Inorganic Nanoparticle-Based Drug Codelivery Nanosystems To

Nov 13, 2013 - on the drug codelivery nanosystem based on the recently developed inorganic material-based DDSs to overcome the. MDR of cancer cells...
0 downloads 0 Views 3MB Size
Review pubs.acs.org/molecularpharmaceutics

Inorganic Nanoparticle-Based Drug Codelivery Nanosystems To Overcome the Multidrug Resistance of Cancer Cells Yu Chen, Hangrong Chen,* and Jianlin Shi* State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China ABSTRACT: Biocompatible inorganic material-based nanosystems provide a novel choice to effectively circumvent the intrinsic drawbacks of traditional organic materials in biomedical applications, especially in overcoming the multidrug resistance (MDR) of cancer cells due to their unique structural and compositional characteristics, for example, high stability, large surface area, tunable compositions, abundant physicochemical multifunctionalities, and specific biological behaviors. In this review, we focus on the recent developments in the construction of inorganic nanoparticles-based drug codelivery nanosystems (mesoporous SiO2, Fe3O4, Au, Ag, quantum dots, carbon nanotubes, graphene oxide, LDH, etc.) to efficiently circumvent the MDR of cancer cells, including the well-known codelivery of small molecular anticancer drug/ macromolecular therapeutic gene and codelivery of small molecular chemosensitizer/anticancer drug, and very recently explored codelivery of targeting ligands/anticancer drug, codelivery of energy/anticancer drug, and codelivery of contrast agent for diagnostic imaging and anticancer drug. The unsolved issues, future developments, and potential clinical translations of these codelivery nanosystems are also discussed. These elaborately designed biocompatible inorganic materials-based nanosystems offer an unprecedented opportunity and show the encouraging bright future for overcoming the MDR of tumors in clinic personalized medicine and the pharmaceutical industry. KEYWORDS: inorganic nanoparticles, multidrug resistance, cancer, nanotechnology, codelivery

1. INTRODUCTION Cancer is now one of the most serious diseases that can cause high rate of death of patients, and presently the cancer incidence and fatality rates unfortunately show the fast increasing trend due to various inducing factors such as environment pollution and bad living habits.1,2 For the successful cancer treatment, there exist four severe issues those need to be addressed: diagnosis in the late stage, aggressive metastasis, severe multidrug resistance (MDR), and recurrence. Chemotherapy, radiotherapy, and surgical resection are the three mostly adopted clinical therapeutic strategies for cancer therapy, among which chemotherapy, as either the single or adjuvant therapy, is considered as the most effective and promising strategies. However, the MDR of cancer cells can cause 90% chemotherapeutic failure of patients with metastatic tumors, and thus it remains a significant obstacle for the successful chemotherapy of cancer.3 Typically, the MDR of tumor cells, caused by the malfunction of genes, mainly comes from either intrinsic high expression of ATP-binding cassette (ABC) transporter proteins or an acquired resistance in cancer cells by the stimulus of anticancer drugs to overexpress ABC transporters.4,5 Such overexpressed ABC transporters can efflux the anticancer drugs from the cytoplasm of cancer cells to reduce their accumulation within cells and subsequently cause the extremely low therapeutic outcome. Although ABC transporters are the most extensively studied mechanism of © 2013 American Chemical Society

MDR, the major mechanisms are rather complicated, which can be specially divided into at least six categories, including decreased drug influx, increased drug efflux (e.g., Pglycoprotein), sequestration of drugs within intracellular organelles, activation of DNA repair, detoxification/inactivation of apoptosis pathways (e.g., B-cell lymphoma), and activation of immune response.6,7 The clinical strategy to overcome the MDR of cancer cells is to employ highly elevated drug doses or MDR modulators (e.g., verapami, cyctosporin A, phenothiazines),8 which will, unfortunately cause indispensible high toxicity and severe toxic side effects but very limited efficacy. The development of drug delivery systems (DDSs) can improve the anticancer indexes by changing the toxicity profiles of conventional chemotherapeutic agents,9−12 and can potentially overcome the prevalent MDR problems in cancer chemotherapy.7,13−17 For instance, intracellular drug delivery mediated by nanoparticles (NPs) can efficiently circumvent the drug efflux pumps located on the membranes of cancer cells due to the typical endocytic pathways of NPs, while the cellular uptake of free anticancer Special Issue: Drug Delivery and Reversal of MDR Received: Revised: Accepted: Published: 2495

October 9, 2013 November 11, 2013 November 13, 2013 November 13, 2013 dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 1. General introduction of inorganic NPs-based codelivery nanosystems. Schematic illustration of inorganic NPs-based codelivery nanosystems to circumvent the MDR of cancer cells. The currently available integrated components within inorganic nanosystems include targeting moiety, anticancer drug, therapeutic gene, energy, and contrast agent. The codelivery of two or even multiple components can efficiently overcome the MDR based on the elaborate design of the inorganic nanocarriers and different synergistic mechanisms. Selected representative TEM images of inorganic nanosystems suitable for drug codelivery, including MSNs (b), magnetic NPs (c), Au nanorods (d), and nanographene oxides (e). Reproduced with permission from ref 46. Copyright 2011, Nature Publishing Group. Reproduced with permission from ref 54. Copyright 2013, Elsevier.

and some special synthetic biomacromolecules,36,37 biocompatible inorganic NPs exhibit some distinguishing compositional and structural features for the construction of codelivery nanosystems to circumvent the MDR.38,39 For instance, inorganic NPs can be easily endowed with well-defined nanoporous structures by soft-templating method for the encapsulation of drug combinations (e.g., MSNs: mesoporous silica nanoparticles, Figure 1b).40−43 In addition, inorganic NPs exhibit intrinsic physicochemical properties to transfer irradiated energy into heat or toxic radicals for hyperthermia, photothermal, or photodynamic therapy, such as magnetic NPs for alternating magnetic field-induce hyperthermia (Figure 1c)44,45 and NIR laser-induced photothermal therapy (e.g., Au nanorods, Figure 1d; nanographene oxide, Figure 1e).46−48 Besides, these multifunctional NPs have been demonstrated as the high-efficient contrast agents for diagnostic imaging.49−52 The abundant surface chemistry of inorganic NPs can be further modified for anchoring the targeting moieties to construct organic/inorganic hybrid nanosystems for organellespecific delivery of therapeutic agents.22,23,53 Therefore, the development of inorganic material-based nanosystems is expected to substantially extend the list of drug codelivery nanosystems from traditional organic nanosystems to inorganic or even organic/inorganic hybrid nanosystems. This comprehensive review aims to introduce the most recent developments of inorganic NPs-based codelivery nanosystems for overcoming the MDR of cancer cells, and some important issues concerning their current obstacles, future developments, and clinical translations are also included.

drugs is generally diffusion-controlled, causing the fact that they can be easily pumped out by drug efflux ABC transporters.18−20 In addition, the codelivery nanosystem that delivers the inhibitors/modulators against drug efflux pump to avoid the efflux by P-glycoprotein (P-gp)17 or targeted delivery of anticancer agents into specific organelles21−24 can efficiently circumvent the MDR of cancer cells. One of the most developed approaches to reverse the MDR is to design and construct a codelivery nanosystem that can concurrently inhibit the action or reduce the expression of the transporters and enhance the activity of anticancer drugs afterward.25−28 These codelivery nanosystems can circulate within the blood vessel and penetrate into the tumor tissue by the enhanced permeability and retention (EPR) effect and/or receptor-medicated active targeting (Figure 1a). The cargoloaded nanosystems are then endocytosized into cancer cells to release the multiple drugs, initiating the synergistic therapy. The most-established codelivery cargos available in literature can be the two or multiple combinations of targeting moiety, anticancer drug, therapeutic gene, energy, and contrast agent. The organic material-based codelivery nanosystems to overcome the MDR have been summarized by several excellent reviews.7,13,17,29 Comparatively, these have been no reviews about the inorganic NPs-based codelivery nanosystems to circumvent the MDR up to now because the related research is now still in its infancy. The rapid development of this research field, however, encourages us to give a comprehensive review on the drug codelivery nanosystem based on the recently developed inorganic material-based DDSs to overcome the MDR of cancer cells. Compared to traditional organic nanosystems, such as emulsion,30,31 liposome,32,33 albumin,34,35 2496

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 2. MSNs as the siRNA/anticancer drug codelivery nanosystem. (a) Schematic illustration of codelivering Dox and Bcl-2-targeted siRNA based on dendrimer-modified MSNs for synergistic chemotherapy. Reproduced with permission from ref 63. Copyright 2011, Wiley-VCH Verlag GmbH & Co. KGaA. TEM images of phosphonate-modified MSNs before (b) and after (c) coating with 10 kD PEI polymer. Confocal images (d) and cell viabilities (e) of KB-V1 cells after the treatment with free Dox, Dox-MSNs, PEI-Dox-MSNP, and siRNA-PEI-Dox-MSNP. Reproduced with permission from ref 68. Copyright 2010, American Chemical Society. (f) Comparisons of the tumor inhibition effects of P-gp siRNA-Dox-MSNP, saline, empty MSNP, free Dox, free siRNA, Dox-MSNP, and Dox-MSNP containing scrambled siRNA. (g) Photograph of collected tumor tissues of each treatment group. Reproduced with permission from ref 66. Copyright 2013, American Chemical Society.

biomacromolecules such as DNA or siRNA.59−62 To address the nonpumping effect-associated MDR, Chen et al. encapsulated doxorubicin (Dox) within ordered mesopores of MSNs and Bcl-2-targeted siRNA on the outer surface of generation 2 (G2) amine-terminated polyamidoamine (PAMAMP) dendrimers-modified MSNs to reverse the MDR of A2780/AD human ovarian cancer cells.63 Bcl-2 protein is an integral outer mitochondrial membrane protein and one of the main antiapoptotic defense proteins causing the MDR.2 The Bcl-2 siNRA can effectively silence the Bcl-2 mRNA and inhibit the expression of Bcl-2 proteins, resulting in the suppressed nonpump Dox resistance and substantially enhanced Dox cytotoxicity against MDR cancer cells (Figure 2a). The same strategy and mechanism on the codelivery of siRNA and Dox to suppress Bcl-2 protein expression and induce the synergistic chemotherapeutic efficacy were also successfully realized based on polyethyleneimine (PEI)-modified nanographene oxide (NGO), a biocompatible carbon material with a two-dimensional structure and high surface area.64 Major progress on inhibiting the expression of drug efflux ABC transporters based on MSNs has been made by Zink et al.67,68 They modified the negatively charged surface of phosphonate-modified MSNs (Phos-MSNP, Figure 2b) with PEI (PEI−Phos-MSNP, Figure 2c), a widely accepted polymer with positive charge, via a general electrostatic interaction for gene delivery/transfection. Thus, negatively charged P-gp siRNA can be anchored onto the MSNs’ surface via electrostatic interaction, while small molecular Dox can be encapsulated within the mesopores.67,68 Such a codelivery nanosystem can knockdown the expression of pumping effectassociated transporter P-gp to restore the Dox sensitivity against KB-V1 cells. Much stronger red fluorescence representing Dox could be observed within KB-V1 cells (Figure 2d) after

2. CODELIVERY OF ANTICANCER DRUG COMBINATIONS 2.1. Codelivery of Small Molecular Anticancer Drug and Macromolecular Therapeutic Genes. The expression of drug efflux ABC transporters, stress−response proteins, and antiapoptotic factors are the main causes of MDR phenotype, among which the overexpression of cell-surface glycoprotein (P-gp) is the most encountered factor of MDR.4 Such transport proteins can promote the drug efflux from the cell or sequester the drug molecules from cellular vesicles. Thus, the drugs are eliminated from cytoplasm by exocytosis to cause the MDR. Down-regulating or replacing the mutated genes and/or knockdowning the overexpressed proteins using antisense oligonucleotides (AODNs) or small interfering RNAs (siRNAs) modulators is an efficient route to mitigate or circumvent the MDR. Currently, the most representative and developed approach to achieve this goal is to codeliver gene-based modulators and anticancer drug, respectively, for silencing the expression of drug efflux transporters and inducing the apoptosis and death of cancer cells. The knockdown of the drug efflux transporters’ expression can restore the intracellular drug concentrations and decrease the drug thresholds required for inducing the cell apoptosis and cytotoxicity. Compared with traditional organic nanocarriers, inorganic material-based nanosystems possess a large surface area, which provides large amounts of anchoring points for drug molecules and therapeutic genes. Especially, MSNs are considered as an excellent platform for multicomponent drug administrations,55−57 especially for the codelivery of small molecular anticancer drug and macromolecular therapeutic genes.40,58 The well-defined mesopores provide the reservoirs for anticancer drug molecules, and the outer organic functional group-modified surface of MSNs provides the anchors for 2497

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 3. MSNs-based codelivery of chemosensitizer and anticancer drug. (a) The comparison of two typical routes between traditional MSNs-based DDSs by the postloading process and the proposed MSNs by the in situ coloading of drugs. (b) TEM image of Dox@CTAB@MSNs. (c) In vitro pH-responsive Dox release from Dox@CTAB@MSNs under different pH values. Cytotoxicity of free drugs (d) and Dox@CTAB@MSNs (e) after the coincubation with MCF-7/ADR cells for 3 days. (f) Intracellular ATP levels in MCF-7/ADR cells after the coincubation with MSNs, free drugs, and Dox@CTAB@MSNs. Reproduced with permission from ref 71. Copyright 2011, Elsevier.

release. Although several recent reports has demonstrated the possibility of gene delivery by loading gene molecules into large pores,69,70 the incorporation of gene within the nanopores for drug/gene codelivery has not been achieved due to the synthetic difficulty of nanoporous materials with concurrent large enough pore sizes and small enough particle sizes. It is anticipated that employing well-defined nanoporous channels for the codelivery of anticancer drug and gene may achieve the enhanced therapeutic outcome and index. 2.2. Codelivery of Chemosensitizer and Small Molecular Anticancer Drug. Although the gene interfering to inhibit the drug transporter function and modulate the transporter expression has been demonstrated as an effective route to circumvent the MDR of cancer cells, the clinical cancer MDR is usually much more complicated due to some less defined mechanisms. Therefore, gene interfering is only suitable for some specific cases with clearly known mechanisms, and the high cost of gene therapy restricts its further clinical scale promotion. The design of codelivery nanosystem containing combinatorial cytotoxic anticancer agents with different mechanisms has been demonstrated as an alternative route to enable higher level of chemotherapeutic efficacy.15 The auxiliary anticancer agents can be defined as the chemosensitizer to promote the other drug’s anticancer efficacy. We have recently developed a double drug-loaded MSNs using surfactant micelles (cetyltrimethylammonium bromide, CTAB) as the chemosensitizer and Dox or CPT as the anticancer agent, which were formed via a micelles-MSNs selfassembly mechanism.71,72 The surfactants, such as CTAB, Tween 80, Triton X-100, P123, F127, Nonidet P-40, dodecyltrimethylammonium bromide (DTAB), and sodium dodecyl benzene sulfonate (SDBS), could not only form the micelles to encapsulate typical anticancer drugs but also can function as the chemosensitizer for synergistically overcoming the MDR in cancer (Figure 3a and b). The Dox molecules trapped within surfactant micelles exhibited the unique pH-

the coincubation with Dox/siRNA-loaded MSNs compared with either free Dox or Dox-loaded MSNs, indicating the lowered Dox pumping effect due to the inhibition of P-gp protein expression. The IC50 value of Dox/siRNA-delivering MSNs was nearly 2.5 times lower than IC50 of free Dox or Doxloaded MSNs (Figure 2e), demonstrating the efficient synergistic therapy between Dox and siRNA against P-gpinduced MDR cancer cells.68 Zink et al. further investigated the codelivery of P-gp siRNA and Dox to inhibit the Dox-resistant MCF-7/ADR tumor growth in a mouse xenograft model.66 The polyethyleneimine− polyethylene glycol (PEI-PEG) was initially grafted onto the surface of MSNs, by which the PEI segment can be used for anchoring siRNA molecules, while the PEG part can improve the suspension stability of NPs in physiological environment to prolong the blood circulation time and enhance tumor accumulation of NPs via the EPR effect. The specific siRNA can be attached onto the surface of PEI−PEG-modified MSNs by an electrostatic interaction, and siRNA can be efficiently protected and delivered into tumor tissues following intravenous administration. It was found that P-gp siRNA−Dox− MSNP exhibited a significantly enhanced inhibition rate (Figure 2f and g) over tumor growth (80%) compared with free Dox (17%), Dox-MSNP (62%), and Dox-loaded MSNPs with scrambled siRNA (62%). This result provides strong evidence that the introduction of P-gp siRNA can restore the in vivo sensitivity and cytotoxicity of Dox in a MDR xenograft. Western blotting analysis demonstrated that this synergistic therapeutic effect resulted from the in vivo P-gp knockdown to restore the sensitivity and cytotoxicity of Dox against cancer cells.66 It is noted that the macromolecular therapeutic genes are typically loaded on the as-modified surface of porous NPs, which does not take the advantage of porous materials for the encapsulation and protection of therapeutic gene molecules to avoid the RNase degradation and their sustained/controlled 2498

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 4. Hollow MSNs as the codelivery nanosystem of two anticancer drug combination. (a) Schematic illustration of HMSNs for the codelivery of hydrophobic and hydrophilic anticancer agents and their similar function as compared to liposomes. TEM (b) and SEM (c) images of HMSNs; CLSM images of MCF-7/ADR cells after coincubation with Dox/CPT−HMSNs (d: blue fluorescence representing CPT, e: red fluorescence representing Dox, f: merged image of d and e); (g) Cell viabilities of free Dox, Dox-HMSNs, and Dox/CPT−HMSNs against MCF-7/ADR cells for 48 h coincubation. Reproduced with permission from ref 65. Copyright 2012, Wiley-VCH Verlag GmbH & Co. KGaA.

than free Dox (21.7%, up to 5 μg/mL DOX) and Dox− HMSNs (47.3%, up to 5 μg/mL DOX), respectively. This enhanced therapeutic outcome of MDR overcoming was attributed to the effects of bypassing the P-gp induced efflux action and CPT-enhanced cytotoxicity of the Dox/CPT− HMSNs codelivery nanosystem. 65 The same enhanced therapeutic efficacy based on the codelivery of CPT and Dox was also achieved by coloading of these two drug combinations onto the surface of folic acid (FA)-modified nanographene oxide (NGO) for targeted drug delivery against MCF-7 breast cancer cells.78 The significant progress based on MSNs for the codelivery of combinatorial anticancer drugs has been made by Brinker et al.79 They coated a liposome layer onto the surface of MSNs, followed by modification with targeting fusogenic peptide (SP94) and PEG to construct a protocell-like organic/inorganic hybrid nanosystem.79 A chemotherapeutic drug cocktail with Dox, 5-fluorouracil, and cisplatin was further loaded within this special protocell. The results showed that only one SP94targeted DOPC protocell was needed to kill a Hep3B cell with an induced MDR1 phenotype while keeping more than 90% hepatocyte cell viable due to the targeting efficiency. The traditional DOPC and DSPC liposomes could not realize the coloading of these drug combinations while only the single loading of Dox, 5-fluorouracil, or cisplatin individually could not reach the high therapeutic efficiency and the selective cytotoxicity against Hep3B cells.79 This first report about MSNs-based delivery vehicles for the concurrent targeted and multicomponent delivery strongly demonstrates the possibility of controlling the compositions and structures of inorganic nanosystems for biomedical engineering, especially for circumventing the MDR of cancer cells. Besides MSNs, Chen et al. coloaded daunorubicin (DNR) and 5-bromotetrandrin (Br Tet) with magnetic iron oxide NPs (DNR/Br Tet-MNPs) for the sustained release of anticancer drugs and overcoming the MDR of cancer cells.80 The introduction of DNR/Br Tet-MNPs can significantly induce

responsive drug releasing performance (Figure 3c), and high anticancer efficacy against MCF-7/ADR cancer cells (Figure 3d and e), which was proved to be a synergistic cell cycle arrest/ apoptosis-inducing effect resulting from the chemosensitization of the surfactant, such as CTAB. The intracellular adenosine triphosphate (ATP) level in MCF-7/ADR cells after the coincubation with Dox−CTAB−MSNs showed the significant reduction compared to MSNs, free Dox, and CTAB−MSNs (Figure 3f), indicating that the Dox/CTAB-co-loaded MSNs could impair the mitochondrial functions of MCF-7/ADR cells by a special ATP-inhibiting effect, leading to the much reduced drug efflux capability of P-gp because the drug efflux process via P-gp is energy (ATP)-driven.71 Hollow mesoporous silica nanoparticles (HMSNs) can easily realize the coloading of hydrophilic and hydrophobic small anticancer molecules with high loading capacity due to their unique hollow nanostructure and mesoporosity.65 The hydrophilic mesopore surfaces are more suitable for the encapsulation of hydrophilic molecules in mesopore channels, while the large hollow interior can function as the reservoir for the loading of hydrophobic agents.18,73 The functions of HMSNs for the codelivery of hydrophobic and hydrophilic agents are very similar to the traditional liposomes for the codelivery of drug combinations (Figure 4a). Uniform HMSNs with spherical morphology and tunable hollow structures can be easily fabricated via a silica-etching chemistry (Figure 4b and c).74−77 By coloading hydrophobic camptothecin (CPT) and hydrophilic Dox, it was found that, by using CLSM (Figure 4d−f) both CPT (Figure 4d, blue fluorescence) and Dox (Figure 4e, red fluorescence) could be delivered within Doxresistance MCF-7/ADR cancer cells mediated by HMSNs. Especially, the codelivery of Dox and CPT exhibited significantly enhanced cytotoxicity compared to either free Dox or Dox-loaded HMSNs, demonstrating the high synergistic effect between two anticancer agents (Figure 4g). The anticancer efficiency of Dox/CPT−HMSNs could reach 62.8% (1.25 μg/mL Dox) in 48 h incubation, much higher 2499

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 5. Nuclear-targeted drug delivery via MSNs. (a) Schematic illustration of nuclear-targeted drug delivery system based on MSNs−TAT to overcome the MDR of cancer cells with enhanced chemotherapeutic efficacy. (b) TEM images of MSNs-TAT; (c) CLSM image of MSNs−TATendocytosized MSNs within the nuclear of MCF-7/ADR cancer cells. (d) Cell viabilities of MCF-7/ADR cells after coincubation with free Dox, Dox−MSNs, and Dox−MSNs−TAT after coincubation for 48 h. Reproduced with permission from ref 22. Copyright 2013, Elsevier.

the 25−50 nm particle size conjugated with TAT peptide (Figure 5b) have been proved to be suitable for transporting across nuclear membrane. Intranuclear accumulation of MSNsTAT could be directly observed in CLSM image (green fluorescent dots in Figure 5c). The nuclear-targeted and intranuclear Dox delivery via MSNs-TAT accumulated high level of Dox concentrations in the nuclei, which could not be pumped out by P-gp transporters; thus a significant enhancement in the anticancer activity could be achieved (Figure 5d). Zou et al. designed anti-P-gp antibody-functionalized oxidized single-walled carbon nanotubes (Ap-SWNTs) via a diimide-activated amidation reaction for the targeted delivery of Dox to the P-gp overexpressed MDR human leukemia cells of K562R.53 The anchored anti-P-gp antibody can specifically recognize the overexpressed P-gp on the cell membrane. In addition, a codelivery system with magnetic iron oxide NPs and surface covalently coated carboxymethyldextran (CMDx) can target the epidermal growth factor receptors (EGFR) on cell membrane, then enter the lysosomes to selectively induce lysosomal membrane permeabilization (LMP) under the irritation of an alternating magnetic field.82 This special LMP process can generate the reactive oxygen species to decrease the tumor cell viability, which can avoid the typical MDR

the apoptosis of drug resistant human leukemia K562/A02 cells. The reverse transcriptase polymerase chain reaction (RTPCR) and Western blotting analysis demonstrate that DNR/Br Tet-MNPs can suppress the gene transcriptions and protein expressions of Bcl-2 and survivin but enhance that of bax and caspase 3. The apoptosis of K562/A02 was induced through elevating the ratio of bax/Bcl-2, activating caspase 3 and inactivating survivin. 2.3. Targeted Delivery: Codelivery of Targeted Ligands and Anticancer Drugs. Targeted delivery of anticancer agents into special organelles, such as nuclei22,23 and mitochondria,24,81 mediated by surface modification or anchoring of targeting moieties has been demonstrated as an efficient approach to avoid the pumping effect of transporters. In addition, the modification of inorganic NPs with targeting ligands is much more feasible than free chemotherapeutics. We have recently reported a novel nuclear-targeted drug delivery system based on TAT peptide-conjugated MSNs (MSNs-TAT) facilitating the nuclear internalization and the release of the encapsulated drugs within nucleoplasm (Figure 5a).22 The presence of TAT peptide facilitates the active nuclear entry of MSNs through the nuclear pore complexes, while the size of the MSNs-TAT is a critical factor in the translocation. MSNs of 2500

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 6. Ag NPs for circumventing the MDR. (a) Schematic illustration of intracellular fate of AgNP-TAT that it is too big to pass through the drug efflux channels in the cell membrane. (b) The P-gp crystal model and its drug efflux channel. (c) The tumor volume changes after various treatments; (d) Photograph of individual tumors after the treatments. Reproduced with permission from ref 21. Copyright 2012, Elsevier.

mechanisms to reverse the MDR of cancer cells. Based on rare earth-doped upconversion fluorescent NPs (NaYF4:Yb3+, Er3+), Lin et al. successfully grafted folic acid (FA) onto the surface of as-synthesized fluorescent NPs for targeted delivery of either platinum(IV) pro-drug83 or Dox84 to achieve enhanced therapeutic efficiency against cancer cells. In addition to traditional therapeutic agents to circumventing the MDR, the intrinsic chemical composition of inorganic NPs can also induce the cell apoptosis and death. Nanosilver (AgNP) has been utilized as a typical nanosystem for clinical antibacterial applications,85 which has been recently demonstrated as the efficient anticancer agent due to the intracellular induction of reactive oxygen species, the JNK pathway activation, and DNA damage.86,87 Huang et al. constructed a cell-penetrating peptide TAT-conjugated Ag NPs (AgNPTAT) to overcome the MDR of B16 melanoma cells.21 The 8-nm-sized AgNP-TAT was too big to be effluxed though P-gp channels in the cell membrane (Figure 6a) because the size of entrance channel was calculated to be 2.2 nm with the widest part of 3 nm based on the P-gp crystal model calculation (Figure 6b). The in vivo results on antitumor growth showed that the AgNP-TAT exhibited a more significant inhibition effect on tumor growth compared to nonmodified AgNP because such a TAT modification could improve the penetrating rate and enhance the cellular uptake of NPs. The AgNP-TAT showed the similar antitumor efficacy while its acquired administration dose was significantly lowered compared to the anticancer drug Dox (Figure 6c and d). Importantly, the histological examination and body-weight monitoring indicated that the administration of Dox could cause the severe toxicity and side-effects, while the treatment with AgNP-TAT caused significantly reduced adverse toxicity,

which also indicates the feasibility for upward adjustment of dosage for improved treatment outcomes.

3. NEWLY EMERGED NANOBIOTECHNOLOGY: CODELIVERY OF ENERGY AND ANTICANCER DRUGS Compared with traditional organic nanocarriers, inorganic material-based nanosystems are featured with distinguished physiochemical properties for biomedical engineering, such as hyperthermia, photothermal therapy, photodynamic therapy, and as the synergistic agents to improve the therapeutic index of high intensity focused ultrasound and radiotherapy.88−93 Very recently, they have been demonstrated as an efficient platform for the codelivery of energy and anticancer agents to circumvent the MDR of cancer cells. Au nanorods (NRs) can efficiently transfer NIR light into local heat due to their unique plasmon resonance absorption for the photothermal therapy of cancer cells. Based on this performance, Liu et al. coated Au NRs within a biodegradable micelle (PEG−PCL−LA) for the concurrent remotely NIRtriggered Dox release and MDR overcoming.94 Dox-loaded Au NRs under NIR light (λ = 808 nm) irradiation could efficiently induce the death of Dox-resistant MCF-7 cells where 38% cell viability was measured at a Dox dosage of 10 μg equiv/mL, but 100% cell viability remained after the treatment with free Dox under the same condition. The IC50 of Dox-Au NRs with NIR light irradiation was 2.4 μg/mL against Dox-resistant MCF-7/ DoxR cells, which was about 6 times lower than that of free Dox and 12 times lower than that of Dox-Au NRs without NIR. This special MDR overcoming is due to the efficient intracellular Dox delivery mediated by Au NPs and fast drug release inside cancer cells upon NIR light irradiation.94 2501

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 7. Nanographene oxide for drug codelivery and photothermal therapy. (a) Thermal images of tumors after the NIR light irradiation (2 W/ cm2 for 120 s). (b) Fluorescence images of tumors of nontargeted PEG-NGO/EPI and targeted PEG−NGO−225/EPI groups (red: EPI, blue: nuclei). (c) Quantitative results of tumor sizes after various treatments (inset: fluorescence images from control and treatment mice). (d) Photographs of representative mice before treatment (left) and 21 days after treatment (right). Reproduced with permission from ref 54. Copyright 2013, Elsevier.

demonstrating the synergistic therapeutic effects by codelivery of heat and anticancer agent. Magnetic NPs possess the intrinsic nature of generating the local heat upon the irradiation of alternative external magnetic field.46,98 Chen et al. coloaded daunorubicin and 5-bromotetrandrine with magnetic Fe3O4 NPs (Fe3O4−MNP−DNR−5BrTet) for combined magnetic hyperthermia and chemotherapy to overcome the MDR of cancer cells.99 It was found that Fe3O4−MNP−DNR−5-BrTet with hyperthermia effect could significantly inhibit the tumor growth, decrease the Pglycoprotein and Bc1−2 expressions, while increasing the Bax and caspase-3 expressions. Thus, the enhanced therapeutic efficiency is attributed to the improved drug accumulation, consequently enhanced apoptosis of cancer cells, and the change in the microenvironment caused by magnetic hyperthermia, which in turn affects the anticancer immunity in vivo. To induce light-responsiveness, Clapham et al. encapsulated a cell impermeable fluorescent dye Alexa546 into streptavidinfunctionalized MSNs.100 Upon light activation, NPs could escape from endosomes due to the endosomes’ membrane damage mediated by reactive oxygen species generated by photoactive compound (Alexa546) during illumination. They further induced stable expression of P-gp−GFP C-terminal fusion protein in wild type LN-229 cells to study the targeting capability of surface-functionalized MSNs. The streptavidin−

Nanographene oxide (NGO) has been extensively explored in biomedical applications due to its high biocompatibility and unique optical adsorption in the near-infrared (NIR) region, which means that NGO can efficiently transfer the NIR light into local heat for photothermal therapy.95−97 Ma et al. constructed a multifunctional codelivery system based on PEGylated NGO by the coloading of epirubicin (EPI) and antiEGFR antibodies (C225) (PEG−NGO−C225/EPI) for the concurrent blocking of EGFR growth signal, targeted chemotherapy, and NIR light-triggered (λ = 808 nm) photothermal therapy.54 In vivo results showed that the temperature of tumor could be raised to 88 °C in 120 s NIR light irradiation in PEG− NGO−C22/EPI-treated group (Figure 7a), demonstrating the high in vivo photothermal effect. The enhancement of targeted delivery efficacy was directly observed by fluorescence imaging (Figure 7b). Much larger amounts of targeted PEG−NGO− C225/EPI could be found within tumor tissue compared to that of nontargeted PEG−NGO/EPI (∼6.3 fold). Free EPI almost had no inhibition effect on tumor growth due to the MDR of cancer cells while PEI-loaded PEG−NGO−C225 could efficiently enhance the EPI chemotherapeutic efficacy. Especially, PEG−NGO−C225/EPI combined with NIR light irradiation (2 W/cm2) not only inhibited the tumor growth but also almost completely erased the tumors (Figure 7c and d), 2502

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 8. CNTs for stimuli-responsive drug release and overcoming the MDR. (a) Schematic illustration of filling payload and gelatin into nanotubes. The payload is first encapsulated into the nanotube array by the vacuum suction at the side of the template followed by the release of Trojan-Horse nanotubes based on the chemical dissolution of AAO template. The payload can be released from the nanotubes by exposing the Trojan-Horse nanotubes to the a.c. magnetic field. (b) In vitro cytotoxicity after CNT treatment. (c) A histone-DNA ELISA assay was conducted to evaluate L3.6 cell apoptosis under different conditions for 36 h treatment. Reproduced with permission from ref 101/ Copyright 2012, American Chemical Society.

MSN conjugates could efficiently target P-gp overexpressing cells. Further illumination on cells can cause the significant dye releasing within P-gp overexpressed cells, while nontargeted cells exhibited no such effect due to the low uptake of NPs. This strategy combines the advantages of targeted drug delivery and temporal control of light activation and thus can bypass the efflux by the P-gp transporter to potentially circumvent the MDR of cancer cells. For stimuli-responsive drug release, Marshall et al. developed a carbon nanotube (CNT)-based on-command drug codelivery system by utilizing a unique physical characteristic of CNTs.101 The CNTs synthesized from AAO templates are intrinsically conductive but possess a high electrical resistivity, which can generate eddy currents and consequential resistive heat via alternating current (a.c.) magnetic field induction. By incorporating a temperature-sensitive hydrogel mixed with drug combinations (paclitaxel and C6-ceramide), the surface tension and viscosity keeps the gel-drug payload inside the tube. After the irradiation of a.c. magnetic field, the inductive heating could cause the phase transformation of temperature sensitive hydrogel to release the loaded drug combinations (Figure 8a). In vitro results against highly drug-resistant pancreatic cancer cells revealed that the a.c. magnetic field could induce the release of Taxol/C6-ceramide from the Trojan-Horse CNTs to cause over 70% cell death, while cells remained almost 100% viability without such a magnetic field activation (Figure 8b). The histone-DNA assay demonstrated that the cells treated with [CNTs + Taxol (0.03 μg/mL) + C6ceramide (0.1 μg/mL)] combined with a.c. magnetic field could achieve similar therapeutic efficacy as the cells received a 100fold higher dose of exogenous Taxol/C6-ceramide (Figure 8c).

This report gives an alternative approach to use the energy for the corelease of drug combinations with an intelligent oncommand manner.

4. THERANOSTIC: CODELIVERY OF CONTRAST AGENTS AND ANTICANCER DRUGS The development of nanobiotechnology can realize the concurrent diagnostic imaging and the MDR reversing of cancer cells based on the elaborately designed multifunctional nanocarriers by advanced nanosynthetic chemistry.102,103 The fabricated multifunctional nanocarriers can deliver the therapeutic agents into the targeted lesion tissues, reversing the MDR of cancer cells, inducing the apoptosis/death of cancer cells and in situ monitoring the evolution of diseases. Recently, we functionalized HMSNs with MnOx NPs by an in situ redox reaction within mesopores for simultaneous pHresponsive T1-weighted magnetic resonance imaging (MRI) and anticancer drug delivery to overcome the MDR of cancer cells.104 The MnOx NPs dispersed within the mesopores disintegrated in a tumor mild acidic environment to enhance the T1-weighted MR imaging, and the hollow nanostructures and well-defined mesopores can function as the reservoirs for the large capacity-storage of anticancer agents (Figure 9a and b). In vivo MR imaging (Figure 9c−g) of tumor tissues showed that a significant T1-weighted positive MR imaging can be achieved after intravenous administration of MnOx−HMSNs caused by the EPR effect. The leakage out of Mn2+ by MnOx disintegration can cause continuous positive contrast enhancement of tumor tissues due to the mild acidic environment in tumor tissues. Substantial cellular uptake of Dox-loaded MnOx−HMSNs could be determined by cytometric analysis 2503

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Figure 9. MnOx−HMSNs for concurrent T1-weighted MRI and overcoming the MDR. (a) Schematic illustration of the microstructure and structure-related theranostic functions of MnOx−HMSNs. (b) TEM images of MnOx−HMSNs. In vivo T1-weighted MR imaging of tumor before (c) and after intravenous administration of MnOx-HMSNs (d: 5 min, e: 15 min, f: 30 min and g: 60 min). (h) The mean fluorescence intensity of Dox within MCF-7/ADR cells at three different coincubation Dox concentrations and three different incubation durations by the introduction of free Dox and Dox-loaded MnOx-HMSNs; MCF-7/ADR cell viabilities after the incubation with free Dox and Dox-loaded MnOx−HMSNs for different time durations (i: 24 h and j: 48 h). (k) The amount of P-gp expression determined by flow cytometry after the incubation with MnOx−HMSNs at elevated concentrations. Reproduced with permission from ref 104. Copyright 2012, Elsevier.

Figure 10. QDs for drug codelivery and fluorescent imaging. Schematic illustration of siRNA-adsorption and Dox-loading onto L-amino acid-β-CDmodified QDs and using the QDs-based codelivery system for MDR1 siRNA and Dox to circumvent the MDR of cancer cells. Reproduced with permission from ref 109. Copyright 2012, Elsevier.

2504

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

5. CONCLUSIONS AND FUTURE DIRECTIONS The repeated administrations of drugs in patients will inevitably result in drug expulsion and MDR of cancer cells during the chemotherapeutic process, causing the necessary dose escalation for eradicating the malignant cells. The multicomponent drug administration has increasingly become a versatile strategy of great significance clinically because the encapsulation of optimized drug combinations into one system may bring about the synergistic therapeutic effects to reverse the MDR of cells compared to the delivery of a single therapeutic agent. In addition, the codelivery of therapeutic and contrast agents can realize the concurrent theranostic function and overcoming of the MDR. Especially, the easily controlled nanostructures, abundant compositions, and diverse physicochemical multifunctionalities of inorganic nanomaterials provide an excellent platform for the codelivery of diverse agents for overcoming the MDR. However, several significant issues should be considered and addressed seriously before translating these inorganic NPs-based codelivery nanosystems into the clinical stage (Figure 11). The first important issue is the biocompatibility regarding the selection of inorganic nanosystems. Compared with the welldeveloped organic nanomaterials, the clinical translation of

(Figure 9h) compared to free Dox within Dox-resistant MCF7/ADR cancer cells. Such high Dox accumulations within cancer cells caused a substantially enhanced therapeutic outcome against MCF-7/ADR cells (Figure 9i and j) because Dox-loaded MnOx−HMSNs can sidestep the drug resistance mechanisms by the endosomal delivery of chemotherapeutic agents. It was also indicated that the coincubation of MnOx− HMSNs could inhibit the P-gp expression (Figure 9k), which was both dose- and time-dependent. In addition, the introduction of MnOx−HMSNs can reduce the adenosine triphosphate (ATP) levels, and the Dox-loaded MnOx− HMSNs were too large to be effluxed by the MDR transporters due to the strict size limitations of pumping substrates by P-gp protein (in the range of 300−2000 Da).21 Thus, the MDR overcoming mechanism could be attributed to the special endocytosis-type cell uptake, P-gp inhibition, and ATP depletion. For T2-weighted MRI, Chen et al modified the surface of hollow iron oxide NPs (HIONPs) by a special dopamine-plushuman serum albumin (HAS) method.105 The HAS modified HIONPs can not only act as the drug carriers for Dox but also can function as the contrast agents for T2-weighted MR imaging. In addition, the hollow structure of HIONPs endows them with enhanced Dox-loading capacity. The OVCAR8-ADR cells were more susceptible to Dox-loaded HIONP (IC50 = 7.2 μg/mL) than to free Dox (IC50 > 10 μg/mL) due to the easy pumping out of free Dox molecules via efflux pump transport but the efficient cell membrane penetration and accumulation effects of Dox-loaded HIONP by endocytosis and phagocytosis. Inorganic QDs have been extensively used for biological fluorescent imaging.106−108 They also provide excellent platforms for the codelivery of therapeutic agents in addition to the capability of real-time tracking or monitoring of the treatment. Mao et al. modified the surface of CdSe/ZnSe QDs with β-CD coupled to L-Arg or L-His (β-CD-L-Arg-QDs or β-CD-L-HisQDs) for simultaneous delivery of Dox and siRNA targeting to MDR1 gene to reverse the MDR of HeLa cells (Figure 10).109 Dox can be encapsulated within the hydrophobic section of NPs, while the L-Arg or L-His modified on particle surface can be utilized for anchoring siRNA. It was found that the MDR1 mRNA expression on HeLa/Dox cells was reduced to 23.2 ± 2.7% by the β-CD-L-Arg-QDs and 18.6 ± 2.5% by the β-CD-LHis-QDs, superior to commercial siPort NeoFX (32.3 ± 2.2%) and HiPerFect (37.5 ± 3.1%). The codelivery of Dox and MDR1 siRNA could cause 3-fold cytotoxicity compared to Dox delivered by non-siRNA binding QDs and nearly 5-fold compared to free Dox. This synergistic therapeutic effect was attributed to the MDR1 gene silencing to suppress the efflux pumping effect by P-gp transporter, which can cause the high drug accumulation within cancer cells and consequently enhanced cell apoptosis and death. Importantly, the intrinsic fluorescence of QDs can be used for the determination of intracellular location of drug carriers and the in situ monitoring for the release of anticancer agents. For theranostic fluorescent imaging, Lin et al. synthesized upconversion NPs-based organic−inorganic hybrid nanosystems for either enhanced cisplatin(IV) delivery110 or thermal-/pH-dependent Dox release.111 The 980 nm laser excitation could produce the upconversion fluorescence for in vitro and in vivo monitoring the uptake of NPs by cells and drug release.

Figure 11. Design strategy for the inorganic material-based codelivery nanosystems and the summary of their current status and future developments. The targeting moieties, therapeutic genes, multiple anticancer drugs, and contrast agents (e.g., magnetic and fluorescent NPs) can be integrated into the matrix of various inorganic nanoplatforms. The nanoporous and hollow nanostructures can be created to enhance the cargo-loading capacity of the carrier, and the surfaces of NPs should be further modified with typical biocompatible macromolecules (e.g., PEG) for improving their physiological stability to satisfy the strict in vivo applications. 2505

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

cancer cells to identify the cell phenotype (sensitive or MDR).124 Such an efficient early MDR diagnosis with good sensitivity and specificity can help the formulation of therapeutic plan or approach. The high in vitro therapeutic index cannot guarantee the same in vivo therapeutic outcome. For the drug codelivery nanosystems, it is still a big obstacle to penetrate the poorly vascularized regions of tumor tissues and to avoid the clearance by reticuloendothelial systems. Therefore, much more efforts should be devoted to controlling the size, morphology, dispersity, and surface modifications, that is, materials optimizations, to satisfy the strict in vivo application requirements, in addition to the elaborate design of the multifunctionality, for the codelivery of drug combinations. Furthermore, much more attention should be focused on the molecular mechanisms of efficient synergistic therapy because different nanocarriers may bring varied mechanisms, by which the drug combinations can be optimized to simplify the carrier design. Furthermore, the interactions between coadministrated agents should be clearly clarified. Much more collaboration between the researchers from different disciplines should be greatly encouraged to promote the clinical translations of these codelivery inorganic nanosystems. Although the development of inorganic nanosystems to circumvent the MDR of cancer cells is still in its preliminary stage, their abundant design/ fabrication strategies and excellent performances, however, will endow them with great clinical application potentials for future personalized healthcare/medicine and pharmaceutical industries.

inorganic nanosystems for drug delivery are still under strong debate due to the lack of enough evidence and data regarding the biosafety, especially the biodegradation behavior, excretion routes, and long-term toxicity assessments, to support their in vivo biosafety. Therefore, the first consideration about the carrier design/selection should be based on the most accepted biocompatible inorganic nanosystems. Currently, the most developed inorganic drug codelivery nanosystems are mainly based on MSNs due to their unique nanoporous features, tunable biodegradable capability, and high corresponding biosafety, which may have the most possibilities for the early clinical translations. Systematic in vivo evaluations have demonstrated the high biocompatibility of MSNs after the investigations of their in vivo biodistribution,112,113 tolerate threshold,114 degradation/clearance,113,115 and hematological/ histological biocompatibility.116 Importantly, the inorganic silica NPs have entered into the clinical human test (stage I) for their potential cancer diagnosis,117 which indicates the great clinical translation potentials of silica-based NPs. Although the preliminary in vivo results show the biocompatibility of graphene and carbon nanotubes at adequate doses,118−120 the toxic effects of carbon nanotubes on the mammalian embryonic development were observed.121 Therefore, the biocompatibility optimization of codelivery carriers is of great significance to reduce their toxicity and determine future clinical translations. Although the development of nanosynthetic chemistry provides the possibility of fabricating multifunctional codelivery nanosystems for biomedical engineering (Figure 11), it should be noted that the construction of codelivery nanosystems typically needs to develop relatively more complex nanosystems with various compositions and nanostructures compared to the delivery of single therapeutic agent. It does not mean that integrating more functionality in one formulation is always beneficial for circumventing the MDR of cancer cells. The evercomplicated integration of more functionalities requires much stricter assessments on the biosafety, indicating the increased cost, enlarged risk, and reduced possibility of clinical translation. For example, the construction of complex theranostic platform for simultaneous diagnostic imaging and overcoming the MDR is the conceptual breakthroughs for the imagingguided chemotherapy, which can in situ monitor the chemotherapy outcome under the suitable imaging modality. However, such composite nanosystems not only need the biocompatibility evaluations of each component, for example, initial supporters and loaded cargos, but also the thorough assessments of integrated whole nanosystems. The present strategies for the synergistic therapy are mainly based on the combinations of conventional genes, chemosensitizers, and chemotherapeutic agents. Other drug combinations, such as photosensitizers and chemotherapeutic agents, and even more multidrug combinations, can be potentially employed for MDR chemotherapy based on chemically engineered inorganic nanoplatforms. Especially, the combination of energy types with anticancer agents can indeed offer a highly efficient nanobiotechnology-based approach for overcoming the MDR, but this research is still in its infancy, and the synergistic mechanism is still unclear to a large extent. In addition to light and heat, the introduction of other energy types, such as clinical ultrasound and X-ray irradiation,122,123 can be potentially employed for the synergistic therapy of MDR. Furthermore, inorganic nanodevices should be developed for the early diagnosis of MDR by electrochemical sensors to assess the functions of cell membrane transporters in MDR



AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS We acknowledge financial support from the National Nature Science Foundation of China (grant no. 51302293, 51132009, 51072212, 21177137), the National Basic Research Program of China (973 Program, grant no. 2011CB707905), China National Funds for Distinguished Young Scientists (grant no. 51225202), Natural Science Foundation of Shanghai (13ZR1463500), Nano special program of the Science and Technology Commission of Shanghai (grant no. 11 nm0506500), and Foundation for Youth Scholar of State Key Laboratory of High Performance Ceramics and Superfine Microstructures (grant no. SKL201203).



REFERENCES

(1) Butler, D. Translational research: Crossing the valley of death. Nature 2008, 453, 840−842. (2) Gao, J.; Feng, S. S.; Guo, Y. J. Nanomedicine against multidrug resistance in cancer treatment. Nanomedicine 2012, 7, 465−468. (3) Luqmani, Y. A. Mechanisms of Drug Resistance in Cancer Chemotherapy. Med. Princ. Pract. 2005, 14, 35−48. (4) Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discovery 2006, 5, 219−234. (5) Gottesman, M. M. Mechanisms of cancer drug resistance. Annu. Rev. Med. 2002, 53, 615−627.

2506

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

(6) Livney, Y. D.; Assaraf, Y. G. Rationally designed nanovehicles to overcome cancer chemoresistance. Adv. Drug Delivery Rev. 2013, DOI: j.addr.2013.08.006. (7) Jabr-Milane, L. S.; van Vlerken, L. E.; Yadav, S.; Amiji, M. M. Multi-functional nanocarriers to overcome tumor drug resistance. Cancer Treat. Rev. 2008, 34, 592−602. (8) Capella, M. A. M.; Capella, L. S. A light in multidrug resistance: Photodynamic treatment of multidrug-resistant tumors. J. Biomed. Sci. 2003, 10, 361−366. (9) Ferrari, M. Cancer nanotechnology: Opportunities and challenges. Nat. Rev. Cancer 2005, 5, 161−171. (10) Wagner, V.; Dullaart, A.; Bock, A. K.; Zweck, A. The emerging nanomedicine landscape. Nat. Biotechnol. 2006, 24, 1211−1217. (11) Peer, D.; Karp, J. M.; Hong, S.; FaroKhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751−760. (12) Cheng, Z. L.; Al Zaki, A.; Hui, J. Z.; Muzykantov, V. R.; Tsourkas, A. Multifunctional Nanoparticles: Cost Versus Benefit of Adding Targeting and Imaging Capabilities. Science 2012, 338, 903− 910. (13) Khan, M.; Ong, Z. Y.; Wiradharma, N.; Attia, A. B. E.; Yang, Y. Y. Advanced Materials for Co-Delivery of Drugs and Genes in Cancer Therapy. Adv. Healthcare Mater. 2012, 1, 373−392. (14) Dong, X. W.; Mumper, R. J. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress. Nanomedicine 2010, 5, 597−615. (15) Hu, C. M. J.; Zhang, L. F. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem. Pharmacol. 2012, 83, 1104−1111. (16) Gao, Z. B.; Zhang, L. N.; Sun, Y. J. Nanotechnology applied to overcome tumor drug resistance. J. Controlled Release 2012, 162, 45− 55. (17) Creixell, M.; Peppas, N. A. Co-delivery of siRNA and therapeutic agents using nanocarriers to overcome cancer resistance. Nano Today 2012, 7, 367−379. (18) Gao, Y.; Chen, Y.; Ji, X. F.; He, X. Y.; Yin, Q.; Zhang, Z. W.; Shi, J. L.; Li, Y. P. Controlled Intracellular Release of Doxorubicin in Multidrug-Resistant Cancer Cells by Tuning the Shell-Pore Sizes of Mesoporous Silica Nanoparticles. ACS Nano 2011, 5, 9788−9798. (19) Wang, F.; Wang, Y. C.; Dou, S.; Xiong, M. H.; Sun, T. M.; Wang, J. Doxorubicin-Tethered Responsive Gold Nanoparticles Facilitate Intracellular Drug Delivery for Overcoming Multidrug Resistance in Cancer Cells. ACS Nano 2011, 5, 3679−3692. (20) Wang, D.; Tang, J. L.; Wang, Y. J.; Ramishetti, S.; Fu, Q.; Racette, K.; Liu, F. Multifunctional Nanoparticles Based on a SingleMolecule Modification for the Treatment of Drug-Resistant Cancer. Mol. Pharmacol. 2013, 10, 1465−1469. (21) Liu, J. H.; Zhao, Y. X.; Guo, Q. Q.; Wang, Z.; Wang, H. Y.; Yang, Y. X.; Huang, Y. Z. TAT-modified nanosilver for combating multidrug-resistant cancer. Biomaterials 2012, 33, 6155−6161. (22) Pan, L. M.; Liu, J. A.; He, Q. J.; Wang, L. J.; Shi, J. L. Overcoming multidrug resistance of cancer cells by direct intranuclear drug delivery using TAT-conjugated mesoporous silica nanoparticles. Biomaterials 2013, 34, 2719−2730. (23) Pan, L. M.; He, Q. J.; Liu, J. N.; Chen, Y.; Ma, M.; Zhang, L. L.; Shi, J. L. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles. J. Am. Chem. Soc. 2012, 134, 5722−5725. (24) Zhang, Z. W.; Liu, Z. Y.; Ma, L.; Jiang, S. J.; Wang, Y. X.; Yu, H. J.; Yin, Q.; Cui, J. B.; Li, Y. P. Reversal of Multidrug Resistance by Mitochondrial Targeted Self-Assembled Nanocarrier Based on Stearylamine. Mol. Pharmacol. 2013, 10, 2426−2434. (25) Shen, J. A.; Sun, H. P.; Xu, P. F.; Yin, Q.; Zhang, Z. W.; Wang, S. L.; Yu, H. J.; Li, Y. P. Simultaneous inhibition of metastasis and growth of breast cancer by co-delivery of twist shRNA and paclitaxel using pluronic P85-PEI/TPGS complex nanoparticles. Biomaterials 2013, 34, 1581−1590. (26) Yin, Q.; Shen, J. A.; Chen, L. L.; Zhang, Z. W.; Gu, W. W.; Li, Y. P. Overcoming multidrug resistance by co-delivery of Mdr-1 and

survivin-targeting RNA with reduction-responsible cationic poly(betaamino esters). Biomaterials 2012, 33, 6495−6506. (27) Saad, M.; Garbuzenko, O. B.; Minko, T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine 2008, 3, 761−776. (28) Chen, Y. C.; Bathula, S. R.; Li, J.; Huang, L. Multifunctional Nanoparticles Delivering Small Interfering RNA and Doxorubicin Overcome Drug Resistance in Cancer. J. Biol. Chem. 2010, 285, 22639−22650. (29) Montesinos, R. N.; Beduneau, A.; Pellequer, Y.; Lamprecht, A. Delivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes. J. Controlled Release 2012, 161, 50−61. (30) Ganta, S.; Amiji, M. Coadministration of Paclitaxel and Curcumin in Nanoemulsion Formulations To Overcome Multidrug Resistance in Tumor Cells. Mol. Pharmaceutics 2009, 6, 928−939. (31) Chavanpatil, M. D.; Khdair, A.; Gerard, B.; Bachmeier, C.; Miller, D. W.; Shekhar, M. P. V.; Panyam, J. Surfactant-polymer nanoparticles overcome P-glycoprotein-mediated drug efflux. Mol. Pharmaceutics 2007, 4, 730−738. (32) Zhao, Y. Z.; Dai, D. D.; Lu, C. T.; Chen, L. J.; Lin, M.; Shen, X. T.; Li, X. K.; Zhang, M.; Jiang, X.; Jin, R. R.; Li, X.; Lv, H. F.; Cai, L.; Huang, P. T. Epirubicin loaded with propylene glycol liposomes significantly overcomes multidrug resistance in breast cancer. Cancer Lett. 2013, 330, 74−83. (33) Goren, D.; Horowitz, A. T.; Tzemach, D.; Tarshish, M.; Zalipsky, S.; Gabizon, A. Nuclear delivery of doxorubicin via folatetargeted liposomes with bypass of multidrug-resistance efflux pump. Clin. Cancer Res. 2000, 6, 1949−1957. (34) Ishima, Y.; Hara, M.; Kragh-Hansen, U.; Inoue, A.; Suenaga, A.; Kai, T.; Watanabe, H.; Otagiri, M.; Maruyama, T. Elucidation of the therapeutic enhancer mechanism of poly-S-nitrosated human serum albumin against multidrug-resistant tumor in animal models. J. Controlled Release 2012, 164, 1−7. (35) Jones, A. K.; Bejugam, N. K.; Nettey, H.; Addo, R.; D’Souza, M. J. Spray-dried doxorubicin-albumin microparticulate systems for treatment of multidrug resistant melanomas. J. Drug Target. 2011, 19, 427−433. (36) Qiu, L. Y.; Zheng, C.; Zhao, Q. H. Mechanisms of Drug Resistance Reversal in Dox-Resistant MCF-7 Cells by pH-Responsive Amphiphilic Polyphosphazene Containing Diisopropylamino Side Groups. Mol. Pharmaceutics 2012, 9, 1109−1117. (37) Gao, Y.; Chen, L. L.; Zhang, Z. W.; Chen, Y.; Li, Y. P. Reversal of multidrug resistance by reduction-sensitive linear cationic click polymer/iMDR1-pDNA complex nanoparticles. Biomaterials 2011, 32, 1738−1747. (38) Kim, C. S.; Tonga, G. Y.; Solfiell, D.; Rotello, V. M. Inorganic nanosystems for therapeutic delivery: Status and prospects. Adv. Drug Delivery Rev. 2013, 65, 93−99. (39) Chow, E. K.; Zhang, X. Q.; Chen, M.; Lam, R.; Robinson, E.; Huang, H. J.; Schaffer, D.; Osawa, E.; Goga, A.; Ho, D. Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment. Sci. Transl. Med. 2011, 3, 73ra21. (40) Chen, Y.; Chen, H.; Shi, J. In Vivo Bio-Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles. Adv. Mater. 2013, 25, 3144−3176. (41) Chen, Y.; Chen, H.-R.; Shi, J.-L. Construction of Homogenous/ Heterogeneous Hollow Mesoporous Silica Nanostructures by SilicaEtching Chemistry: Principles, Synthesis, and Applications. Acc. Chem. Res. 2013, DOI: 10.1021/ar400091e. (42) Shi, J. L.; Chen, Y.; Chen, H. R. Progress on the Multifunctional Mesoporous Silica-based Nanotheranostics. J. Inorg. Mater. 2013, 28, 1−11. (43) Yang, P. P.; Gai, S. L.; Lin, J. Functionalized mesoporous silica materials for controlled drug delivery. Chem. Soc. Rev. 2012, 41, 3679− 3698. (44) Fortin, J. P.; Wilhelm, C.; Servais, J.; Menager, C.; Bacri, J. C.; Gazeau, F. Size-sorted anionic iron oxide nanomagnets as colloidal 2507

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

mediators for magnetic hyperthermia. J. Am. Chem. Soc. 2007, 129, 2628−2635. (45) Kumar, C.; Mohammad, F. Magnetic nanomaterials for hyperthermia-based therapy and controlled drug delivery. Adv. Drug Delivery Rev. 2011, 63, 789−808. (46) Lee, J. H.; Jang, J. T.; Choi, J. S.; Moon, S. H.; Noh, S. H.; Kim, J. W.; Kim, J. G.; Kim, I. S.; Park, K. I.; Cheon, J. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nat. Nanotechnol. 2011, 6, 418−422. (47) Yavuz, M. S.; Cheng, Y. Y.; Chen, J. Y.; Cobley, C. M.; Zhang, Q.; Rycenga, M.; Xie, J. W.; Kim, C.; Song, K. H.; Schwartz, A. G.; Wang, L. H. V.; Xia, Y. N. Gold nanocages covered by smart polymers for controlled release with near-infrared light. Nat. Mater. 2009, 8, 935−939. (48) Mao, H. Y.; Laurent, S.; Chen, W.; Akhavan, O.; Imani, M.; Ashkarran, A. A.; Mahmoudi, M. Graphene: Promises, Facts, Opportunities, and Challenges in Nanomedicine. Chem. Rev. 2013, 113, 3407−3424. (49) Liu, Y. L.; Ai, K. L.; Lu, L. H. Nanoparticulate X-ray Computed Tomography Contrast Agents: From Design Validation to in Vivo Applications. Acc. Chem. Res. 2012, 45, 1817−1827. (50) Hu, F. Q.; Wei, L.; Zhou, Z.; Ran, Y. L.; Li, Z.; Gao, M. Y. Preparation of biocompatible magnetite nanocrystals for in vivo magnetic resonance detection of cancer. Adv. Mater. 2006, 18, 2553− 2556. (51) Lee, J. E.; Lee, N.; Kim, T.; Kim, J.; Hyeon, T. Multifunctional Mesoporous Silica Nanocomposite Nanoparticles for Theranostic Applications. Acc. Chem. Res. 2011, 44, 893−902. (52) Chen, Y.; Chen, H. R.; Zhang, S. J.; Chen, F.; Zhang, L. X.; Zhang, J. M.; Zhu, M.; Wu, H. X.; Guo, L. M.; Feng, J. W.; Shi, J. L. Multifunctional Mesoporous Nanoellipsoids for Biological Bimodal Imaging and Magnetically Targeted Delivery of Anticancer Drugs. Adv. Funct. Mater. 2011, 21, 270−278. (53) Li, R. B.; Wu, R.; Zhao, L.; Wu, M. H.; Yang, L.; Zou, H. F. PGlycoprotein Antibody Functionalized Carbon Nanotube Overcomes the Multidrug Resistance of Human Leukemia Cells. ACS Nano 2010, 4, 1399−1408. (54) Yang, H. W.; Lu, Y. J.; Lin, K. J.; Hsu, S. C.; Huang, C. Y.; She, S. H.; Liu, H. L.; Lin, C. W.; Xiao, M. C.; Wey, S. P.; Chen, P. Y.; Yen, T. C.; Wei, K. C.; Ma, C. C. M. EGRF conjugated PEGylated nanographene oxide for targeted chemotherapy and photothermal therapy. Biomaterials 2013, 34, 7204−7214. (55) Giri, S.; Trewyn, B. G.; Stellmaker, M. P.; Lin, V. S. Y. Stimuliresponsive controlled-release delivery system based on mesoporous silica nanorods capped with magnetic nanoparticles. Angew. Chem., Int. Ed. 2005, 44, 5038−5044. (56) Douroumis, D.; Onyesom, I.; Maniruzzaman, M.; Mitchell, J. Mesoporous silica nanoparticles in nanotechnology. Crit. Rev. Biotechnol. 2013, 33, 229−245. (57) Vallet-Regi, M.; Balas, F.; Arcos, D. Mesoporous materials for drug delivery. Angew. Chem., Int. Ed. 2007, 46, 7548−7558. (58) Slowing, I. I.; Vivero-Escoto, J. L.; Wu, C. W.; Lin, V. S. Y. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv. Drug Delivery Rev. 2008, 60, 1278− 1288. (59) Qin, F.; Zhou, Y. C.; Shi, J. L.; Zhang, Y. L. A DNA transporter based on mesoporous silica nanospheres mediated with polycation poly(allylamine hydrochloride) coating on mesopore surface. J. Biomed. Mater. Res., Part A 2009, 90A, 333−338. (60) Torney, F.; Trewyn, B. G.; Lin, V. S. Y.; Wang, K. Mesoporous silica nanoparticles deliver DNA and chemicals into plants. Nat. Nanotechnol. 2007, 2, 295−300. (61) Radu, D. R.; Lai, C. Y.; Jeftinija, K.; Rowe, E. W.; Jeftinija, S.; Lin, V. S. Y. A polyamidoamine dendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. J. Am. Chem. Soc. 2004, 126, 13216−13217. (62) Kim, M. H.; Na, H. K.; Kim, Y. K.; Ryoo, S. R.; Cho, H. S.; Lee, K. E.; Jeon, H.; Ryoo, R.; Min, D. H. Facile Synthesis of Monodispersed Mesoporous Silica Nanoparticles with Ultralarge

Pores and Their Application in Gene Delivery. ACS Nano 2011, 5, 3568−3576. (63) Chen, A. M.; Zhang, M.; Wei, D. G.; Stueber, D.; Taratula, O.; Minko, T.; He, H. X. Co-delivery of Doxorubicin and Bcl-2 siRNA by Mesoporous Silica Nanoparticles Enhances the Efficacy of Chemotherapy in Multidrug-Resistant Cancer Cells. Small 2009, 5, 2673− 2677. (64) Zhang, L. M.; Lu, Z. X.; Zhao, Q. H.; Huang, J.; Shen, H.; Zhang, Z. J. Enhanced Chemotherapy Efficacy by Sequential Delivery of siRNA and Anticancer Drugs Using PEI-Grafted Graphene Oxide. Small 2011, 7, 460−464. (65) Chen, Y.; Gao, Y.; Chen, H. R.; Zeng, D. P.; Li, Y. P.; Zheng, Y. Y.; Li, F. Q.; Ji, X. F.; Wang, X.; Chen, F.; He, Q. J.; Zhang, L. L.; Shi, J. L. Engineering Inorganic Nanoemulsions/Nanoliposomes by Fluoride-Silica Chemistry for Efficient Delivery/Co-Delivery of Hydrophobic Agents. Adv. Funct. Mater. 2012, 22, 1586−1597. (66) Meng, H.; Mai, W. X.; Zhang, H. Y.; Xue, M.; Xia, T.; Lin, S. J.; Wang, X.; Zhao, Y.; Ji, Z. X.; Zink, J. I.; Nel, A. E. Codelivery of an Optimal Drug/siRNA Combination Using Mesoporous Silica Nanoparticles To Overcome Drug Resistance in Breast Cancer in Vitro and in Vivo. ACS Nano 2013, 7, 994−1005. (67) Xia, T. A.; Kovochich, M.; Liong, M.; Meng, H.; Kabehie, S.; George, S.; Zink, J. I.; Nel, A. E. Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs. ACS Nano 2009, 3, 3273−3286. (68) Meng, H. A.; Liong, M.; Xia, T. A.; Li, Z. X.; Ji, Z. X.; Zink, J. I.; Nel, A. E. Engineered Design of Mesoporous Silica Nanoparticles to Deliver Doxorubicin and P-Glycoprotein siRNA to Overcome Drug Resistance in a Cancer Cell Line. ACS Nano 2010, 4, 4539−4550. (69) Na, H. K.; Kim, M. H.; Park, K.; Ryoo, S. R.; Lee, K. E.; Jeon, H.; Ryoo, R.; Hyeon, C.; Min, D. H. Efficient Functional Delivery of siRNA using Mesoporous Silica Nanoparticles with Ultralarge Pores. Small 2012, 8, 1752−1761. (70) Hartono, S. B.; Gu, W. Y.; Kleitz, F.; Liu, J.; He, L. Z.; Middelberg, A. P. J.; Yu, C. Z.; Lu, G. Q.; Qiao, S. Z. Poly-L-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery. ACS Nano 2012, 6, 2104−2117. (71) He, Q. J.; Gao, Y.; Zhang, L. X.; Zhang, Z. W.; Gao, F.; Ji, X. F.; Li, Y. P.; Shi, J. L. A pH-responsive mesoporous silica nanoparticlesbased multi-drug delivery system for overcoming multi-drug resistance. Biomaterials 2011, 32, 7711−7720. (72) He, Q. J.; Gao, Y.; Zhang, L. X.; Bu, W. B.; Chen, H. R.; Li, Y. P.; Shi, J. L. One-pot self-assembly of mesoporous silica nanoparticlebased pH-responsive anti-cancer nano drug delivery system. J. Mater. Chem. 2011, 21, 15190−15192. (73) Chen, Y.; Chen, H. R.; Ma, M.; Chen, F.; Guo, L. M.; Zhang, L. X.; Shi, J. L. Double mesoporous silica shelled spherical/ellipsoidal nanostructures: Synthesis and hydrophilic/hydrophobic anticancer drug delivery. J. Mater. Chem. 2011, 21, 5290−5298. (74) Chen, Y.; Chen, H. R.; Guo, L. M.; He, Q. J.; Chen, F.; Zhou, J.; Feng, J. W.; Shi, J. L. Hollow/Rattle-Type Mesoporous Nanostructures by a Structural Difference-Based Selective Etching Strategy. ACS Nano 2010, 4, 529−539. (75) Chen, Y.; Chen, H. R.; Zeng, D. P.; Tian, Y. B.; Chen, F.; Feng, J. W.; Shi, J. L. Core/Shell Structured Hollow Mesoporous Nanocapsules: A Potential Platform for Simultaneous Cell Imaging and Anticancer Drug Delivery. ACS Nano 2010, 4, 6001−6013. (76) Chen, Y.; Chu, C.; Zhou, Y. C.; Ru, Y. F.; Chen, H. R.; Chen, F.; He, Q. J.; Zhang, Y. L.; Zhang, L. L.; Shi, J. L. Reversible PoreStructure Evolution in Hollow Silica Nanocapsules: Large Pores for siRNA Delivery and Nanoparticle Collecting. Small 2011, 7, 2935− 2944. (77) Chen, Y.; Chen, H. R.; Guo, L. M.; Shi, J. L. Magnetic Hollow Mesoporous Silica Nanospheres: Facile Fabrication and Ultrafast Immobilization of Enzymes. J. Nanosci. Nanotechnol. 2011, 11, 10844− 10848. 2508

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

(78) Zhang, L. M.; Xia, J. G.; Zhao, Q. H.; Liu, L. W.; Zhang, Z. J. Functional Graphene Oxide as a Nanocarrier for Controlled Loading and Targeted Delivery of Mixed Anticancer Drugs. Small 2010, 6, 537−544. (79) Ashley, C. E.; Carnes, E. C.; Phillips, G. K.; Padilla, D.; Durfee, P. N.; Brown, P. A.; Hanna, T. N.; Liu, J. W.; Phillips, B.; Carter, M. B.; Carroll, N. J.; Jiang, X. M.; Dunphy, D. R.; Willman, C. L.; Petsev, D. N.; Evans, D. G.; Parikh, A. N.; Chackerian, B.; Wharton, W.; Peabody, D. S.; Brinker, C. J. The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat. Mater. 2011, 10, 389−397. (80) Wang, J.; Chen, B. A.; Cheng, J.; Cai, X. H.; Xia, G. H.; Liu, R.; Wang, X. M. Apoptotic mechanism of human leukemia K562/A02 cells induced by magnetic iron oxide nanoparticles co-loaded with daunorubicin and 5-bromotetrandrin. Int. J. Nanomed. 2011, 6, 1027− 1034. (81) Riganti, C.; Rolando, B.; Kopecka, J.; Campia, I.; Chegaev, K.; Lazzarato, L.; Federico, A.; Fruttero, R.; Ghigo, D. MitochondrialTargeting Nitrooxy-doxorubicin: A New Approach To Overcome Drug Resistance. Mol. Pharmacol. 2013, 10, 161−174. (82) Domenech, M.; Marrero-Berrios, I.; Torres-Lugo, M.; Rinaldi, C. Lysosomal Membrane Permeabilization by Targeted Magnetic Nanoparticles in Alternating Magnetic Fields. ACS Nano 2013, 7, 5091−5101. (83) Dai, Y. L.; Kang, X. J.; Yang, D. M.; Li, X. J.; Zhang, X.; Li, C. X.; Hou, Z. Y.; Cheng, Z. Y.; Ma, P. A.; Lin, J. Platinum (IV) Pro-Drug Conjugated NaYF4:Yb3+/Er3+Nanoparticles for Targeted Drug Delivery and Up-Conversion Cell Imaging. Adv. Healthcare Mater. 2013, 2, 562−567. (84) Li, C.; Hou, Z.; Dai, Y.; Yang, D.; Cheng, Z.; Ma, P. A.; Lin, J. A facile fabrication of upconversion luminescent and mesoporous coreshell structured [small beta]-NaYF4:Yb3+, Er3+@mSiO2 nanocomposite spheres for anti-cancer drug delivery and cell imaging. Biomater. Sci. 2013, 1, 213−223. (85) Ragaseema, V. M.; Unnikrishnan, S.; Krishnan, V. K.; Krishnan, L. K. The antithrombotic and antimicrobial properties of PEGprotected silver nanoparticle coated surfaces. Biomaterials 2012, 33, 3083−3092. (86) Sriram, M. I.; Kanth, S. B. M.; Kalishwaralal, K.; Gurunathan, S. Antitumor activity of silver nanoparticles in Dalton’s lymphoma ascites tumor model. Int. J. Nanomed. 2010, 5, 753−762. (87) Sanpui, P.; Chattopadhyay, A.; Ghosh, S. S. Induction of Apoptosis in Cancer Cells at Low Silver Nanoparticle Concentrations using Chitosan Nanocarrier. ACS Appl. Mater. Interfaces 2011, 3 (2), 218−228. (88) Zhang, Z.; Wang, J.; Chen, C. Near-Infrared Light-Mediated Nanoplatforms for Cancer Thermo-Chemotherapy and Optical Imaging. Adv. Mater. 2013, 25, 3869−3880. (89) Wang, X.; Chen, H. R.; Chen, Y.; Ma, M.; Zhang, K.; Li, F. Q.; Zheng, Y. Y.; Zeng, D. P.; Wang, Q.; Shi, J. L. PerfluorohexaneEncapsulated Mesoporous Silica Nanocapsules as Enhancement Agents for Highly Efficient High Intensity Focused Ultrasound (HIFU). Adv. Mater. 2012, 24, 785−791. (90) Wang, X.; Chen, H.; Zheng, Y.; Ma, M.; Chen, Y.; Zhang, K.; Zeng, D.; Shi, J. Au-nanoparticle coated mesoporous silica nanocapsule-based multifunctional platform for ultrasound mediated imaging, cytoclasis and tumor ablation. Biomaterials 2013, 34, 2057− 2068. (91) Chen, Y.; Chen, H. R.; Sun, Y.; Zheng, Y. Y.; Zeng, D. P.; Li, F. Q.; Zhang, S. J.; Wang, X.; Zhang, K.; Ma, M.; He, Q. J.; Zhang, L. L.; Shi, J. L. Multifunctional Mesoporous Composite Nanocapsules for Highly Efficient MRI-Guided High-Intensity Focused Ultrasound Cancer Surgery. Angew. Chem., Int. Ed. 2011, 50, 12505−12509. (92) Kobayashi, K.; Usami, N.; Porcel, E.; Lacombe, S.; Le Sech, C. Enhancement of radiation effect by heavy elements. Mutat. Res. Rev. Mutat. Res. 2010, 704, 123−131. (93) Le Duc, G.; Miladi, I.; Alric, C.; Mowat, P.; Brauer-Krisch, E.; Bouchet, A.; Khalil, E.; Billotey, C.; Janier, M.; Lux, F.; Epicier, T.; Perriat, P.; Roux, S.; Tillement, O. Toward an Image-Guided

Microbeam Radiation Therapy Using Gadolinium-Based Nanoparticles. ACS Nano 2011, 5, 9566−9574. (94) Zhong, Y. N.; Wang, C.; Cheng, L.; Meng, F. H.; Zhong, Z. Y.; Liu, Z. Gold Nanorod-Cored Biodegradable Micelles as a Robust and Remotely Controllable Doxorubicin Release System for Potent Inhibition of Drug-Sensitive and -Resistant Cancer Cells. Biomacromolecules 2013, 14 (7), 2411−2419. (95) Chung, C.; Kim, Y.-K.; Shin, D.; Ryoo, S.-R.; Hong, B. H.; Min, D.-H. Biomedical Applications of Graphene and Graphene Oxide. Acc. Chem. Res. 2013, DOI: 10.1021/ar300159f. (96) Feng, L. Y.; Wu, L.; Qu, X. G. New Horizons for Diagnostics and Therapeutic Applications of Graphene and Graphene Oxide. Adv. Mater. 2013, 25, 168−186. (97) Bitounis, D.; Ali-Boucetta, H.; Hong, B. H.; Min, D. H.; Kostarelos, K. Prospects and Challenges of Graphene in Biomedical Applications. Adv. Mater. 2013, 25, 2258−2268. (98) Lartigue, L.; Innocenti, C.; Kalaivani, T.; Awwad, A.; Duque, M. D. S.; Guari, Y.; Larionova, J.; Guerin, C.; Montero, J. L. G.; BarraganMontero, V.; Arosio, P.; Lascialfari, A.; Gatteschi, D.; Sangregorio, C. Water-Dispersible Sugar-Coated Iron Oxide Nanoparticles. An Evaluation of their Relaxometric and Magnetic Hyperthermia Properties. J. Am. Chem. Soc. 2011, 133, 10459−10472. (99) Ren, Y. Y.; Zhang, H. J.; Chen, B. A.; Cheng, J.; Cai, X. H.; Liu, R.; Xia, G. H.; Wu, W. W.; Wang, S.; Ding, J. H.; Gao, C.; Wang, J.; Bao, W.; Wang, L.; Tian, L.; Song, H. H.; Wang, X. M. Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance. Int. J. Nanomed. 2012, 7, 2261−2269. (100) Baeza, A.; Guisasola, E.; Ruiz-Hernandez, E.; Vallet-Regi, M. Magnetically Triggered Multidrug Release by Hybrid Mesoporous Silica Nanoparticles. Chem. Mater. 2012, 24, 517−524. (101) Wu, C. H.; Cao, C.; Kim, J. H.; Hsu, C. H.; Wanebo, H. J.; Bowen, W. D.; Xu, J.; Marshall, J. Trojan-Horse Nanotube OnCommand Intracellular Drug Delivery. Nano Lett. 2012, 12, 5475− 5480. (102) Terreno, E.; Uggeri, F.; Aime, S. Image guided therapy: The advent of theranostic agents. J. Controlled Release 2012, 161, 328−337. (103) Ryu, J. H.; Koo, H.; Sun, I. C.; Yuk, S. H.; Choi, K.; Kim, K.; Kwon, I. C. Tumor-targeting multi-functional nanoparticles for theragnosis: New paradigm for cancer therapy. Adv. Drug Delivery Rev. 2012, 64, 1447−1458. (104) Chen, Y.; Yin, Q.; Ji, X. F.; Zhang, S. J.; Chen, H. R.; Zheng, Y. Y.; Sun, Y.; Qu, H. Y.; Wang, Z.; Li, Y. P.; Wang, X.; Zhang, K.; Zhang, L. L.; Shi, J. L. Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells. Biomaterials 2012, 33, 7126−7137. (105) Xing, R. J.; Bhirde, A. A.; Wang, S. J.; Sun, X. L.; Liu, G.; Hou, Y. L.; Chen, X. Y. Hollow iron oxide nanoparticles as multidrug resistant drug delivery and imaging vehicles. Nano Res. 2013, 6, 1−9. (106) Michalet, X.; Pinaud, F. F.; Bentolila, L. A.; Tsay, J. M.; Doose, S.; Li, J. J.; Sundaresan, G.; Wu, A. M.; Gambhir, S. S.; Weiss, S. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 2005, 307, 538−544. (107) Gao, X. H.; Cui, Y. Y.; Levenson, R. M.; Chung, L. W. K.; Nie, S. M. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 2004, 22, 969−976. (108) Hou, Z. Y.; Li, C. X.; Ma, P. A.; Li, G. G.; Cheng, Z. Y.; Peng, C.; Yang, D. M.; Yang, P. P.; Lin, J. Electrospinning Preparation and Drug-Delivery Properties of an Up-conversion Luminescent Porous NaYF4:Yb3+, Er3+@Silica Fiber Nanocomposite. Adv. Funct. Mater. 2011, 21, 2356−2365. (109) Li, J. M.; Wang, Y. Y.; Zhao, M. X.; Tan, C. P.; Li, Y. Q.; Le, X. Y.; Ji, L. N.; Mao, Z. W. Multifunctional QD-based co-delivery of siRNA and doxorubicin to HeLa cells for reversal of multidrug resistance and real-time tracking. Biomaterials 2012, 33, 2780−2790. (110) Ma, P. A.; Xiao, H.; Li, X.; Li, C.; Dai, Y.; Cheng, Z.; Jing, X.; Lin, J. Rational Design of Multifunctional Upconversion Nanocrystals/ 2509

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510

Molecular Pharmaceutics

Review

Polymer Nanocomposites for Cisplatin (IV) Delivery and Biomedical Imaging. Adv. Mater. 2013, 25, 4898−4905. (111) Dai, Y. L.; Ma, P. A.; Cheng, Z. Y.; Kang, X. J.; Zhang, X.; Hou, Z. Y.; Li, C. X.; Yang, D. M.; Zhai, X. F.; Lin, J. Up-Conversion Cell Imaging and pH-Induced Thermally Controlled Drug Release from NaYF4:Yb3+/Er3+@Hydrogel Core-Shell Hybrid Microspheres. ACS Nano 2012, 6, 3327−3338. (112) Wu, S. H.; Lin, Y. S.; Hung, Y.; Chou, Y. H.; Hsu, Y. H.; Chang, C.; Mou, C. Y. Multifunctional mesoporous silica nanoparticles for intracellular labeling and animal magnetic resonance imaging studies. ChemBioChem 2008, 9, 53−57. (113) He, Q. J.; Zhang, Z. W.; Gao, F.; Li, Y. P.; Shi, J. L. In vivo Biodistribution and Urinary Excretion of Mesoporous Silica Nanoparticles: Effects of Particle Size and PEGylation. Small 2011, 7, 271− 280. (114) Hudson, S. P.; Padera, R. F.; Langer, R.; Kohane, D. S. The biocompatibility of mesoporous silicates. Biomaterials 2008, 29, 4045− 4055. (115) Souris, J. S.; Lee, C. H.; Cheng, S. H.; Chen, C. T.; Yang, C. S.; Ho, J. A. A.; Mou, C. Y.; Lo, L. W. Surface charge-mediated rapid hepatobiliary excretion of mesoporous silica nanoparticles. Biomaterials 2010, 31, 5564−5574. (116) Huang, X. L.; Li, L. L.; Liu, T. L.; Hao, N. J.; Liu, H. Y.; Chen, D.; Tang, F. Q. The Shape Effect of Mesoporous Silica Nanoparticles on Biodistribution, Clearance, and Biocompatibility in Vivo. ACS Nano 2011, 5, 5390−5399. (117) Benezra, M.; Penate-Medina, O.; Zanzonico, P. B.; Schaer, D.; Ow, H.; Burns, A.; DeStanchina, E.; Longo, V.; Herz, E.; Iyer, S.; Wolchok, J.; Larson, S. M.; Wiesner, U.; Bradbury, M. S. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. J. Clin. Invest. 2011, 121, 2768−2780. (118) Bai, Y. H.; Zhang, Y.; Zhang, J. P.; Mu, Q. X.; Zhang, W. D.; Butch, E. R.; Snyder, S. E.; Yan, B. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nat. Nanotechnol. 2010, 5, 683−689. (119) Yang, K.; Feng, L. Z.; Shi, X. Z.; Liu, Z. Nano-graphene in biomedicine: theranostic applications. Chem. Soc. Rev. 2013, 42, 530− 547. (120) Yang, K.; Gong, H.; Shi, X. Z.; Wan, J. M.; Zhang, Y. J.; Liu, Z. In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal administration. Biomaterials 2013, 34, 2787−2795. (121) Pietroiusti, A.; Massimiani, M.; Fenoglio, I.; Colonna, M.; Valentini, F.; Palleschi, G.; Camaioni, A.; Magrini, A.; Siracusa, G.; Bergamaschi, A.; Sgambato, A.; Campagnolo, L. Low Doses of Pristine and Oxidized Single-Wall Carbon Nanotubes Affect Mammalian Embryonic Development. ACS Nano 2011, 5, 4624−4633. (122) Rapoport, N. Combined cancer therapy by micellarencapsulated drug and ultrasound. Int. J. Pharmaceutics 2004, 277, 155−162. (123) Marin, A.; Sun, H.; Husseini, G. A.; Pitt, W. G.; Christensen, D. A.; Rapoport, N. Y. Drug delivery in pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake. J. Controlled Release 2002, 84, 39−47. (124) Zhang, H. J.; Jiang, H.; Sun, F. F.; Wang, H. P.; Zhao, J. A.; Chen, B. A.; Wang, X. M. Rapid diagnosis of multidrug resistance in cancer by electrochemical sensor based on carbon nanotubes-drug supramolecular nanocomposites. Biosens. Bioelectron. 2011, 26, 3361− 3366.

2510

dx.doi.org/10.1021/mp400596v | Mol. Pharmaceutics 2014, 11, 2495−2510