Redox-responsive Drug Release Research Articles

Co-delivery of Interferon Regulatory Factor 5 (IRF5) siRNA and dasatinib by a disulfide bond bearing polymeric carrier for enhanced anti-inflammatory effects

Co-delivery of chemical drugs and nucleic acids has attracted a great interest recently for treatment of inflammatory diseases. Dasatinib (DB), a tyrosine kinase inhibitor with anti-cancer effects, and Interferon Regulatory Factor 5 (IRF5) siRNA have shown anti-inflammatory effects. In the present study, a novel redox-responsive polymeric micelle was designed for co-delivery of DB and IRF5 siRNA-expressing plasmid (psiRF5) to enhance anti-inflammatory effects on macrophages. psiRF5 was condensed efficiently to redox-responsive micelles of DB-conjugated chitosan (CN) composed of disulfide bond, from different molecular weights of CN to form CN-SS-DB/psiRF5 micelles. The micelles with optimum N/P ratios had particle sizes of 287.8 and 245.4 nm and positive zeta potentials. The disulfide bond bearing micelles showed a redox-responsive drug release, protected the plasmid from being dissociated or degraded in exposure with heparin, serum and DNase I, and significantly enhanced the transfection efficiency and IRF5-gene silencing compared to naked psiRF5. The optimum micelles exhibited a dramatic reduction in IRF5 expression and revealed a notably higher anti-inflammatory effect than either DB or psiRF5, as indicated by more IL-10 and less IL-6 and TNF-α production by LPS-stimulated RAW264.7 macrophages incubated with the co-delivery system. The resultant nanocarriers might be promising for more effective treatment of inflammatory diseases.

Redox-responsive hyaluronic acid-celastrol prodrug micelles with glycyrrhetinic acid co-delivery for tumor combination therapy

Combining cytotoxic drugs with tumor microenvironment (TME) modulator agents is an effective strategy to enhance anti-tumor effects. In this study, two natural anti-tumor active ingredients celastrol (CEL) and glycyrrhetinic acid (GA) were combined for tumor treatment. In order to ensure the precise co-delivery and controllable synchronous release of combined drugs to tumors, it is necessary to construct a suitable nano-drug delivery platform. Based on this, we coupled hyaluronic acid (HA) with CEL by amide reaction to obtain an amphiphilic polymer prodrug HA-SS-CEL, and GA was spontaneously loaded into polymer micelles by self-assembly to obtain G/HSSC-M. G/HSSC-M has ideal size distribution, redox-responsive synchronous drug release, enhanced tumor cell internalization and in vivo tumor targeting. Compared with free drugs, the construction of multifunctional polymer micelles makes G/HSSC-M show better anticancer effect at the same concentration, and can significantly inhibit the proliferation and migration of HepG2 and 4T1 cells. In the in vivo experiments, G/HSSC-M inhibited tumor as high as 75.12% in H22 tumor-bearing mice. The mechanism included regulation of M1/M2 macrophage polarization, inhibition of Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signaling pathway, and remodeling of tumor blood vessels. Therefore, the development of prodrug micelles co-loaded with CEL and GA provides a promising drug co-delivery strategy for combined cancer therapy.

Doxorubicin-loaded Polymeric Biotin-PEG-SeSe-PBLA Micelles with surface Binding of Biotin-Mediated Cancer Cell Targeting and Redox-Responsive Drug release for enhanced anticancer efficacy

Biotin receptors are overexpressed in various cancer cell types, essential in tumor development, metabolism, and metastasis. Chemotherapeutic agents may be more effective and have fewer adverse effects if they specifically target the biotin receptors on cancer cells. Polymeric micelles (PMs) with nanoscale size via the EPR effect to accumulate near tumor tissue. We utilized the solvent exchange technique to crate polymeric Biotin-PEG-SeSe-PBLA micelles. This underwent self-assembly to create uniformly dispersed PMs with a hydrodynamic diameter of 81.54 ± 0.23 nm. The resulting PMs characterized by 1HNMR, 13CNMR, FTIR, and Raman spectroscopy. PMs exhibited a high efficacy of Doxorubicin encapsulation (EE) and loading content (DLC), with values of 5.93 wt% and 74.32 %, respectively. DOX@Biotin-PEG-SeSe-PBLA micelles showed optimal DOX release, around 89 % and 74 % in 10 mM glutathione and 0.1 % H2O2, respectively, within 72 hours, in the simulated cancer redox pool. Fascinatingly, the blank Biotin-PEG-SeSe-PBLA micelles did not affect the HaCaT or HeLa cell lines; approximately 85 % of the cells were metabolically active. Contrarily, at a 5 μg/ml concentration, DOX@Biotin-PEG-SeSe-PBLA specifically inhibited the proliferation of roughly 76 % of HeLa cells and 11 % of HaCaT cells. The fluorescence microscopy results demonstrated that biotin-decorated micelles were more successfully internalized by HeLa cells, which overexpress the biotin receptor, than by non-targeted micelles in vitro. In summary, the diselenide-linked Biotin-PEGSeSe-PBLA formed smart PMs that could offer DOX specific to cancer cells with precision and are physiologically durable.

Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported Lipid Bilayers as Targeted Delivery Vehicles.

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.

Cystine-cored diphenylalanine appended peptide-based self-assembled fluorescent nanostructures direct redox-responsive drug delivery

Fabrication of stimuli-responsive superstructure capable of delivering chemotherapeutics directly to the cancer cell by sparing healthy cells is crucial. Herein, we developed redox-responsive hollow spherical assemblies through self-assembly of disulfide-linked cysteine-diphenylalanine (SN). These fluorescent hollow spheres display intrinsic green fluorescence, are proteolytically stable and biocompatible, and allow for real-time monitoring of their intracellular entry. The disulfide bond facilitates selective degradation in the presence of high glutathione (GSH) concentrations, prevalent in cancer cells. We achieved efficient encapsulation (68.72%) of the anticancer drug doxorubicin (Dox) and demonstrated GSH-dependent, redox-responsive drug release within cancerous cells. SN-Dox exhibited a 20-fold lower effective concentration (2.5μM) for compromising breast cancer cell viability compared to non-malignant cells (50μM). The ability of SN-Dox to initiate DNA damage signaling and trigger apoptosis was comparable to that of the unencapsulated drug. Our findings highlight the potential of SN for creating site-specific drug delivery vehicles for sustained therapeutic release.

Hyaluronan-based nano-formulation with mesoporous silica enhances the anticancer efficacy of phloroglucinol against gastrointestinal cancers

Gastrointestinal cancers are one among the most frequently reported cancers where colorectal and gastric cancers ranks third leading cause of cancer related death worldwide. Phloroglucinol, a well-known therapeutic agent for cancer, where its usage has been limited due to its poor water solubility and bioavailability. Hence, our study aims to synthesize and characterize Hyaluronan grafted phloroglucinol loaded Mesoporous silica nanoparticles (MSN-PG-HA). Our nano-formulation hasn't shown any teratogenic effect on Zebrafish embryos, no hemolysis and toxic effect with normal fibroblast cells with a maximum concentration of 300 μg/mL. The cumulative drug release profile of MSN-PG-HA showed a maximum drug release of 96.9 % with 5 mM GSH under redox responsive drug release, which is crucial for targeting cancer cells. In addition, the MSN-PG-HA nanoparticles showed significant a cytotoxic effect against HCT-116, AGS and SW-620 with IC50 values of 86.5 μg/mL, 80.65 μg/mL and 109.255 μg/mL respectively. Also, the cellular uptake assay has shown an increased uptake of FITC-labeled-MSN-PG-HA by HA-receptor mediated endocytosis than FITC-labeled-MSN-PG without HA modification in CD44+ gastrointestinal cancer cell lines. The ability of MSN-PG-HA to target CD44+ cells was further exploited for its application in cancer stem cell research utilizing in silico analysis with various stem cell pathway related targets, in which PG showed higher binding affinity with Gli 1 and the simulation studies proving its effectiveness in disrupting the protein structure. Thus, the findings of our study with nano-formulation are safe and non-toxic to recommend for targeted drug delivery against gastrointestinal cancers as well as its affinity towards cancer stem cell pathway related proteins proving to be a significant formulation for cancer stem cell research.

Human serum albumin and sialic acid co-modified liposome nanoreactors with tumor-specific activable cascade reactions for cooperative cancer therapy

Herein, a new type of human serum albumin (HSA) and sialic acid (SA) co-modified liposome nanoreactor was prepared to realize chemotherapy and chemodynamic therapy cooperative treatment of tumor. Firstly, Paclitaxel (PTX) acidic sensitive prodrug with a maleimide-terminated functional group and a sialic acid-modified reduced glutathione (GSH) sensitive paclitaxel prodrug have been synthesized. Then, a liposome nanoreactor was prepared by using PTX prodrugs, lecithin, and cholesterol as membrane materials, and simultaneously encapsulating water-soluble Fe3O4 and glucose oxidase. Finally, HSA was bound to the surface of liposomes through the Michael addition between maleimide-terminated functional group of PTX prodrug and the thiol group at the cysteine 34 residue of human serum albumin. The cumulative release rates of PTX in nanoreactor were 43.98 % at pH = 5.5 and 14.98 % at pH 7.4 after 96h respectively, exhibiting pH sensitive drug release behavior. Also 25.98 % and 17.52 % of PTX release were observed respectively in the medium with 10 mM DTT and without DTT after 96h, displaying redox responsive drug release behavior. The fluorescence intensity of tumor sites for the Dir loaded nanoreactor was higher than that of the free Dir group, displaying the targeting ability of HSA and SA. In tumor site, glucose oxidase can catalyze glucose to generate hydrogen peroxide, and hydroxyl radical is generated under an iron-based Fenton reaction between hydrogen peroxide and iron ion to kill tumor cells to realize chemodynamic therapy. After administration, the average tumor weight of the NS group was 2.516g, while nanoreactor group was 0.322g, displaying the synergistic therapy and excellent anticancer efficacy.

Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is rapidly progressed hematologic malignancy with relapsed and refractory characteristics. Cytarabine combined with the BCL2 inhibitor venetoclax showed impressive response rates in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML), while it requires complicated administration regimens and brings added toxicity. In this work, we synthesized a mercaptopropionic acid-substituted derivative of Ara-C (Ara-SH) and used it as the trigger to fabricate a smart cytarabine and venetoclax-coloaded nanoparticle (AV-NP) through self-assembly. The AV-NP characterized with redox-responsive drug release, rapid uptake by leukemia cells, and long retention in circulation had the potential to accumulate in leukemia-enriched sites. It generated a remarkable synergistic effect with higher antileukemia activity in vitro and better safety in the hematologic system compared with free drugs and significantly improved the therapeutic effect on orthotopic AML mice in vivo. These similar results were also confirmed in primary cells from R/R-AML patients. Besides, the AV-NP has the superiority of facile fabrication and generalizability, rendering it easy for clinical translation.

Colon-Targeting Angelica sinensis Polysaccharide Nanoparticles with Dual Responsiveness for Alleviation of Ulcerative Colitis.

Intestinal immune dysfunction and gut microbiota dysbiosis are critically causative factors in the pathogenesis of ulcerative colitis (UC); however, the current first-line drugs for UC treatment in clinics often remain great challenges due to their nontargeting therapeutic efficacy and severe side effects. In the current study, colon-targeting nanoparticles based on Angelica sinensis polysaccharide with pH- and redox-responsiveness were fabricated to specifically release the naturally active compound ginsenoside Rh2 in the colonic inflammatory site, which greatly alleviated the UC symptoms and improved the gut microbial homeostasis. These dual responsive Rh2-loaded nanoparticles (Rh2/LA-UASP NPs) with a particle size of 117.00 ± 4.80 nm were prepared using the polymer LA-UASP obtained by grafting A. sinensis polysaccharide with urocanic acid and α-lipoic acid (α-LA). As expected, these Rh2/LA-UASP NPs achieved dual pH- and redox-responsive drug release at pH 5.5 and 10 mM GSH. The stability, biocompatibility, and in vivo safety experiments exhibited these prepared nanoparticles had excellent colon-targeting ability and significant accumulation of Rh2 in the inflammatory colon. Meanwhile, these Rh2/LA-UASP NPs could escape from lysosomes and be efficiently internalized into intestinal mucosal cells, thereby effectively inhibiting the release of proinflammatory cytokines. The animal experiments indicated that Rh2/LA-UASP NPs significantly improved the integrity of intestinal mucosa and increased the colon length compared with UC mice. Additionally, the weight loss, histological damage, and inflammation level were greatly ameliorated. The homeostasis of intestinal flora and the level of short-chain fatty acids (SCFAs) were significantly improved after being treated with Rh2/LA-UASP NPs in UC mice. Our study proved that these Rh2/LA-UASP NPs with dual pH-and redox-responsiveness are promising candidates for UC treatment.

Targeted Delivery of Doxorubicin to Hepatoma Cells by Lactobionic Acid-Decorated Dual Redox-Responsive Polyethylene Glycol-Doxorubicin Nanoparticles

In this work, we synthesized lactobionic acid-decorated diselenide-linked polyethylene glycol-doxorubicin conjugate (LA-PEG-SeSe-DOX) and prepared free DOX-loaded LA-PEG-SeSe-DOX(DOX@LA-PEG-SeSe-DOX) nanoparticles for hepatoma-targeted DOX delivery. LA-PEG-SeSe-DOX can self-assemble into nanoparticles in deionized water and DOX@LA-PEG-SeSe-DOX nanoparticles were prepared by loading free DOX into LA-PEG-Se-Se-DOX nanoparticles under sonication. DOX@LA-PEG-SeSe-DOX nanoparticles have high DOX loading content of 31.3%. The dynamic scattering analysis shows that DOX@LA-PEG-SeSe-DOX nanoparticles have small size (hydrodynamic diameter [Formula: see text][Formula: see text]nm), near neutral zeta potential, and excellent colloidal stability. The in vitro drug release study indicates that DOX@LA-PEG-SeSe-DOX nanoparticles exhibit dual redox-responsive drug release characteristics. The cellular uptake study reveals that DOX@LA-PEG-SeSe-DOX nanoparticles can be taken up by hepatoma cells by asialoglycoprotein receptor (ASGPR)-mediated pathway. Finally, DOX@LA-PEG-SeSe-DOX nanoparticles exhibit enhanced cytotoxicity against HepG2 cells as compared to LA-PEG-SeSe-DOX nanoparticles, underlining the significance of releasing free DOX for effective tumor cell proliferation inhibition. This work provides a facile and effective strategy for targeted delivery of DOX to hepatoma cells.

Probing the Role of Connecting Bonds and Modifying Chains in the Rational Design of Prodrug Nanoassemblies.

Prodrug-based self-assembled nanoparticles combined with the merits of nanotechnology and prodrugs strategies have gradually become a research trending topic in the field of drug delivery. These prodrugs usually consist of parent drugs, connecting bonds, and modifying chains. The influences of the connecting bonds and modifying chains on the pharmaceutical characteristics, in vivo delivery fate, and antitumor activity of prodrug nanoassemblies remain elusive. Herein, three docetaxel (DTX) prodrugs were designed using sulfur bonds (thioether bond or disulfide bond) as connecting bonds and fatty alcohols (straight chain or branched chain) as modifying chains. Interestingly, the difference between connecting bonds and modifying chains deeply influenced the colloidal stability, redox responsive drug release, cytotoxicity, pharmacokinetic properties, tumor accumulation, and antitumor effect of prodrug nanoassemblies. DTX conjugated with branched chain fatty alcohols via disulfide bonds (HUA-SS-DTX) significantly improved the antitumor efficiency of DTX and reduced the systematic toxicity. Our study elaborates on the vital role of connecting bonds and modifying chains in the rational design of prodrug nanoassemblies.

Mixed-Ligand Metal-Organic Frameworks for All-in-One Theranostics with Controlled Drug Delivery and Enhanced Photodynamic Therapy.

Mixed-ligand metal-organic frameworks (MOFs) multiply the properties and improve the versatility of conventional MOFs for theranostic applications. A tumor targeting and tumoral microenvironment-responsive system is significant for specific and efficient cancer theranostics. Herein, we report a kind of versatile mixed-porphyrin ligand MOF as a multifunctional matrix for multimodality-imaging-guided synergistic therapy. Tetrakis(4-carboxyphenyl)porphyrin (TCPP) shows the properties of fluorescence (FL) and photodynamic therapy (PDT), while Mn-TCPP owns magically the properties of T1-weighted magnetic resonance (MR) imaging and photothermal conversion for photothermal imaging and photothermal therapy (PTT). Because of the same coordination capacity and mode of TCPP and Mn-TCPP to Zr4+ ions, MOFs with adjustable ligand ratios were easily prepared. The mixed-ligand MOFs exhibited a high drug loading capacity for 10-hydroxycamptothecin (HCPT, 65%). After modification with hyaluronic acid (HA) through a disulfide bond (-S-S-), the MOF-S-S-HA composites possess enhanced PDT and tumor-targeted redox-responsive drug release properties due to the -S-S- bond. Thus, excellent fluorescence, MR, and photothermal trimodality imaging, redox-responsive drug release, and enhanced PDT/PTT are integrated together in the mixed-ligand MOFs as "all-in-one" theranostic agents.

Redox-responsive glycosylated combretastatin A-4 derivative as novel tubulin polymerization inhibitor for glioma and drug delivery.

Combretastatin A-4 (CA4), a tubulin inhibitor, binds to the colchicine site of tubulin, inhibits tubulin polymerization, and leads to the apoptosis of tumor cells. However, the poor hydrophilicity and blood-brain barrier (BBB) penetration ability of CA4 hampers its application in the treatment of glioma. In this study, a novel combretastatin A-4 derivative (CA4D) was designed and developed, which was further conjugated with glucose via disulfide-bond-bridged (CA4D-SS-Glu) to enhance the BBB penetration capacity. The obtained CA4D-SS-Glu conjugate displayed a suitable water partition coefficient and the superior ability across BBB in vitro and in vivo. In addition, the CA4D-SS-Glu exhibited rapid redox-responsive drug release in the presence of glutathione, enhanced in vitro cytotoxicity, and cell apoptosis. Our data further confirmed that CA4D-SS-Glu inhibited proliferation, and restrained migration via affecting microtubule stabilization. Additionally, the conjugate also showed the highest antiproliferative and antitumor action on glioma in vivo as compared to CA4D and CA4. Taken together, the novel CA4D-SS-Glu conjugate possess improved physicochemical property and BBB penetration ability, reduction triggered release of CA4D, and efficient antiproliferative activity. These results provided a novel and effective entry to the treatment of glioma.

Drug Release from Disulfide-Linked Prodrugs: Role of Thiol Agents.

The disulfide bond (SS) has been widely used in prodrugs for the redox-responsive drug release, but its drug release mechanism and rate were seldom compared in different thiol agents. Herein, self-assembling nanoaggregates (NAs) formed by camptothecin (CPT)-oleic acid (OA) prodrugs linked by two frequently used SS linkers (ETCSS and ACSS) were used for such comparative investigation. It is found that the cleavage of ETCSS was directly coupled with CPT release, whereas the breakage of ACSS resulted in the generation of CPT intermediates, the chemical stability of which determined CPT release. In both cases, the redox-responsive drug release was highly dependent on the reactivity between SS and thiol agents, with an order of dithiothreitol > cysteine ≈ glutathione. Moreover, the presence of SS significantly accelerated the extracellular CPT release, which was around 3-4 fold higher than intracellular CPT release. Therefore, the in vitro cytotoxicity of SS-linked CPT-OA NAs could not be ascribed to the glutathione-trigged intracellular drug release but rather to the SS-accelerated extracellular CPT release. The above results would effectively guide the rational design and evaluation of SS-linked prodrug NAs for efficient drug delivery.

Interface-sensitized prodrug nanoaggregate as an effective in situ antitumor vaccine

In situ antitumor vaccines have been widely explored as an effective strategy to inhibit tumor growth by stimulating antitumor immune responses. Herein, we reported a simple and effective in situ antitumor vaccine, which was prepared by co-assembling cationic lipids (DOTAP) with the disulfide bond-linked lipid-drug conjugates of camptothecin and resiquimod. The resulting vaccine had a rod-sharped morphology with nanoscale sizes (average hydrodynamic diameter of ∼163.7 nm) and positively-charged interfaces (zeta potential ∼ +36.2 mV). The interfacial cationization of nanoaggregate resulted in 1000 folds faster redox-responsive drug release than that of unmodified ones, which induced a much more potent in vivo antitumor immune by accelerating the glutathione-responsive drug release at the tumor site. Such cationic lipid-drug nanoaggregates displayed many benefits, such as high co-loading capacity, simple preparation process, and wide applicability, which would serve as a promising new approach to design effective in situ antitumor vaccines.

Redox-sensitive carrier-free nanoparticles self-assembled by disulfide-linked paclitaxel-tetramethylpyrazine conjugate for combination cancer chemotherapy.

Rationale: Combinations of two or more therapeutic agents targeting different signaling pathways involved in tumor progression can have synergistic anticancer effects. However, combination chemotherapies are greatly limited by the different pharmacokinetics, tumor targeting, and cellular uptake capacities of the combined drugs. We have previously demonstrated the potential synergistic efficacy of paclitaxel (PTX) and the natural anti-angiogenic agent tetramethylpyrazine (TMP) for suppressing ovarian carcinoma growth. An efficient, facile, and smart nanosystem to deliver PTX and TMP simultaneously in vivo is greatly desired.Methods: We constructed a redox-sensitive nanosystem based on the amphiphilic PTX-ss-TMP conjugate, in which PTX and TMP are linked by a disulfide bond. We characterized the structure of the drug conjugate by 1H NMR and LC-MS, and then prepared PTX-ss-TMP NPs by a one-step nanoprecipitation method. We investigated the redox sensitivity, tumor-targeting ability, anticancer efficacy, and anti-angiogenesis activity of PTX-ss-TMP NPs in vitro and in vivo.Results: The amphiphilic PTX-ss-TMP conjugate readily self-assembled into stable nanoparticles in aqueous solution with a low critical association concentration of 1.35 µg/mL, well-defined spherical structure, small particle size (152 nm), high drug loading, redox-responsive drug release, high biocompatibility, and high storage stability. In cancer cells pretreated with GSH-OEt, PTX-ss-TMP NPs exhibited higher cytotoxicity, apoptosis rate, and cell-cycle arrest than monotherapy or combination therapy with free drugs, which was attributed to their improved cellular uptake and rapid intracellular drug release. Additionally, PTX-ss-TMP NPs also had a stronger anti-angiogenesis effect in HUVECs than free drug, which was mediated by VEGFR2-involved downstream signals. Finally, PTX-ss-TMP NPs showed tumor-specific accumulation and excellent antitumor activity in A2780 xenograft mice compared with free drug.Conclusions: These in vitro and in vivo results provide clear evidence that this redox-responsive carrier-free nanosystem with intrinsic amphiphilicity has great potential for combination cancer chemotherapy.

Interfacial cationization to quicken redox-responsive drug release.

Interfacial cationization could greatly increase the redox-responsiveness of disulfide bond-linked lipid-drug nanoassemblies (NAs) due to the generation and concentration of ionized thiols at the alkalized NAs' cationic interface. This strategy could be used to prepare redox-ultrasensitive nanocarriers for efficient intracellular drug delivery.

Pure redox-sensitive paclitaxel–maleimide prodrug nanoparticles: Endogenous albumin-induced size switching and improved antitumor efficiency

A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer. However, its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier. Herein, we report an albumin-bound tumor redox-responsive paclitaxel prodrugs nano-delivery strategy. Using diverse linkages (thioether bond and disulfide bond), paclitaxel (PTX) was conjugated with an albumin-binding maleimide (MAL) functional group. These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles (NPs) in aqueous solution without any excipients. By immediately binding to blood circulating albumin after intravenous administration, NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo, facilitating PTX prodrugs accumulation in the tumor region via albumin receptor-mediated active targeting. The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells. Moreover, disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo. This simple and facile strategy integrates the biomimetic characteristic of albumin, tumor redox-responsive on-demand drug release, and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.

Regenerated keratin-encapsulated gold nanorods for chemo-photothermal synergistic therapy.

Gold nanorods (AuNRs) have been widely applied to photothermal therapy against cancer. However, the chemically synthesized AuNRs such as that via seed-mediate method usually demonstrated a high cytotoxicity due to the existence of cetyltrimethylammonium bromide (CTAB) coating. In this work, keratin, a family of cysteine-rich structural fibrous proteins was used for the first time to encapsulate AuNRs by a simple mixing method. Compared with CTAB-AuNRs, the keratin-encapsulated AuNRs (AuNRs@Kr) showed an improved colloid stability and good biocompatibility including low cytotoxicity and hemolytic effect. Moreover, AuNRs@Kr exhibited great potential as drug carriers with redox-responsive drug release behavior, due to the high concentration of disulfide crosslinking in keratin coating, and the DOX-loaded AuNRs@Kr demonstrated higher chemo-photothermal synergistic therapy efficiency against 4T1 cells compared with either free DOX or AuNRs@Kr alone, suggesting a promising nanoplatform for cancer therapy.

Paclitaxel and quercetin co-loaded functional mesoporous silica nanoparticles overcoming multidrug resistance in breast cancer

Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) (MSNs-ChS@PQ) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC50 value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo. Taken together, our research provides a viable approach to overcome MDR in breast cancer.