Redox-responsive Drug Delivery System Research Articles

Fluorescence color-changeable branched-form heptamethine cyanine dye as a redox-responsive multi-functional drug delivery system for enhanced cancer diagnosis and chemophototherapy

A multifunctional drug delivery system (MDDS) based on near-infrared (NIR) imaging was developed in various conformations for the accurate diagnosis and therapy of cancer. However, it remains challenging to develop an ideal structure for an MDDS with both exact and variable functionality. Herein, we report a fluorescence color-changeable branched-form heptamethine cyanine dye (PEG-4-CyP) that has both a simple structure and various functionality. The PEG-4-CyP was not only able to construct the nanoparticle (NP) structure by encapsulating DOX (PEG-4-CyP/DOX), but also showed change in the NIR fluorescence color by reacting with glutathione (GSH). The PEG-4-CyP/DOX was broken down in the redox microenvironment inside cancers because of the reduction reaction of PEG-4-CyP to GSH. As a result, the NP disruption, DOX release, and reactivity of PEG-4-CyP to GSH were visualized by NIR fluorescence color-change. Moreover, PEG-4-CyP/DOX showed an excellent chemophototherapeutic effect in cancer cells. This NIR fluorescence color-change strategy demonstrates the applicability of PEG-4-CyP as a novel MDDS able to provide a variety of information with a simple NP structure.

Doxorobicin as cargo in a redox-responsive drug delivery system capped with water dispersible ZnS nanoparticles.

In this work, we have prepared and investigated a redox-responsive drug delivery system (DDS) based on a porous carrier. Doxorubicin (DOX), a chemotherapy medication for treatment of different kinds of cancer, was used as a model drug in the study. DOX was loaded in ordered hexagonal mesoporous silica SBA-15, a nanoporous material with good biocompatibility, stability, large pore size and specific surface area (SBET = 908 m2 g−1, VP = 0.79 cm3 g−1, d = 5.9 nm) and easy surface modification. To prepare the redox-responsive system, cystamine derivative ligands, with redox active disulphide linkers were grafted onto the surface of SBA-15. To ensure no significant premature release of DOX from the porous system, thioglycolic acid modified ZnS nanoparticles (ZnS–COOH NPs) were used as pore capping agents. The grafted redox-responsive cystamine derivative ligand containing disulphide linkers was bonded by a peptide bond to the thioglycolic acid groups of ZnS–COOH NPs, capping the pores. Once the disulphide bond was cleaved, the ZnS–COOH NPs caps were released and pores were opened to deliver the DOX cargo. The dithiol bond was cleavable by redox active molecules such as dithiothreitol (DTT) or glutathione, the concentration of which in cancer cells is 4 times higher than in healthy cells. The redox release of DOX was studied in two different media, physiological saline solution with DTT and saline without DTT. The prepared DDS proved the concept of redox responsive release. All samples were characterised by powder X-ray diffraction (XRD), transition electron microscopy (TEM), nitrogen adsorption/desorption at 77 K, Fourier-transform infrared spectroscopy (FTIR), thermal analysis and zeta potential measurements. The presence of semiconducting ZnS nanoparticle caps on the pore openings was detected by magnetic measurements using SQUID magnetometry showing that such cargo systems could be monitored using magnetic measurements which opens up the possibilities of using such drug delivery systems as theranostic agents.

Adjudin-loaded redox-sensitive paclitaxel-prodrug micelles for overcoming multidrug resistance with efficient targeted Colon cancer therapy

Multidrug resistance (MDR) is the primary cause for the failure of chemotherapy in the treatment of colon cancer. Recent research has indicated that the combination of a chemotherapeutic agent and a mitochondrial inhibitor might represent a promising strategy to help overcome MDR. However, for this approach to be clinically effective, it is important that the two drugs can be actively and simultaneously delivered into tumor cells at an optimal ratio and completely released drug within cells. To address these challenges, we designed and prepared a folate receptor-targeted and redox-responsive drug delivery system (FA- ss -P/A) that was able to co-deliver paclitaxel (PTX) and adjudin (ADD) to reverse colon cancer MDR. The PTX prodrug was obtained by conjugating PTX to dextrin via a disulfide-linkage. Then, folic acid (FA) was modified on the PTX prodrug. Finally, ADD, a mitochondrial inhibitor, was encapsulated in the PTX prodrug-formed micelles. A series of in vitro and in vivo experiments subsequently demonstrated that FA- ss -P/A can effectively reverse MDR by increasing cell uptake, inhibiting PTX efflux, and improving drug release.

Gradient Redox-Responsive and Two-Stage Rocket-Mimetic Drug Delivery System for Improved Tumor Accumulation and Safe Chemotherapy.

Recent drug delivery nanosystems for cancer treatment still suffer from the poor tumor accumulation and low therapeutic efficacy due to the complex in vivo biological barriers. To resolve these problems, in this work, a novel gradient redox-responsive and two-stage rocket-mimetic drug nanocarrier is designed and constructed for improved tumor accumulation and safe chemotherapy. The nanocarrier is constructed on the basis of the disulfide-doped organosilica-micellar hybrid nanoparticles and the following dual-functional modification with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine (PEI). First, prolonged circulation duration in the bloodstream is guaranteed due to the shielding of the outer PEG chains. Once the nanocarrier accumulates at the tumoral extracellular microenvironment with low glutathione (GSH) concentrations, the first-stage redox-responsive behavior with the separation of PEG and the exposure of PEI is triggered, leading to the improved tumor accumulation and cellular internalization. Furthermore, with their endocytosis by tumor cells, a high concentration of GSH induces the second-stage redox-responsiveness with the degradation of silsesquioxane framework and the release of the encapsulated drugs. As a result, the rocket-mimetic drug carrier displays longer circulation duration in the bloodstream, higher tumor accumulation capability, and improved antitumor efficacy (which is 2.5 times higher than that with inseparable PEG). It is envisioned that the rocket-mimetic strategy can provide new solutions for improving tumor accumulation and safety of nanocarriers in further cancer chemotherapy.

Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.

Redox Sensitive Polysaccharide Based Nanoparticles for Improved Cancer Treatment: A Comprehensive Review.

Among the numerous bio-responsive polymeric drug delivery systems developed recently, redox-triggered release of molecular payloads have gained great deal of attention, especially in the field of anticancer drug delivery. In most cases, these systems rely on disulfide bonds located either in the matrix crosslinks, or in auxiliary chains to achieve stimuli-responsive drug release. These bonds keep their stability in extracellular environments, yet, rapidly break by thiol-disulfide exchange reactions in the cytosol, due to the presence of greater levels of glutathione. Polysaccharides are macromolecules with low cost, natural abundance, biocompatibility, biodegradability, appropriate physical and chemical properties, and presence of numerous functional groups which facilitate chemical or physical cross-linking. With regards to the remarkable advantages of polysaccharides, in the current study, various polysaccharide-based redox-responsive drug delivery systems are reviewed. In most cases the in vitro/in vivo effects of the developed system were also evaluated. Considering the hypoxic and reducing nature of the tumor microenvironment, with several folds higher glutathione levels than the systemic tissues, redox-sensitive polymeric systems could be implemented for tumorspecific drug delivery and the results of the previous researches in this field indicated satisfactory achievements. According to the reviewed papers, the efficiency of diverse redox-responsive polysaccharide-based nanoparticles with therapeutic payloads in cancer chemotherapy could be concluded. Nevertheless, more comprehensive studies are required to understand the exact intracellular and systemic fate of these nano-carriers, as well as their clinical efficacy for cancer treatment.

Smart copolymer coated SPIONs for colon cancer chemotherapy

Human colon cancer is one of the higher aggressive solid tumors, whose high mortality, much like many other solid tumors, results from metastasis formation. To reduce this high mortality, more effective chemotherapy, allowing a specific tumor accumulation and an efficient early-stage medical imaging as well, are still needed. At this regard, stimuli-responsive nanocarriers for anticancer drug delivery are promising strategy in cancer therapy. For this purpose, a dual targeted redox-responsive drug delivery system, prepared by coating superparamagnetic nanoparticles (SPIONs) with the amphiphilic copolymer INU-LA-PEG-FA and loading doxorubicin (DOXO-SPIONs) was investigated as tool for solid tumor chemotherapy. Folic acid (FA) has been chosen as active targeting agent as its receptor is upregulated in many tumors, including colon cancer. Lipoic acid (LA) has been used to act as the redox-responsive moiety, due to the presence of the -S-S- linkage into its structure, which can undergo intracellular reductive-induced cleavage, and therefore, a modification of stability and release profile of the nanocarrier. Accumulation by magnetic attraction was used as synergistic targeting strategy. Improved anticancer activity was demonstrated in mice by evaluating tumor volume reduction, immunohistochemical analyses and imaging properties using magnetic resonance imaging (MRI).

Mesoporous silica nanoparticles capped with graphene quantum dots as multifunctional drug carriers for photo-thermal and redox-responsive release

Abstract A novel photo-thermal and redox-responsive drug delivery carrier was developed by capping mesoporous silica nanoparticles (MSNs) with graphene quantum dots (GQDs). The disulfide bonds were introduced by amidation reaction between cystine and amino functionalized MSNs. Rhodamine B (RhB), a red fluorescent dye, was loaded into the mesopores of MSNs as the model drug and GQDs capped on MSNs as gatekeepers could prevent the release of RhB. Transmission electron microscopy (TEM), nitrogen adsorption and desorption analysis, X-ray diffraction (XRD), thermogravimetric (TG) analysis and Fourier transform infrared spectroscopy (FTIR) proved that the nanocomposites MSNs capped with GODs were achieved successfully. The nanocomposites with the size of about 100 nm have excellent photo-thermal property originated from GQDs. Moreover, the nanocomposites were endowed with remarkable redox-responsion to glutathione (GSH) from disulfide bonds, and hence the loaded drugs could release controlably. In this work, we provided an exploration of photo-thermal and redox-responsive drug delivery system and the results proved that this drug delivery system can be considered as a promising candidate for drug delivery and stimuli-responsive release.

A degradable triple temperature-, pH-, and redox-responsive drug system for cancer chemotherapy.

In order to achieve a precise therapeutic effect of cancer treatment and improve the utilization of drugs, a temperature-, pH-, and redox-responsive drug delivery system were synthesized. Methacrylic acid (MAA), poly(N-isopropylacrylamide) (PNIPAM), 2-hydroxyethylmethacrylate (HEMA), and N,N'-bis(acryloyl)cystamine (BACy), a disulfide bond contained cross-linker, were polymerized by a distillation-precipitation polymerization. Doxorubicin (DOX), an anti-cancer drug, can be loaded into the loose nanoparticle (NP) effectively. The prepared drug delivery remains stable during blood circulation and, when the vectors accumulated at tumor tissues, the pH-response of MMA and temperature-response of PNIPAM makes volume shrinkage of vectors which benefit the diffusion of vectors into tumor tissues. After being endocytosed into tumor cell, the disulfide bond that contained in the drug delivery can be cleaved by glutathione (GSH), causing the decomposition of NPs, and then release all of the drug. Under the influence of three trigger factors, the triple stimuli-responsive drug delivery vectors can realize tumor accumulation, tumor penetration and controlled drug release. Thus, the prepared multi-responsive NP is ideal drug carriers for developing novel drug delivery systems. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3203-3210, 2018.

Poly(aspartic acid) hydrogels showing reversible volume change upon redox stimulus

Redox and pH responsive hydrogels were synthesized, which can serve as matrices for smart drug delivery systems exploiting the redox and pH gradients in the human body. Water soluble thiolated poly(aspartic acid), a biocompatible synthetic polymer, enables us to cross-link in water with a non-cleavable cross-linker, poly(ethylene glycol) diglycidyl ether. The permanent cross-linker establishes stable polymer hydrogels regardless of the redox environment, thus the gels swell but do not dissolve upon redox stimuli. The reversible response upon redox stimulus was induced by thiol-disulphide transformation inside the hydrogel. The degree of swelling and the stiffness of the macroscopic hydrogels were controlled by their chemical composition including thiol content and cross-linking ratio as well as the redox state of the hydrogels. The degree of swelling of the hydrogels showed strong pH dependence due to the polyelectrolyte nature of the polymer network. Release of a macromolecular model drug was considerably faster in reducing than in oxidising environment, which indicates the potential use of the synthesized hydrogels as redox responsive drug delivery systems. Nanogels were prepared in water-in-oil emulsion and displayed redox-responsive properties. The hydrodynamic diameter of the nanogels strongly increased upon the cleavage of the disulphide linkages in reducing solution without the disruption of the gels.

Redox-responsive micelles for triggered drug delivery and effective laryngopharyngeal cancer therapy

In this study, we reported a redox-responsive drug delivery system (DDS) based on heparosan and deoxycholic acid conjugates (HSDs) for effective treatment of laryngopharyngeal carcinoma. The amphiphilic HSDs can self-assemble into stable nanoscale micelles in aqueous medium with favorable drug loading capacity for doxorubicin (DOX). The HSD micelles can exhibit glutathione (GSH)-triggered drug release behavior and reach a nearly 100% release rate in a high GSH level (10 mM) environment. Moreover, FaDu cancer cells can internalize HSD micelles by clathrin-mediated endocytosis, which is energy dependent, fast, and effective. The DOX@HSD induced inhibition of FaDu cancer cells can achieve a minimum of 10-fold selectivity relative to that of COS-7 normal cells. Overall, the redox-responsive DDSs show good biocompatibility and are promising in the clinical treatment of laryngopharyngeal carcinoma.

Redox-responsive and pH-sensitive nanoparticles enhanced stability and anticancer ability of erlotinib to treat lung cancer in vivo.

PurposeErlotinib (ETB) is a well-established therapeutic for non-small-cell lung cancer (NSCLC). To overcome drug resistance and severe toxicities in the clinical application, redox-responsive and pH-sensitive nanoparticle drug delivery systems were designed for the encapsulation of ETB.MethodsPoly(acrylic acid)-cystamine-oleic acid (PAA-ss-OA) was synthesized. PAA-ss-OA-modified ETB-loaded lipid nanoparticles (PAA-ETB-NPs) were prepared using the emulsification and solvent evaporation method. The tumor inhibition efficacy of PAA-ETB-NPs was compared with that of ETB-loaded lipid nanoparticles (ETB-NPs) and free ETB anticancer drugs in tumor-bearing mice.ResultsPAA-ETB-NPs had a size of 170 nm, with a zeta potential of −32 mV. The encapsulation efficiency and drug loading capacity of PAA-ETB-NPs were over 85% and 2.6%, respectively. In vitro cytotoxicity of ETB-NPs were higher than that of ETB solution. The cytotoxicity of PAA-ETB-NPs was the highest. The in vivo tumor growth inhibition by PAA-ETB-NP treatment was significantly higher than that by ETB-NPs and ETB solution. No obvious weight loss was observed in any of the treatment groups, indicating that all the treatments were well tolerated.ConclusionPAA-ETB-NPs could enhance the stability and anti-cancer ability of ETB to treat lung cancer and are a promising drug delivery system for lung cancer treatment.

Hyaluronic acid and carbon dots-gated hollow mesoporous silica for redox and enzyme-triggered targeted drug delivery and bioimaging

In this work, a redox and enzyme dual-stimuli responsive drug delivery system (DDS) with tracking function (HMSN-SS-CDPEI@HA) based on carbon dots capped hollow mesoporous silica nanoparticles (HMSN) has been developed for targeted drug delivery. The positively charged CDPEI nanoparticles prepared by polyethylenimine (PEI) were grafted on the pore openings of HMSN through disulfide bonds and were used as “gatekeepers” to trap the drugs within the hollow cavity. The hyaluronic acid (HA), a natural polysaccharide, was further grafted on the surface of HMSN to realize targeted drug delivery, controlled drug release and improved the stability. Doxorubicin (DOX) was chosen as a model drug due to its wide clinical application. In vitro drug release profiles demonstrated that DOX-loaded HMSN-SS-CDPEI@HA exhibited redox and enzyme dual-responsive drug release property. In addition, the prepared HMSN-SS-CDPEI@HA exhibited excellent fluorescent properties and biocompatibility. Confocal laser scanning microscope (CLSM) and flow cytometry (FCM) illustrated that HMSN-SS-CDPEI@HA exhibited a higher cellular uptake via the CD44 receptor-mediated endocytosis by CD44-receptor over-expressed A549 cells than NIH-3T3 (receptor-negative) cells, leading to higher cytotoxicity against A549 cells than NIH 3T3 cells. This work suggested an exploration of dual-stimuli responsive as well as real-time imaging targeted drug delivery system based on HMSN and the prepared HMSN-SS-CDPEI@HA could be a promising platform for cancer therapy.

Multifunctional Peptide-Amphiphile End-Capped Mesoporous Silica Nanoparticles for Tumor Targeting Drug Delivery.

A tumor targeting redox-responsive drug delivery system (DDS) with bioactive surface was constructed by immobilizing peptide-based amphiphile C12-CGRKKRRQRRRPPQRGDS (defined as ADDA-TCPP) onto the mesoporous silica nanoparticles (MSNs) as an end-capping nanovalve, which consists of two main segments: a hydrophobic alkyl chain ADDA and a hydrophilic amino acid sequence containing a Tat48-60 peptide sequence with a thiol terminal group and an RGDS targeting ligand, via a disulfide linkage for redox-triggered intracellular drug delivery. A series of characterizations confirmed that the nanosystem had been successfully fabricated. The antitumor drug doxorubicin (DOX) was selected as a model drug and efficiently trapped in the pores of MSNs, and an in vitro release experiment demonstrated that the mesopores of the resulting DOX-loaded MSNs (DOX@MSN-ss-ADDA-TCPP) could be sealed tightly with ADDA-TCPP self-assemblies through hydrophobic interactions between the alkyl chains; the resulting DDS exhibited "zero premature release" of DOX in the physical environment. However, a burst drug release was triggered by a high concentration of glutathione (GSH) in simulated cellular cytosol. Moreover, detailed investigations confirmed that incorporation of RGDS peptide facilitated the active targeting delivery of DOX to αvβ3 integrin overexpressed tumor cells, and Tat48-60 modification on MSNs could enhance intracellular drug delivery, exhibiting an obvious toxicity to tumor cells. The multifunctional nanosystem constructed here can realize the controlled drug release and serve as a platform for designing multifunctional nanocarriers using diversified bioactive peptide-based amphiphile.

A carbon based drug delivery system derived from a one-dimensional coordination polymer, doxorubicin loading and redox-responsive release

A redox-responsive drug delivery system has been fabricated through the modification of –S–S– bonds on coordination polymer derived mesoporous carbon nanoparticles with Ag as a “gatekeeper”.

A54 Peptide Modified and Redox-Responsive Glucolipid Conjugate Micelles for Intracellular Delivery of Doxorubicin in Hepatocarcinoma Therapy.

Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox-responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCssA) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCssA could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 μg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCssA micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCssA micelles toward the hepatoma cells (BEL-7402) compared to that toward HepG2 cells. In contrast with the nonresponsive conjugate, the drug was released from APCssA micelles more quickly in 10 mM level of GSH concentration (tumor cells). Moreover, the DOX-loaded APCssA micelles displayed an increased cytotoxicity which was 1.6- to 2.0-fold that of unmodified and nonresponsive micelles. In vivo, the APCssA micelles had stronger distribution to liver and hepatoma tissue and prolonged the circulation and retention time, while the drug release only occurred in the tumor tissue. The APCssA/DOX showed the tumor inhibition rate equal to that of commercial doxorubicin hydrochloric without negative consequence. This study suggested that the APCssA/DOX showed promising potential to treat the tumor for its special tumor targeting, selective intracellular drug release, enhanced antitumor activity, and reduced toxicity on normal tissues.

Redox-responsive minimized fragmentation of three-armed oligo(ethylene glycol) gels for protein release

Redox-responsive drug delivery system (DDS) carriers cross-linked by disulfide bonds have attracted attention, because disulfide bonds can be cleaved in the presence of high glutathione (GSH) concentrations found in cancer cells. In this study, to obtain redox-responsive degradable hydrogels, three-armed oligo(ethylene glycol) (trisOEG) gels were prepared through terminal cross-linking reaction that linked together low-molecular-weight trisOEG molecules via a disulfide bond. The stability of the trisOEG gels was investigated in the presence of a reductant, dithiothreitol (DTT) or reduced GSH, in phosphate buffered saline solution. TrisOEG gels were fragmented by a redox-stimulus, returning the decomposed hydrophilic oligomers to a low-molecular-weight state, similar to the raw material that would be expected to be excreted in vivo by the renal system. In addition, protein-immobilized trisOEG micro-gels were prepared. While no release of entrapped protein from trisOEG micro-gel was observed in the absence of GSH, release of entrapped protein was observed in the presence of GSH at a concentration found in cytoplasm.

Multifunctional mesoporous silica nanoparticles modified with tumor-shedable hyaluronic acid as carriers for doxorubicin

In this paper, a CD44-targeted and redox-responsive drug delivery system based on mesoporous silica nanoparticles (MSNs) was synthesized by conjugating tumor-shedable hyaluronic acid (HA) on the surface of MSNs via disulfide bonds. Doxorubicin hydrochloride (DOX·HCl) was physically encapsulated into HA modified MSNs (MSNs/SS/HA@DOX) as a model drug. MSNs/SS/HA@DOX (40nm) had a high drug loading (14.1%) and redox-responsive drug release property. The cellular uptake behaviors of MSNs/SS/HA@DOX by HeLa and LO2 cells were evaluated by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM). MSNs/SS/HA@DOX exhibited higher cellular uptake efficacy via CD44-mediated endocytosis by HeLa cells (CD44 over-expressed cells) than by LO2 cells (CD44 deficient cells). The in vitro cytotoxicity assay demonstrated that MSNs/SS/HA@DOX exhibited higher cytotoxicity to HeLa cells than to LO2 cells. These results indicated that MSNs/SS/HA@DOX might be promising as a multifunctional drug delivery system to improve the anti-tumor efficacy of chemotherapeutic drugs.

Disulfide-crosslinked poly(L-glutamic acid) grafted mesoporous silica nanoparticles and their potential application in drug delivery

Poly(L-glutamic acid)(PLGA) was grafted onto the surface of mesoporous silica nanoparticles(MSN) via the ring opening polymerization of γ-benzyl-L-glutamate N-carboxyanhydride(BLG-NCA) and its subsequent deprotection of benzyl groups. The PLGA chains were cross-linked with cystamine, and thus forming a type of redox responsive drug delivery system(MSN-cPLGA). The structures were characterized by Fourier transform infrared spectrometry(FTIR), transmission electron microscopy(TEM) and energy disperse spectrometry(EDS), demonstrating that disulfide groups existed on the surfaces of MSN-cPLGA particles. The thermal gravimetric analysis(TGA) results show that the PLGA mass fraction is about 33.4% in the MSN-cPLGA hybrid. The in vitro drug release experiments showed that the MSN-cPLGA hybrid can realize the controlled release of model drugs(5-fluorouracil) in response to redox environment. Even 0.1 mmol/L dithiothreitol(DTT) can accelerate the drug release speed, and a concentration of 10.0 mmol/L DTT is higher enough to trigger the open of cross-linked PLGA network so as to realize rapid release of drugs. All the results demonstrate that the cross-linked PLGA chains on the surface of MSN could act as efficient gatekeepers to control the on-off of the pores, showing potential application in drug delivery system.

Selective redox-responsive drug release in tumor cells mediated by chitosan based glycolipid-like nanocarrier

The redox responsive nanocarriers have made a considerable progress in achieving triggered drug release by responding to the endogenous occurring difference between the extra- and intra- cellular redox environments. Despite the promises, this redox difference exists both in normal and tumor tissue. So a non-selective redox responsive drug delivery system may result in an undesired drug release in normal cells and relevant side-effects. To overcome these limitations, we have developed a chitosan based glycolipid-like nanocarrier (CSO-ss-SA) which selectively responded to the reducing environment in tumor cells. The CSO-ss-SA showed an improved reduction-sensitivity which only fast degraded and released drug in 10mM levels of glutathione (GSH). The CSO-ss-SA could transport the drug fast into the human ovarian cancer SKOV-3 cells and human normal liver L-02 cells by internalization, but only fast release drug in SKOV-3 cells. By regulating the intracellular GSH concentration in SKOV-3 cells, it indicated that the cellular inhibition of the PTX-loaded CSO-ss-SA showed a positive correlation with the GSH concentration. The CSO-ss-SA was mainly located in the liver, spleen and tumor in vivo, which evidenced the passive tumor targeting ability. Despite the high uptake of liver and spleen, drug release was mainly occurred in tumor. PTX-loaded CSO-ss-SA achieved a remarkable tumor growth inhibition effect with rather low dose of PTX. This study demonstrates that a smartly designed glycolipid-like nanocarrier with selective redox sensitivity could serve as an excellent platform to achieve minimal toxicity and rapid intracellular drug release in tumor cells.