Biodegradable Smart Nanogels: A New Platform for Targeting Drug

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Invited Feature Article

Biodegradable Smart Nanogels: A New Platform for Targeting Drug Delivery and Biomedical Diagnostics Hai-Qiu Wu, and Changchun Wang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.6b00842 • Publication Date (Web): 02 Jun 2016 Downloaded from http://pubs.acs.org on June 4, 2016

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Biodegradable Smart Nanogels: A New Platform for Targeting Drug Delivery and Biomedical Diagnostics Hai-Qiu Wu and Chang-Chun Wang,*

State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, and Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.

ABSTRACT Nanogels (or nanohydrogels) have been extensively investigated as one of the most promising nanoparticulate biomedical platforms owing to their advantageous properties that combining the characteristics of hydrogel systems with nanoparticles. Among them, smart nanogels which have the ability to respond to external stimuli, such as pH, redox, temperature, enzymes, light, magnetic field etc., are most attractive in the area of drug delivery. Besides, numerous multi-functionalized nanogels with high sensitivity and specificity were designed for diagnostic applications. In this feature article, we have reviewed and discussed the recent progress of the biodegradable nanogels as smart nanocarriers of anti-cancer drugs and biomedical diagnostic agents for cancer. 1. INTRODUCTION Hydrogels are polymeric networks with three-dimensional configuration that exhibit a swelling behavior and have the capable of retain large quantities of water, but will not dissolve in the aqueous surrounding environment due to the critical crosslinks present in their structures. Nanogels, nanometer-sized hydrogels, show the features and characteristics of hydrogels and nanoparticles at the same time. When applied in pharmacy field, nanogels exhibit both advantages, including hydrophilicity, flexibility, versatility, high water absorptivity, and biocompatibility of hydrogels, as well as the small size and capable of actively or passively targeting to the desired biophase (such as 1

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tumor sites for enhanced permeability and retention (EPR) effect).1 Smart nanogels are a class of intelligent polymeric nanocarriers that are designed to undergo property responses according to the changes of their ambient conditions or external stimuli. Strategies exploiting the unique characters of tumors that are different from healthy tissues, such as low pH, redox potential, or enzymes as the molecular stimulation to switch on drug release, have received widespread attention.2 Besides, drug delivery system (DDS) responding to external changes, magnetic field an light for examples, provides additional approach to improve the benefits from nanogel system.3 The flexibility and versatility of nanogels have received great attention in the biomedical field, and intense research efforts have been made in past few decades. Several valuable reviews about different aspects of nanogels, such as synthesis, characterization, applications as drug carriers, have been published.2, 4-6 In this feature article, we will focus on the most recent research about biodegradable smart nanogels for targeting drug (including chemotherapy drugs and immunomodulatory biologics) delivery and biomedical diagnostic for cancer. 2. APPLICATION OF NANOGELS FOR ANTI-CANCER DRUG DELIVERY Well known as one of the most effective drug delivery systems, nanogels provide significant advantages.4 First of all, their regulatable size and versatile surface modifications help them to avoid rapid clearance by phagocytic cells and achieve both passive and active drug targeting. Besides, the controlled targeting release of the payload can improve the effectiveness of the therapies and reduce side effects, compared with conventional drug administration protocols. Moreover, the large surface area/volume ratio of nanoparticles provides the capability to load large amounts of payload and can be achieved without chemical reactions, which is an important factor for preserving the drug activity. Furthermore, the ability to reach the smallest capillary vessels contributed form the small size of the vehicles, and to penetrate the tissues either through the paracellular or the transcellular pathways. Finally, the in vivo solubility and stability of active pharmaceutical agents (APIs) can be improved by

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the nano-carriers, providing administration potentials through various routes, including oral, pulmonary, nasal, parenteral, intra-ocular etc. Chemotherapy is commonly used to treat cancer patients. Nevertheless, delivery of conventional chemotherapeutics faces a lot of challenges, including issues of solubility, poor pharmacokinetics, in vivo stability, toxicity and thereby side effects. Immunomodulatory biologics, such as antigenic proteins, peptides, nucleic acids and DNAs, provide a novel therapy or prevention of cancers. Directly targeting to the general abnormalities in cancer cells, which is usually anomalies in some proteins that restrain apoptosis, the immunomodulatory biologics could efficiently and specifically modulate one or multiple targets. Natheless, defects of immunomodulatory therapy, including low transfection efficiency, high side effects, uncontrollable and untraceable gene transfer, have enormously hampered its successful in clinical applications. The advantages of nanogel drug delivery system (NG-DDS), especially stimuli responsive ones, can overcome most of the conventional challenges. 2.1.1 Single-responsive delivery system 2.1.1.1 pH-responsive nanogels Developing pH-responsive NG-DDS is the most commonly employed strategy in cancer therapy, because the extracellular pH (pHex, ∼6.5) of tumor is slightly lower than that of normal tissue and blood (∼7.4), which is resulted from the hypoxia-induced production of excess lactic acid in the tumor microenvironments. Besides, the strong acidity of intracellular endolysosomes (pH at ~5) makes acid responsive vehicles to easily degrade or release payloads.5 The pH-responsive nanogels are usually cross-linked polymer networks fabricated by incorporating pH-responsive polymers or pH-sensitive bonds (such as hydrozone, cis-aconityl and acetal) into their structures. Acetal bonds were introduced into a biocompatible, degradable and hydrophilic polymer that based on dextrin and contained numerous hydroxyl groups which are ready to be modified. Using dextrin as a starting material, Sriamornsak’s group fabricated pH-responsive dextrin nanogels (GDNGs) with glyoxal by an emulsion cross-linking approach (Figure 1A). The average diameter of 3


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GDNGs could be regulated by mole ratio of dextrin to glyoxal. The DNGs showed slightly negative surface charge, and the doxorubicin (DOX) release displayed a pH-dependent behave, slow at pH 7.4 and increased with decreasing pH.7 Recently, they improved the GDNGs by applying formaldehyde as a cross-linker (FDNGs) rather than glyoxal (Figure 1B). The FDNGs exhibited smaller size, compared to GDNGs. The acid-sensitive acetal bond remarkably benefited the selective delivery of DOX to colorectal cancer.

8

Using the unique pH depending characteristic of boronate linking, a

lysosome-targeted acidity-responsive nanogel was prepared by self-assembly of dextran (Dex) and phenylboronic acid modified cholesterol (Chol-PBA) (Figure 2). The Chol-PBA/Dex displayed nearly no cytotoxicity and could remain structurally stable under the simulated physiological conditions. The biosafety can be benefited from serum tolerability of Dex and the transmembrane ability associated with cholesterol, both all which are natural materials. The Chol-PBA/Dex nanogel was proved to be collapsed and release DOX with triggering by the lysosomal acidity.9

Figure 1. Schematic of pH-responsive GDNGs with acetal bonds: (A) glyoxal as cross-linker, (B) formaldehyde as cross-linker. Reproduced with permission from ref. 7 and 8. Copyright 2014 and 2015 Elsevier.

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Figure 2. Illustration of acidity-responsive Chol-PBA/Dex nanogels with boronate linking and the cell uptake process. Reproduced with permission from ref. 9. Copyright 2015 Elsevier. Benzacetal bonds were utilized to generate biodegradable, protein resistant polyglycerol nanogels on different length scales.10 The size-defined polyglycerol nanogels were obtained via in situ crosslinking of dPG7.7-10-p-PBDMA and dPG7.7[N3]7 by bioorthogonal copper catalyzed click chemistry (Figure 3). The benzacetal bonds in the nanogel made it quickly degraded into low molecular weight fragments at acidic pH value but remained stable at physiological pH values for a long time. These polyglycerol nanogels were reported to encapsulate labile biomacromolecules such as proteins, including the therapeutic relevant enzyme asparaginase, with encapsulation efficacies higher than 99% under full retention of activity and structural integrity. 10

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Figure 3. Preparation of pH sensitive polyglycerol nanogels that contained benzacetal bonds via nanoprecipitation. Reproduced with permission from ref 10. Copyright 2015 Elsevier. Deep tumor penetration, which means delivering the drugs deep into the center of tumor tissue, is one of the major challenges in DDS for anti-cancer drugs. For the reason that solid tumors are usually featured with an abnormal tumor vasculature and the dense tumor extracellular matrix (ECM).11 Focusing on this issue to enhance therapeutic efficacy, a pH-dependent reversible swelling-shrinking nanogel

was

developed

as

a

sequential

intra-intercellular

nanoparticles

delivery.

The

all-biopolymer-based nanogel comprised of a polyelectrolyte core and a crosslinked negatively charged protein shell. When under physiological conditions (pH 7.4), the nanogels was slightly negative charged. But when they were internalized by the cells and got into endosomes and lysosomes, the pH of 5.0–6.0 made the amino groups in the core protonated promptly and positive charged. Therefore, strong electrostatic repulsion triggers the swelling of core and also rapid release of the encapsulated DOX. The massive volume expansion resulted in endo-lysosomal bursting and release the nanogels into the cytosol, where pH changed back to 6.8–7.4 and the nanogels shrunk to their original size. After the DOX killing the cancer cell, the nanogel of original size escaped from the dead cell and entered other tumor cells nearby. This repeatedly infection helped the nanogels and also the drugs penetrate deep into the tumor tissue.11 Recently, another pH depending swelling-shrinking nanogel was obtained from natural and non-immunogenic gelatin and acrylamidoglycolic acid (AGA) 6


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via free radical emulsion polymerization, with high encapsulation efficiency of curcumin (ranged from 42 to 48%). This pH sensitive nanogel increased its size slowly in the solutions of pH 1.2 to 5.0, but swelled rapidly in the solutions of pH 5.0 to 8.5. This swelling-shrinking nature was resulted in the ionization of carboxylic groups as the pH increasing from 5.0 to 8.5. The repulsion interaction increased with the ionization, and triggers the volume expansion of the nanogel. Besides, the nanogels exhibited higher stability in a wide pH range, benefiting from dual crosslinking via covalent bonds and imine linkages, as well as the inter- and intra-molecular hydrogen bonds among the polymer chains.12 Unlike swelling-shrinking nanogels, a dual pH-triggered multistage drug delivery system was constructed via host–guest interactions for deep tissue penetration (Figure 4). The polymeric nanogels, was prepared by copolymers of AD-benzoic imine-linked PPEGMA-co-PHEMA-AD and DOX-hydrazone-linked PHPMA-co- PPMA-DOX-CD via host–guest interaction between AD and β-CD moieties, with size of about 220 nm. When pH values decreased to 6.5, near pHex of tumor tissue, the nanogels reorganized into smaller nanoparticles (about 25 nm) due to cleavage of the benzoic imine linkage in the PPEGMA-co-PHEMA-AD, which can facilitate deep penetration into the tumor tissue. Moreover, DOX can be released quickly in endosomal or lysosomal acidity (pH ~5), due to the existence of pH-cleavable hydrazone linkage.13

Figure 3. (A) Schematic illustration of dual pH-triggered mode of polymeric nanogels with benzoic imine linker and hydrazine linker. (B) Structure of PPEGMA-co-PHEMA-AD and PHPMA-co-PPMA -DOX-CD. Reproduced with permission from ref. 13. Copyright 2014 Royal Society of Chemistry. 7


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2.1.1.2 Thermosensitive nanogels As distinct hyperpyrexia locally is another common characteristic in certain malignant tumour, thermosensitive (or temperature-sensitive) nanogels which can respond to the environmental temperature by changing their particle volume have gained considerable attention. The size change has been conveniently utilized to control the release of drugs from these nanogels. Nanogels

based

on

Poly(N-isopropylacrylamide)

(PNIPAAm)

usually

exhibit

good

thermosensitivity and have a lower critical solution temperature (LCST) around 32oC in distilled water. So N-isopropylacrylamide (NIPAAm) is the mostly used monomer in thermosensitive drug delivery system. A thermosensitive nanogel based on chitosan (CTS) and N-isopropylacrylamide (NIPAAm) together with acrylamide (AAm) was developed through the free radical polymerization in order to optimize the volume phase transition temperature (VPTT).14 When coplymerized NIPAAm with 5.5 wt% AAm, the nanogel achieved a VPTT of 38oC in contrast to 32oC of the CTS-PNIPAAm polymer. After loading coumarin-6 to increase cellular uptake, the thermosensitive nanogels loaded paclitaxel (PTX) exhibited noticeably enhanced antitumor efficacy against human colon carcinoma cells HT-29 xenograft nude mice model. Another PNIPAAm based nanogels were reported to exhibited a lower critical solution temperature (LCST) of 34oC, using poly(N-isopropylacrylamide-co-undecylenic acid) acrylamide as a macromonomer and copolymerized with NIPAAm and propyl acrylic acid (PAAc) monomers. After modifying with arginine-glycine-aspartic acid (RGD) as targeting molecule, significantly enhanced cellular uptake of DOX-loaded nanogels was observed. For the thermosensitive feature, DOX could be efficiently released from the nanogels and killed tumor cells.15 On the view of biodegradable that required in clinical applications, thermo-responsive nanogels from poly(L-lactide)-g-pullulan (PLP) copolymers with phase transition temperature of 35oC were investigated as DOX carrier. A great difference in the initial release by PLP nanogels was observed between 37 and 42oC. Besides, the total amount of DOX released from the PLP nanogels could keep

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increasing for 50 h with increasing temperature. The results suggested that self-assembled PLP nanogels, under temperature triggering, could be used as a long-term DDS for cancer treatment. 16 When emphasizing the upper critical solution temperature (UCST)-like behavior, characterized by swelling rather than deswelling at increased temperature, interesting phenomenon was found that swollen hydrogels did enhance the release of drugs resulted from lower polymer density. The combination of acrylamide and acrylic acid was studied as an UCST-like system, since hydrogen bonds between acrylic acid and acrylamide may break at elevated temperatures, causing the hydrogel matrix to swell. On this basis, temperature-sensitive nanogels formed on the combination of acrylic acid and acrylamide were presented for delivery of chemodrug cisplatin (CDDP). The in vitro cytotoxicity experiments showed that CDDP-NPs had a remarkably greater efficacy at slightly higher temperatures.17 2.1.1.3 Redox-responsive nanogels The concentration of glutathione (GSH), that is able to reduce disulfide bonds by serving as an electron donor, in the reducing intracellular fluids (about 2∼10 mM) was reported to be about 1000 times higher than that in the relatively oxidizing extracellular milieu (about 2∼20 µM). In addition, it is found that some tumor tissues present about 4-fold higher concentrations than that in normal tissues.2 Furthermore, some studies indicated that a great amount of γ-interferon-inducible lysosomal thiol reductase (GILT), which could reduce the disulfide bonds in proteins and cysteine at low pH, was contained in endosomes and lysosomes.18 Therefore, the development of redox-responsive vehicles, that could maintain stable in extracellular environment with lower concentration of reducing reagents while easily degrading in a reducing intracellular environment with high concentration of reducing reagents, is a promising approach. A series of studies on anti-cancer DDS have employed disulfide bond, which is a linkage that is easy to break down in the reduction potential environment. A heparin (HEP)-based nanogel with redox sensitivity was synthsized in aqueous medium via a surfactant free method, by copolymerizing 9


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cystamine bisacrylamide with HEP that was derivatized with vinyl group firstly. 19 This biodegradable and bio-reducible nanogel had a high DOX loading content of 30% and loading efficiency of 90%. In addition, its arresting superior in vivo antitumor activity also was benefited from HEP, which was reported to restrain tumor growth and metastasis in three ways, caspase-mediated apoptosis, inhibition of heparinase, and selectin-mediated interactions. Anionic alginate (AG), a biodegradable natural polymer, can effectively encapsulate cationic molecules (such as DOX) via electrostatic interactions. Based on AG, a kind of nanosized hydrogels was prepared by using cystamine (Cys), which contained a disulfide bond in the structure, as a cross-linker to realize redox sensitivity. 20 A high loading capacity of DOX could achieved for the strong electrostatic interactions between the anionic AG and the cationic DOX/HCl. In another AG/DOX system, the DOX was loaded by chemically anchoring onto the nanogel matrix via a disulfide bond for enhancing accumulation at target sites and reducing the chance of leakage in the delivery pathway.21 Moreover, this nanogel also introduced aminated superparamagnetic iron oxide nanoparticles (SPIONs) as a core to enhance accumulation at target sites, and via strong electrostatic interactions between the amino-groups and carboxyl groups of GA to obtain the superparamagnetic nanogels. Also concerned with the safety of the delivery systems, Thayumanavan et al. introduced a redox responsive polyamide nanogel system with glutamic acid (a naturally occurring amino acid) and putrescine (simplest of the polyamine-based cell cycle regulators) as components of a degradable polyamide backbone, while oligoethylene glycol and thiopropionic acid as the side chain substituents. This disulfide cross-linked polymeric nanogels was designed as being composed of the molecules that could be used as food additives or as medical devices. Neither the in vitro tissue culture cytotoxicity assay nor a more rigorous and highly sensitive mammalian preimplantation development assay of the nanogels exhibited discernible toxicity.22 Various inorganic or organic small molecules containing Se are widely studied as anticancer drugs with high anti-tumor activities. In addition, Se-Se bond is stimuli responsive to both reductive and 10


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oxidative condition, owing to the low bond energy (Se-Se 172 kJ mol−1). Particularly, Se-Se bond can be easily cleaved by reactive oxygen species (ROS).23 Taking advantage of Se-Se bonds, Yan et al. prepared a redox sensitive nanogel with a crosslinked poly(diselenidephosphate) core and a polyethylene glycol (PEG) crown (Figure 5). This self-delivery anticancer nanomedicine had an average diameter of about 150 nm, and was much less cytotoxicity to normal cells than Se-containing polymeric anticancer drug. The hydrophobic Se-Se bonds in the polyphosphate core could speed up the dissociation of the nanogel with 0.1 wt% H2O2 or 10 mM GSH, and the synchronously released Se-species would kill the tumor cells rapidly. The hydrophilic PEG crown could protect the nanogel against attack from proteins in the bloodstream and retain stable in physiological conditions.23

Figure 5. Preparation of redox-responsive polymeric nanogels containing diselenide bonds in the polymer network. Reproduced with permission from ref. 23. Copyright 2015 Elsevier. Introducing redox sensitive disulfide bonds is also a common strategy to develop smart delivery vaccines for Immunomodulatory biologics. Bioreducible cationic AG-based nanogels was reported for antigen delivery. between

AG

24

These disulfide cross-linked nanogels were prepared by electrostatic interaction and

branched

PEI2k,

and

succedently

cross-linking

with

3,3′-dithiobis(sulfosuccinimidylpropionate) (DTSSP) as cross-linker. High antigen-loading capacity, little cytotoxicity, facilitated antigen uptake, promoted intracellular antigen degradation and cytosolic release were achieved by this novel delivery vaccine. Furthermore, these nanogels could significantly enhance vaccine-induced antibody production and cytolysis mediated by CD8+ T cell. The disulfide 11


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cross-linking was also introduced into a core-shell protein nanocapsule to make it stimuli-responsive degradable. The protein in the core is recombinant maltose-binding protein fused apoptin (MBP-APO), which could assemble into a multimeric protein that displayed the necessary functions and selectivity of

the

crude

apoptin.

The

redox

sensitive

shell

was

prepared

by

copolymerizing

N-(3-aminopropyl)methacrylamide (APMAAm) and acrylamide (AAm), with N,N-methylene bisacrylamide as crosslinking agent to make the shell degrade quickly in the redox environment in cytoplasm. This shell with slightly positively charged could not only shield the protein core from surrounding environment and serum proteases, but also enhance the cellular uptake of the nanogel through

endocytosis.25

Dai

et

al.

designed

a

multifunctional

intracellular

microenvironment-responsive, fluorescence label-free, and biodegradable nanogel with branched PEI L-cystine, which contained disulfide bond in structure, for highly efficient and traceable gene delivery. Autofluorescence was mediated by potential n→π* electron transition in Schiff-basestructure (－N＝ C － ), that was produced via reaction between L-cystine and aldehyde. Owing to the disulfide-bond-linked double Schiff-bases, these nanogels were sensitive to both intracellular reducing agent GSH and the weakly acidic environment of tumor. Moreover, these cationic nanogels could self-assemble with negatively charged plasmid DNA (pDNA) to form uniform nanosized polyplexes, but effectively release the pDNA after cellular uptake, resulting in greatly improved gene transfection efficiency.26 Another reductively responsive siRNA deliver strategy was designed by polymerizing the siRNA to nanogels that prepared via particle replication in nonwetting templates (PRINT), with a degradable, disulfide linkage.27 2.1.1.4 Enzyme-sensitive nanogels Hyaluronic acid (HA) is a kind of biodegradable natural material with active tumor targeting property, for the fact that many over-expressed HA-binding receptors exist on the surface of numerous tumor cells. Additionally, most types of cancers overexpress hyaluronidases (HAase) that can biodegrade HA intracellularly and extracellularly. Therefore, HA becomes a popular natural ligand for 12


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anticancer drug delivery, and many hyaluronic acid-based nanogel DDSs have been reported. Recently, work from Jiang’s group reported enzyme sensitive HA nanogels via a methacrylation strategy to functionalize HA with double bonds and subsequently copolymerized with di(ethylene glycol) diacrylate (DEGDA).28 These HA nanogels containing enzyme-sensitive groups could be disassembled by actions of lipase and hyaluronidase, and significantly targeted to the tumor area. Thus they enhanced DOX accumulation in the tumor site and prolonged DOX circulation time. Na et al. employed the HA degradation by hyaluronidase to regain the cationic charge on the degradable cationic nanogel (DpNG) consisted with acetylated pullulan and low molecular weight polyethyleneimine (LowbPEI, 1.8 kDa) (Figure 6).29 The DpNG induces necrosis, which leads to paracellular transport of the nanogels due to reduced cell density that is caused by necrosis. Therefore, the DpNG loaded with PTX can deep penetrate into heterogeneous tumours, released PTX from the DpNGs in deep tissues, and widespread over a broad region, to enhanced anticancer effect.

Figure 6. Schematic illustration of enzyme-sensitive DpNGs and their way of penetrating into tissue. Reproduced with permission from ref. 29. Copyright 2013 Elsevier. Tumor tissues also secrete high amounts of proteolytic enzymes, such as matrix metalloproteinases (MMPs), which degrade the basement membrane and natural ECM, opening up more space for tumor growth. Based on this fact, an enzyme-sensitive self-assembled nanogels formed by electrostatic

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interaction between negative biodegradable natural polypeptide gelatin and positive surfactant micelles were designed.30 Core-shell-like structure could provide stable hydrophobic pockets in the micelle cores to encapsulate hydrophobic drugs and efficiently separate the micelles from outside environments, resulting in prevention of effortless diffusing and high encapsulation stability of hydrophobic drugs. The size of these physical cross-linked nanogels could be systematically tuned via changing micelle-forming molecules. As soon as the nangels got into the tumor cells, the drugs could be quickly released for the degradation of nanogels with highly overexpressed MMPs. Similarly, magnetic iron oxide nanoparticles (MIONPs) coated with functional PEG that modified with integrin-targeting RGD and matrixmetalloproteinase (MMP)-degradable sequence were prepared. The functional PEG coated nanoparticles exhibited 11 times more efficient in cellular uptake than these without PEG coating. After being efficiently delivered into cancer cells, they could fleetly release therapeutic agent DOX within 2 h under the condition of high MMP concentration in tumor cells. 31 A differential nanogel drug delivery featured with bacteria-sensitive triple-layered nanogel (TLN) was demonstrated to deliver drugs to the fabricated bacteria-accumulated tumor environment (Figure 7). The drug release was in the “OFF” state in the absence of bacteria, but the drug could selectively release in response to a lipase-secreting bacteria-infected tumor environment. As DOX-loaded TLN (TLND) was selectively degraded, the DOX releasing could only be triggered by tumor cells and selectively killing them. This concept can be extended and optimized by employing other substances secreted by bacteria or modifying materials with other functional skeletons to develop a differential drug carrier for certain unique tumor environment. Hence, this system shows great potential for wide applications in drug delivery. 3

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Figure 7. Schematic illustration of drug delivery of triple-layered nanogel (TLND) to a lipase-secreting bacteriainfected tumor. Reproduced with permission from ref. 3. Copyright 2015 American Chemical Society. 2.1.1.5 Light-responsive nanogels Near-infrared (NIR) light, with wavelength in the range of 750–1300 nm, is one of the most promising external stimulus of DDSs in the light of the superiorities of NIR light, including high tissue penetration but low damage. In recent year, more and more biocompatible organic molecules that can absorbe NIR light have been introduced into DDSs as NIR-light absorber and heat producer. Indocyanine green (ICG) is a water-soluble NIR dye approved by the United States Food and Drug Administration (FDA). For the safety and NIR absorption character, ICG is very widely used in light-responsive DDSs. For example, Ge et al. constructed nanogels from AD-conjugated random copolymers

PPEGMA-co-PHPMA-co-PADMA and β-CD functionalized poly(amidoamine)

dendrimer (PAMAM-CD) via host-guest interaction. With simultaneous encapsulation of ICG and DOX, both encapsulation efficiency (EE) and loading efficiency (LE) of ICG and DOX improved remarkably owing to the strong electrostatic interaction between PAMAM, DOX, and ICG. Under 805 nm NIR laser irradiation, this system exhibited outstanding photothermal effects, triggering an increase in temperature, disassembly of the nanogels, and release of DOX. The synergistic effects of photothermal-chemotherapy showed superior tumor growth suppression.3 ICG was also introduced into diselenide-cross-linked poly(methacrylic acid) (PMAA)-based nanogels as a trigger. 15


32

In this

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novel near-infrared light-responsive nanogels, a diselenide cross-linker can be cleaved by reactive oxygen species (ROS, such as singlet oxygen, superoxide anions, and hydroxyl radicals) that produced by ICG upon NIR light irradiation, resulting in the dissociation of nanogels and release of DOX (Figure 8).

Figure 8. Preparation, biodegradable behavior, and controlled drug release of diselenide-cross-linked nanogels. Reproduced with permission from ref. 32. Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA. 2.1.2 Multi-responsive delivery system 2.1.2.1 pH-thermal dual responsive nanogels N-isopropylacrylamide

(NIPAm),

a

thermal-responsive

unit,

was

introduced

into

MAA-co-mPEGMA nanogel, which could encapsulate cisplatin via conjugation with the carboxyl groups, to diminish the Cl- triggering release of cisplatin from the nanogels. Successfully, NIPAm introduction slowered cisplatin released at 37 oC in pH = 7.38 buffer in the present of Cl- (150 mM) than that without NIPAm. In vitro release behavior study, the releasing of cisplatin from the NIPAm containing nanogels, was found to be accelerated by H+ attacking and reduced by temperature arising. Thus, the dual-stimuli responsive nanogel is a suitable candidate for cisplatin delivery.33 Poly(N-isopropyl acrylamide-co-acrylic acid) nanogels conjugated with fluorescent bovine serum 16


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albumin (BSA) encapsulated gold nanoclusters (Au NCs) on the surface of nanogels and functionalization of tumor targeting peptide iRGD onto the BSA for tumor targeting were reported to deliver DOX. 34 The DOX-encapsulated iRGD-decorated nanogels, by electrostatic adsorption at pH 7.4, maintained both thermo- and pH-responsive properties, which are favorable for achieving a controlled drug release in tumor tissues. Two novel dual temperature/pH-sensitive superparamagnetic nanogels, composed of poly(N-isopropylacrylamide/ dimethylaminoethyl methacrylate quaternary ammonium

alkyl

halide/methacrylic

acid)

poly(N-isopropylacrylamide/dimethylaminoethyl

P(NIPAAm/DMAEMA-Q/MAA)

methacrylate

quaternary

halide/methacrylic acid/hydroxyethyl methacrylate) P(NIPAAm/

ammonium

and alkyl

DMAEMA-Q/MAA/HEMA)

copolymers, were developed with the aim of simultaneously delivering doxorubicin (DOX) and methotrexate (MTX). They avoided premature drug release during blood circulation while having a rapid release upon reaching tumorous tissue, indicating a potential cancer therapy with dual anticancer drug-loaded thermo/pH-sensitive nanogels.35 Another NIPAm-based thermal/pH dual responsive nanogel, copolymering methacrylate sulfadiazine with NIPAM, was introduced to improve the low drug-loading amount and poor sustained releasing properties of PNIPAm nanogels. In addition, Pickering emulsion combined with solvent evaporation (PESE) is developed firstly as a new drug-loading technique with high efficiency and sustained-releasing ability. Owing to ionic bonding interaction

of

DOX

molecules

and

sulfonamide

groups,

DOX

loaded

poly(N-isopropylacrylamide-co-methacrylate sulfadiazine) (PNS-D) nanogels show a slow releasing behavior (only 13.2% for 48 h) in pure water, but increased to 29.5%, 41.6% and 48.0% respectively in 0.9 wt%, 3.0 wt% and 5.0 wt% of NaCl solutions for 48 h. 36 Acetal bonds in 2,2-dimethacroyloxy-1-ethoxypropane (DMAEP) were introduced as a cross-linker into the well-defined poly(vinylcaprolactam)-based nanogels (Figure 9) reported by Yang et al.37 Interestingly, these nanogels could reduce in size when temperature increased and displayed a higher volume phase transition temperature (VPTT) with higher concentration of 17


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hydrolyzed polymaleic anhydride (HPMA). In combination with the pH-responsive ketal linkages, the nanogels exhibited accelerated degradation with lowering the pH and increasing temperature. Thus DOX could keep little drug leakage at neutral pH, but very fast and complete release in acidic conditions. Acid-sensitive ketal derivative was also applied in an injectable dual-responsive micellar nanogel system for their more pH-sensitive at the lower pH of tumors but more stable in the pH 7.4 environment of the blood.38 The dual thermo- and pH-responsive nanogel was self-assembled from a degradable pH-responsive ketal derivative, mPEG2000-isopropylideneglycerol (mPEG-IS, PI) polymer. The dual-responsive micellar nanogel possessed a sol-gel transition at 37 oC, and could be degraded with lower pH, following efficiently release of PTX.

Figure 9. Preparation, thermo-responsive behavior and ketal based acid-triggered drug release of the P(VCL-ketal-HPMA) nanogel. Reproduced with permission from ref. 37. Copyright 2015 Royal Society of Chemistry. 2.1.2.2 pH and redox dual-responsive nanogel Slightly lower pHex and relative reducing intracellular environment were the two main characteristics of tumor tissue, so the pH and redox dual-responsive DDSs were the most studied. A dual responsive prodrug nanogel system was presented based on highly biocompatible hyperbranched polyglycerol (hPG) that cross-linked with disulfide bonds via a thiol-disulfide exchange reaction and 18


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thiol-Michael addition reaction. The degradable system, showing very low unspecific drug leaching but efficient intracellular release of the payload triggered by the intracellular conditions, conjugated DOX by an acid-labile hydrazone linker.39 Quick acid responsive cis-aconityl bond was introduced into a reduction-sensitive poly(vinyl alcohol) (PVA) nanogels to achieve charge-conversional for enhanced cell uptake and efficient intracellular doxorubicin release (Figure 10).40 The introduction of carboxyl group into the PVA nanogels could highly improve the DOX encapsulation due to the strong electrostatic interaction, the strength of which could drastically decrease under endosomal pH. With the addition of intervening disulfide bonds cleavage under a high GSH concentration, the resulted release of DOX to be rapid and sufficient.

Figure 10. Illustration of cis-aconityl bond based charge-conversional and disulfide bond based reduction-sensitive PVA nanogels. Reproduced with permission from ref. 40. Copyright 2015 Elsevier. A smart nanogel based on a quaternary ammonium salt was prepared through ring-opening polymerization of L-glutamate N-carboxyanhydrides, deprotection of benzyl group and subsequent quaternization reaction between γ-2-chloroethyl-L-glutamate unit in polypeptide block and 2,2′-dithiobis(N,N-dimethylethylamine).41 This system is likely destabilized in the acidic endo/lysosomal compartments by ionization of PDEA block as well as cleavage of the redox sensitive disulfide bonds, resulting in efficient intracellular release of DOX.42 Another quaternary ammonium groups based dual-sensitive drug delivery system were synthesized in two steps: first, monomethoxyl poly(ethylene glycol)-block-poly-(N,N′-diethylaminoethyl methacrylate) (mPEG-b-PDEA) was 19


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polymerized via atom transfer radical polymerization (ATRP) with macroinitiator mPEG-Br; followed by quaternization reaction between the nitrogen from DEA and the bromine from the cross-linker N,N′-bis(bromoacetyl) cystamine to produce polymeric nanogels. 42 Using methacrylic acid (MAA) as monomer and N,N-bis(acryloyl)cystamine (BAC) as crosslinker, our group have developed many kinds of biodegradable pH/redox dual-responsive nanogels, which had various responses to dithiothreitol and glutathione for controlled release of DOX. In the continuous study of this hydrophilic system, we developed reflux precipitation polymerization for the first time to improve the distillation precipitation polymerizatio,43 and found that the hydrophobic drug PTX could be loaded in surprise.44 Besides, combination of N-(2-hydroxypropyl)methacrylamide monomer into above polymer system was further reported to improve the non-immunogenic and biocompatible properties, without impacting the pH/redox responsivities.45 Moreover, an acid-dissolvable magnetic supraparticle (MSP) core was introduced into this dual-responsive system. When paclitaxel (TXL) and DOX were loaded separately into the core and the shell domains, this nanogel exhibited better inhibitive efficacy than the free drugs under the same dosing level, demonstrating the great potential of programmed and stimuli-responsive drug release characteristics.46 Inspired by zinc finger proteins in nature system, we recently reported a new kind of Zn (II) crosslinked poly(methacrylic acid) nanogels (ZCLNs) with dual stimuli triggered degradation for the first time.47 As shown in Figure 11, zinc dimethacrylate (ZDMA) as a crosslinker, by reflux-precipitation polymerization with MAA, nanogels of about 100 nm were obtained. After modification with PEG and folic acid (FA), the nanogels simultaneously showed excellent colloidal stability and folate-targeted ability. Besides, under weak acidic pH and a relatively high GSH concentration environment, this new nanogel could quickly degrade into small molecules with average molecule weight (Mn) of 1536 in a possible mechanism as described in Figure 11, and the encapsulated DOX in DOX-loaded PZCLNs could be quickly released over 90% within 48 h.

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Figure 11. Preparation of FPZCLNs and the possible reaction mechanism for disassembly of nanohydrogels under high GSH concentration and weak acid. Reproduced with permission from ref. 47. Copyright 2015 Elsevier. Nanocarriers with cationic surface charge are much easier to internalize by the cells for their higher affinity to the negatively charged phospholipid bilayer of cell membranes. To enhance cellular uptake, disulfide based nanogels with the ability of reversible pH-responsive surface charge generation was designed by Thayumanavan’s group.48 The nanogels were generated by crosslinking the pyridyldisulfide (PDS) moieties within the hydrophobic interior of the amphiphilic copolymers, which was obtained by copolymerizing 2-(diisopropylamino)ethyl methacrylate (DPA), polyethyleneglycol methacrylate (PEGMA) and 2-(pyridyldisulfide) ethyl methacrylate (PDSMA) monomers. DPA moieties played the key role in the design, because the pKa of the protonated form of the amine was around 6.2. So they were hydrophobic and buried within the interior of the nanogels at neutral pH, but are protonated at pHe of tumor to generate a positively charged surface, without any small molecule byproducts and being reversible. Intracellular delivery of these nanogels was greatly enhanced in an acidic pH environment due to the surface charge generation. Another pH and redox dual-responsive DDS with the ability of pH-responsive surface charge generation was developed by Thayumanavan et al.

49

In this work, two disparate supramolecular assemblies of very different stimuli-sensitive

characteristics were brought together to composite the nanostructures with a block copolymer micelle 21


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core and nanogel shell, as shown in Figure 12. The block copolymer was based on poly(2-(diisopropylamino)ethylmethacrylate-b-2-aminoethylmethacrylate

hydrochloride),

which

contains a pH-sensitive DPA moieties. And the redox-sensitive nanogel was derived from a poly(oligoethyleneglycolmonomethylethermethacrylate-co-glycidylmethacrylate-co-pyridyldisulfide ethylmethacrylate). Composite nanostructures could obtain via the reaction of the amine moiety in micelles and the epoxide ring in nanogels. As discussed above, when the pH was reduced to 6.5, a voluminous amine moiety in the micelles was protonated and decreased the hydrophobicity of the block, resulting the micelle at the core disassembled. Since the nanogels were covalently attached to the block copolymer micelle, the dissociation of the micelle at the core made the positively charged protonated tertiary amine block on the surface of the nanogels. Besides, the disulfide bonds in the nanogels could be reduced by GSH, resulted in an uncrosslinking of the nanogel, and released guest molecules. The independent response to two different triggers of this system could be utilized in areas such as theranostics and dual drug delivery.

Figure 12. Fabrication of the composite nanostructure assembly and its disassembly stimulated by pH and GSH. Reproduced with permission from ref. 49. Copyright 2014 Royal Society of Chemistry. 2.1.2.3 Other multi-responsive nanogel As discussed above, the special properties of HA make it very promising as ligand to develop DDSs for anti-cancer drugs. Jayakumar et al. tried the application of HA with chitin, an amino polysaccharide that is biocompatible, biodegradable and non-toxic, to develop targeted drug delivery 22


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systems.50 They also used Cys to make chitin-HA composite nanogels redox responsive. These dual responsive nanogels were loaded with DOX and targeted for delivery to colon cancer cells, showing higher in vitro drug release in the presence of glutathione and more toxicity towards CD-44+ve cells (HT-29 cells). A triple responsive and biodegradable nanogel, functionalized with galactose as targeting ligand, was designed to delivery anti-tumor drug DOX.51 This PVCL-based nanogels comprised an interior BAC-cross-linked polymer network formed by copolymerizing of temperature-sensitive PVCL and pH sensitive poly(methacrylic acid), and a PEG-rich corona to stabilize the particles. High drug load content could obtain by effectively encapsulate DOX via electrostatic interaction. DOX could be quickly released in acidic or redox environment, but keep stable in physiological condition. Likewise, another pH, thermal, and redox potential triple-responsive expansile nanogel system (TRN) was reported by Nieminen et al.52 Based on the poly[(2-(pyridin-2-yldisulfanyl)-co-[poly(ethylene glycol)]] (PDA-PEG) polymer, which showed self-expanding property in reducing environment, a thermal responsive polymer, PNIPAm, was incorporated into the PDA-PEG by free radical polymerization. The resulted TRN could swells quickly from 108 nm to over 1200 nm (in diameter) at acidic pH, body temperature, and reducing environment within 2 h. Further targeting functionalization of TRN can effectively target head and neck tumor and help Pc4 achieve enhanced photodynamic therapy efficacy. Based on our study of the protease/redox/pH stimuli responsive PEGlated PMAA nanogels,44 we found that the covalently grafted PEG and FA could enhance their long in vivo circulation lifetime and active targeting ability to the tumor cells and tissues. The good biocompatibility of the related nanogels was also found with LD50 of 499.7 mg/kg in acute toxicity study. 53 3. APPLICATION OF NANOGELS IN DIAGNASTIC SYSTEM 3.1 Application of nanogels in diagnostic system 3.1.1 Nanogels with magnetic resonance imaging system

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Magnetic resonance imaging (MRI) is one of the most important and efficient tools in clinical diagnostic, especially for the early diagnosis of cancer, due to its advantages of high anatomical resolution with unlimited tissue depth and soft tissue contrast. However, relative insensitivity is a defect in MRI, so tailored contrast agents (CAs) are usually required. The CAs can affect 1H signals of surrounding water and thus highlight anatomical and pathological features in the imaged tissues by enhancing images contrast.54 SPIONs, causing protons in their vicinity to undergo spin-spin relaxation and produce “negative” (or dark) MR images, usually have the function as T2 MR contrast agents. Clusters of SPIONs coated with a pH-responsive hydrogel are reported to increase image contrast in an MRI measurement. This unique architecture is shown to enhance the transverse relaxation rate by up to 85% compared to clusters without coating, because that the lower diffusivity of water inside the coating and near the particle surface prolonged the interaction between the water protons and the high magnetic fields near the particle. In addition, a clear increase in relaxivity could be observed as the coating swelled responding to pH.55 Another system based on SPIO for highly efficient, T1 and T2 dual-mode MRI imaging was synthesized by assembling SPIO into polysaccharide nanogels, followed by in-situ reduction of the manganese species on the nanogels and a final mild polymerization (Figure 13). The resulted hybrid SPIO@GCS/acryl/biotin@Mn-gel (SGM) showed pH-responsive feature. With both T1 and T2 relaxivities turned “ON”, an increase in the r1 and r2 relaxivity values by 1.7-fold (from 8.9 to 15.3 mM-1 S-1) and 4.9-fold (from 45.7 to 226 mM-1 S-1) was found in acidic environment, due to desirable silencing and de-silencing effects. In vivo MRI results further verified the tumor acidity responsiveness of this smart nanogel, with both significantly brightened signal of tumor tissue in T1-weighted MR images and a darkened signal in T2-weighted MR images 50 min post-injection of SGM. 56

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Figure 13. Fabrication of SGM and its smart dual-mode MRI that results from the responsive Mn ion release. Reproduced with permission from ref. 56. Copyright 2015 American Chemical Society. Paramagnetic materials such as gadolinium (Gd) complexes and manganese (Mn) oxide nanoparticles, facilitating the spin-lattice relaxation of protons and causing a “positive” (or bright) MR image, usually function as T1 MR contrast agents. A novel Gd-chelated hydrogel-lipid hybrid nanoparticle

(HLN)

was

developed

using

thermal

responsive

poly(N-isopropylacrylamide-coacrylamide) (NIPAM-co-AM) nanogels crosslinked by Gd3+ chelated bisallylamidodiethylenetriaminetriacetic acid. These Gd-based nanogels were loaded into a larger hydrophobic solid lipid nanoparticle matrix to shield the T1-weighted contrast signal enhancement at low temperature (

Biodegradable Smart Nanogels: A New Platform for Targeting Drug

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