in cancer cells is observed to be primarily by a glycolysis and lactic acid fermentation, rather than by glycolysis and pyruvate oxidation in mitochondria as observed in most normal cells; Tumor xenograft, Tumour specimens which can be grown mainly in immuno-compromised rodents, such as nude mice, to provide tumour models with the same complexities of many human tumours; Stimuli-responsive smart nanoarchitectures, chemically engineered drug loaded nanoparticles which are designed to be responsive mainly to specific triggers in order to release their loads upon exposure to these triggers; Theranostics, The dual utilization of smart nano drug delivery systems as a simultaneous diagnostic and therapeutic tools for more effective individualized chemotherapy.


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Stimuli-Responsive Nano-Architecture Drug-Delivery Systems to Solid

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