Reduction-responsive Drug Release Research Articles

Carbon-Spaced Tandem-Disulfide Bond Bridge Design Addresses Limitations of Homodimer Prodrug Nanoassemblies: Enhancing Both Stability and Activatability.

Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.

Drug delivery using reduction-responsive hydrogel based on carboxyethyl-succinoglycan with highly improved rheological, antibacterial, and antioxidant properties

The development of exopolysaccharide-based polymers is gaining increasing attention in various industrial biotechnology fields for materials such as thickeners, texture modifiers, anti-freeze agents, antioxidants, and antibacterial agents. High-viscosity carboxyethyl-succinoglycan (CE-SG) was directly synthesized from succinoglycan (SG) isolated from Sinorhizobium meliloti Rm 1021, and its structural, rheological, and physiological properties were investigated. The viscosity of CE-SG gradually increased in proportion to the degree of carboxyethylation substitution. In particular, when the molar ratio of SG and 3-chloropropionic acid was 1:100, the viscosity was significantly improved by 21.18 times at a shear rate of 10 s−1. Increased carboxyethylation of SG also improved the thermal stability of CE-SG. Furthermore, the CE-SG solution showed 90.18 and 91.78 % antibacterial effects against Escherichia coli and Staphylococcus aureus and effective antioxidant activity against DPPH and hydroxyl radicals. In particular, CE-SG hydrogels coordinated with Fe3+ ions, which improved both viscosity and rheological properties, while also exhibiting reduction-responsive drug release through 1,4-dithiothreitol. The results of this study suggest that SG derivatives, such as CE-SG, can be used as functional biomaterials in various fields such as food, cosmetics, and pharmaceutical industries.

An Engineered Butyrate-Derived Polymer Nanoplatform as a Mucosa-Healing Enhancer Potentiates the Therapeutic Effect of Magnolol in Inflammatory Bowel Disease.

Colonic epithelial damage and dysregulated immune response are crucial factors in the progression and exacerbation of inflammatory bowel disease (IBD). Nanoenabled targeted drug delivery to the inflamed intestinal mucosa has shown promise in inducing and maintaining colitis remission, while minimizing side effects. Inspired by the excellent antioxidative and anti-inflammatory efficacy of naturally derived magnolol (Mag) and gut homeostasis regulation of microbiota-derived butyrate, we developed a pH/redox dual-responsive butyrate-rich polymer nanoparticle (PSBA) as an oral Mag delivery system for combinational therapy of IBD. PSBA showed a high butyrate content of 22% and effectively encapsulated Mag. The Mag-loaded nanoparticles (PSBA@Mag) demonstrated colonic pH and reduction-responsive drug release, ensuring efficient retention and adhesion in the colon of colitis mice. PSBA@Mag not only normalized the level of reactive oxygen species and inflammatory effectors in inflamed colonic mucosa but also restored the epithelial barrier function in both ulcerative colitis and Crohn's disease mouse models. Importantly, PSBA promoted the migration and healing ability of intestinal epithelial cells in vitro and in vivo, sensitizing the therapeutic efficacy of Mag in animal models. Moreover, transcriptomics and metabolism analyses revealed that PSBA@Mag mitigated inflammation by suppressing the production of pro-inflammatory cytokines and chemokines and restoring the lipid metabolism. Additionally, this nanomedicine modulated the gut microbiota by inhibiting pathogenic Proteus and Escherichia-Shigella and promoting the proliferation of beneficial probiotics, including Lachnoclostridium, Lachnospiraceae_NK4A136_group and norank_f_Ruminococcaceae. Overall, our findings highlight the potential of butyrate-functionalized polymethacrylates as versatile and effective nanoplatforms for colonic drug delivery and mucosa repair in combating IBD and other gastrointestinal disorders.

Synthesis of Amphiphilic Block Polyphosphoester and Exploring Its Potential in Reduction-Responsive Drug Release

Synthesis of Amphiphilic Block Polyphosphoester and Exploring Its Potential in Reduction-Responsive Drug Release

Hydroxyethyl starch-folic acid conjugates stabilized theranostic nanoparticles for cancer therapy.

Small molecular prodrug-based nanomedicines with high drug-loading efficiency and tumor selectivity have attracted great attention for cancer therapy against solid tumors, including triple negative breast cancers (TNBC). However, abnormal tumor mechanical microenvironment (TMME) severely restricts antitumor efficacy of prodrug nanomedicines by limiting drug delivery and fostering cancer stem cells (CSCs). Herein, we employed carbamate disulfide bridged doxorubicin dimeric prodrug as pharmaceutical ingredient, marketed IR780 iodide as photothermal agent, and biocompatible hydroxyethyl starch-folic acid conjugates as amphiphilic surfactant to prepare a theranostic nanomedicine (FDINs), which could actively target at TNBC 4T1 tumor tissues and achieve reduction-responsive drug release with high glutathione concentration in cancer cells and CSCs. Importantly, in addition to directly causing damage to cancer cells and sensitizing chemotherapy, FDINs-mediated photothermal effect regulates aberrant TMME via reducing cancer associated fibroblasts and depleting extracellular matrix proteins, thereby normalizing intratumor vessel structure and function to facilitate drug and oxygen delivery. Furthermore, FDINs potently eliminate CSCs by disrupting unique CSCs niche and consuming intracellular GSH in CSCs. As a result, FDINs significantly suppress tumor growth in both subcutaneous and orthotopic 4T1 tumors. This study provides novel insights on rational design of prodrug nanomedicines for superior therapeutic effect against stroma- and CSCs-rich solid malignancies.

Injectable and biocompatible alginate-derived porous hydrogels cross-linked by IEDDA click chemistry for reduction-responsive drug release application

In this work, novel injectable and reduction-responsive hydrogels were successfully prepared via inverse electron demand Diels-Alder reaction between alginate-norbornene and a water-soluble PEG based disulfide cross-linker. The reduction-responsive cross-linker was designed to contain a PEG chain within two disulfide linkages, and two terminal tetrazine groups. The resulting hydrogels possessed high swelling ratios, porous morphology, excellent drug loading efficiency (~92%), and suitable mechanical properties. The drug release experiments demonstrated that the hydrogels released more than 90% of the encapsulated doxorubicin (DOX) in the presence of 10 mM glutathione while a minimal DOX release (<25%) was measured in physiological buffer (PBS, pH = 7.4) after 11 d. The cross-linker and hydrogels did not exhibit any apparent cytotoxicity to fibroblast cells. In contrast, DOX-loaded hydrogels induced anti-tumor activity against cancer cells. The injectable and reduction-responsive hydrogels hold great potential as a biomaterial for stimuli responsive drug delivery applications.

EGFR-targeted pemetrexed therapy of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare malignancy with poor prognosis, for which chemotherapy with pemetrexed (PEM) is among the few clinical treatments. PEM suffers, however, fast clearance, moderate drug exposure, and dose-limiting toxicities. Here, we report on epidermal growth factor receptor (EGFR)-targeted disulfide-crosslinked biodegradable chimaeric polymersomes (EGFR-CPs) to firmly load PEM and boost chemotherapy of MPM. EGFR-CPs encapsulating 8.7-16.4 wt.% PEM (EGFR-CPs-PEM) showed diameters of 62-65nm and reduction-responsive drug release property. EGFR-CPs-PEM was more efficiently taken up by EGFR-overexpressed MSTO-211H cells, inducing about 4.7-fold enhanced anticancer activity compared with non-targeted CPs-PEM control. Intriguingly, the in vivo experiments in MSTO-211H xenograft mouse model revealed that EGFR-CPs-PEM brought about superior tumor deposition and penetration to CPs-PEM, and significantly more potent tumor repression than CPs-PEM and free PEM. This polymersome-enabled EGFR-targeted delivery of PEM offers an appealing therapeutic strategy for MPM.

Sonochemical fabrication of magnetic reduction-responsive alginate-based microcapsules for drug delivery

The magnetic reduction-responsive alginate-based microcapsules (MRAMCs) have been developed successfully with thiolated alginate and oleic acid (OA) modified Fe3O4 nanoparticles (OA-Fe3O4 NPs) via a facile sonochemical method. The obtained MRAMCs could be used as multifunctional carriers for hydrophobic drugs targeted delivery and triggered release due to their merits, such as biocompatibility, non-immunogenicity, magnetic targeting drug delivery and reduction-responsive drug release. The MRAMCs were endowed with magnetic targeting function owing to the encapsulation of the superparamagnetic OA-Fe3O4 NPs, which was confirmed by transmission electron microscope and vibrating sample magnetometer. In addition, the MRAMCs presented excellent reduction-responsive release ability for hydrophobic drugs on account of the disulfide bonds in the wall of microcapsules, which were formed by the cross-linking of sulfhydryl groups on thiolated alginate under ulstrasonication. Meanwhile, confocal laser scanning microscopy measurement indicated that coumarin 6 acted as a hydrophobic model drug could be loaded into MRAMCs easily by dissolving in soybean oil before ultrasonication. Overall, these results demonstrated that MRAMCs would be a promising platform to build controllable drug delivery systems for targeted delivery and triggered release of hydrophobic drugs in biomedical application.

Dimeric camptothecin-loaded mPEG-PCL nanoparticles with high drug loading and reduction-responsive drug release

Camptothecin (CPT) is a potent and broad-spectrum anti-tumor drug, but its clinical application is limited due to its poor water solubility, toxicity, and low drug-loading potential. Different delivery protocols have been developed to optimize the therapeutic effects of CPT. In this study, CPT was modified into a dimer (CPT-Mal-CPT), in which two CPT molecules are connected by a reduction-responsive maleimide thioether bond. Moreover, biocompatible methoxy poly(ethylene glycol)-b-poly(e-caprolactone) (mPEG–PCL)-loaded CPT-Mal-CPT nanoparticles were prepared to overcome the limits of CPT application. The power X-ray diffractometer (PXRD) results indicate low crystallinity and amorphous nature of CPT-Mal-CPT. The CPT-Mal-CPT-loaded micelles showed a drug-loading content of 9.6% and a drug-loading efficiency of 56%. In addition, dimeric CPT micelles showed reduction-responsive release under 10-mM dithiothreitol (DTT), while negligible CPT release was detected in the absence of DTT. MTT assay indicated that cytotoxicity of dimeric CPT micelle was similar to free CPT.

Reduction-Responsive Polymer Prodrug Micelles with Enhanced Endosomal Escape Capability for Efficient Intracellular Translocation and Drug Release.

High-efficiency endosomal escape of drug delivery nanocarriers for glutathione-based reduction-responsive drug release in cytoplasm can significantly enhance the therapeutic efficacy of the loaded therapeutic drugs. In this report, we develop the polymer prodrug micelles self-assembled from the amphiphilic block copolymer prodrug, PEG-b-P(CPTM-co-ImOAMA), consisting of poly(ethylene glycol) (PEG) and copolymerized segments of disulfide bond-linked camptothecin methacrylate monomer (CPTM) and 1-(1H-imidazole-4-yl)-2-(octylamino)-2-oxoethyl methacrylate (ImOAMA). After cellular internalization through endocytosis, PEG-b-P(CPTM-co-ImOAMA) micelles are trapped in endosomes inside the tumor cells. The endosomal pH can trigger the protonation of the imidazole moieties of PImOAMA segments, which may facilitate endosome escape through the proton sponge effect and the improved interactions between protonated imidazole groups, hydrophobic octyl moieties, and endosomal membranes. Moreover, the high concentration of glutathione in the cytoplasm of cancer cells can trigger the release of active camptothecin (CPT) through cleavage of the disulfide linkers from PCPTM. The in vitro results showed that PEG-b-P(CPTM-co-ImOAMA) micelles could be effectively internalized into cells followed by endosomal escape, which contributed to the significantly improved cancer cell-killing efficacy. Moreover, in vivo studies confirmed that the PEG-b-P(CPTM-co-ImOAMA) micelles realized efficient tumor growth inhibition without obvious side toxicity. Therefore, the proposed reduction-responsive polymeric prodrug micelles with high endosomal escape capability could provide a brilliant potential in a drug delivery platform to achieve enhanced antitumor efficacy.

Cyclic RGD-Functionalized and Disulfide-Crosslinked Iodine-Rich Polymersomes as a Robust and Smart Theranostic Agent for Targeted CT Imaging and Chemotherapy of Tumor.

There is tremendous interest in integrating CT imaging with chemotherapy; however, reported iodine-based nanosystems such as nanogels and nano-emulsions display typically reduced contrast coefficient, low drug loading and stability, and poor targetability. Here, cRGD-functionalized disulfide-crosslinked iodine-rich polymersomes (cRGD-XIPs) were designed as a novel, robust and smart theranostic agent and investigated for targeted CT imaging and chemotherapy of malignant tumors.Methods: cRGD-XIPs were prepared from co-self-assembly of poly(ethylene glycol)-b-poly(dithiolane trimethylene carbonate-co-iodinated trimethylene carbonate) (PEG-P(DTC-IC)) and cRGD-PEG-P(DTC-IC) block copolymers. In vitro and in vivo CT contrast effect of cRGD-XIPs was studied using αvβ3-overexpressing B16 melanoma as a tumor model in comparison with clinical agent iohexol. The therapeutic efficacy of doxorubicin-loaded cRGD-XIPs (cRGD-XIPs-Dox) to B16 melanoma was investigated and compared with XIPs-Dox (non-targeted), cRGD-IPs-Dox (non-crosslinked) and free Dox.Results: cRGD-XIPs were formed with 55.5 wt.% iodine and ca. 90 nm in diameter. cRGD-XIPs-Dox with a Dox loading of 15.3 wt.% bared superior colloidal stability and reduction-responsive drug release. Notably, blank cRGD-XIPs showed a maximum-tolerated dose (MTD) > 400 mg iodine equiv./kg while cRGD-XIPs-Dox had an MTD > 150 mg Dox equiv./kg, ca. 15-fold improvement over free Dox. cRGD-XIPs revealed superior CT contrast effect and achieved 46.5- and 24.0-fold better enhancement of CT imaging of B16 melanoma than iohexol at 4 h following intratumoral and intravenous injection, respectively. cRGD-XIPs-Dox displayed an elimination half-life of 6.5 h and an elevated accumulation of 6.68% ID/g in the tumors. Furthermore, cRGD-XIPs-Dox was significantly more effective than XIPs-Dox and cRGD-XPs-Dox in inhibiting growth of B16 melanoma model.Conclusion: This proof-of-concept study demonstrates that cRGD-XIPs are a robust, non-toxic and smart polymeric theranostic agent that can not only significantly enhance CT imaging of tumors but also mediate efficient tumor-targeted chemotherapy. XIPs offer a unique and safe platform for theranostic polymersomes that pre-select patients using CT imaging prior to targeted chemotherapy with the same system.

A stage-specific cancer chemotherapy strategy through flexible combination of reduction-activated charge-conversional core-shell nanoparticles.

Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA).Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed.Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively.Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.

Reduction-responsive amphiphilic polymeric prodrugs of camptothecin-polyphosphoester for cancer chemotherapy.

As one of the promising prodrug strategies, amphiphilic polymeric prodrugs can be constructed by conjugating some small molecular hydrophobic anticancer drugs onto a hydrophilic biodegradable and biocompatible polymer, which further self-assembles into nanoparticles with controllable drug loading. Here, a biocompatible and biodegradable polyphosphoester and a broad-spectrum anticancer drug camptothecin (CPT) were selected as model compounds. We first designed and synthesized a novel cyclic phosphoester monomer (CPTSP) containing a disulfide bond linker and CPT as a side group. Then a reduction-responsive amphiphilic polymeric prodrug (PCPTSP-co-PEEP) was prepared through the ring-opening copolymerization of CPTSP and a common cyclic phosphoester monomer containing ethyl (EEP) as the side group, which was initiated by benzyl alcohol with 1,8-diazabicycloundec-7-ene (DBU) and thiourea (TU) as catalysts. The resulting PCPTSP-co-PEEPs could self-assemble into micelles in water due to their hydrophilic polyphosphoester main chain and some hydrophobic CPT side groups. The average size and the drug loading content of these micelles can be controlled by adjusting the feed molar ratio of EEP and CPTSP. The average hydrodynamic diameter increased from 190 nm to 250 nm when the molar ratio of EEP/CPTSP was adjusted from 9/1 to 49/1. These micelles possessed appropriate stability under physiological conditions and degraded in the reduction medium according to their change in size monitored by DLS measurement. Their reduction-responsive properties were also confirmed by the in vitro drug release behavior. Moreover, these micelles could enter into HT29 tumor cells via endocytosis and released CPT efficiently to inhibit their proliferation. The in vivo tumor inhibition rate of these polymeric prodrugs was 73.4%, which was about two fold that for free CPT (36.5%). This approach of polymeric prodrugs based on polyphosphoesters can be extended to other anticancer drugs to construct smart drug delivery systems for cancer treatment.

Reduction-Triggered Release of CPT from Acid-Degradable Polymeric Prodrug Micelles Bearing Boronate Ester Bonds with Enhanced Cellular Uptake.

The aim of this research is to develop a novel type of camptothecin (CPT) prodrug micelles bearing boronate ester bonds as a smart nanosystem with enhanced cellular uptake and controlled drug release based on diblock copolymer abbreviated as PEG-BC-PGlu-ss-CPT. Particularly, boronate ester bond was introduced to achieve acid-triggered de-PEGylation and succeeding boronic acid-mediated enhanced cellular uptake. Besides, CPT was conjugated to the prodrug monomer through a disulfide bond to realize reduction-responsive drug release. The resultant copolymer PEG-BC-PGlu-ss-CPT could self-assemble into spherical nanomicelles in water. The degradation half-life time of PEG-BC-PGlu-ss-CPT copolymer decreased sharply from 96.27 h to only 5.7 h with pH value decreasing from 7.4 to 5.0, indicating the acid-degradable potential, which corresponded to size change monitoring. The cumulative CPT release from prodrug micelles increased significantly from 8.5 ± 1.73 to 82.9 ± 2.29% with an increase of dithiothreitol (DTT) concentration from 20 μM to 10 mM at pH 7.4, illustrating the reduction-responsive drug release property of prodrug micelles. The half maximal inhibitory concentration (IC50) value of prodrug micelles against HepG2 cells decreased from 1.06 to 0.68 μg/mL with the decrement of pH value from 7.4 to 6.0, proving that the utilization of boronate ester bonds was beneficial for enhancing antiproliferative activity. Interestingly, prodrug micelles exhibited enhanced cellular uptake ability against HepG2 cells compared to that of HL7702 cells, further confirming boronic acid-mediated enhanced endocytosis. In brief, this novel type of intelligent prodrug micelles possessed great potential as a smart nanosystem for antitumor drug delivery.

Selenylsulfide Bond-Launched Reduction-Responsive Superparamagnetic Nanogel Combined of Acid-Responsiveness for Achievement of Efficient Therapy with Low Side Effect.

With the objective to achieve in-between reduction-responsive drug release, selenylsulfide bond was first explored as a reduction cleavable linkage, compared with the most commonly employed disulfide and diselenide bonds. The reductive nanogel, with a combination of superparamagnetic and acid responsiveness, was fabricated. The expected release profiles were testified. Cytotoxicity assays illustrated the remarkable inhibition to the growth of HeLa cells, in contrast, high tolerance to L02 cells. In vivo investigation exhibited the obvious shrinkage in tumor but a healthy appearance. Hematoxylin-eosin staining and histological examination revealed the lower toxicity. The complex nanogels would have appeared highly promising in cancer therapy.

A theranostic gemcitabine prodrug with AIE-based intracellular light-up characteristics for selective suppression of pancreatic cancer cells

Event Abstract Back to Event A theranostic gemcitabine prodrug with AIE-based intracellular light-up characteristics for selective suppression of pancreatic cancer cells Qiao Jin1, Haijie Han1, Haibo Wang1 and Jian Ji1 1 Zhejiang University, Department of Polymer Science and Engineering, China Pancreatic cancer is one of the most lethal malignancies with a 5 year survival rate of 5% [1]. Gemcitabine (GEM) is currently the first line drug available for treatment of pancreatic cancer. Unfortunately, the clinical application of GEM is severely limited since it can undergo rapid deamination into inactive metabolite [2]. Meanwhile, in the clinical management of pancreatic cancer patients, timely assessment of therapeutic response to a given therapy is critical for making treatment decisions. A new class of fluorescent probes with aggregation-induced emission (AIE) behaviours was reported as a powerful tool in biosensing and bioimaging [3]. In this research, we designed a novel theranostic tetraphenylene (TPE)-containing gemcitabine prodrug TPE-GEM-RGD, which can be used for targeted light-up imaging and selective release of GEM under intracellular reductive environment (Figure 1). Figure 1. TPE-GEM-RGD for cathepsin B-responsive fluorescence light up and reduction-responsive drug release. In order to evaluate the light-up capability of TPE-GEM-RGD prodrug, the fluorescent spectra of TPE-GEM-RGD incubated with cathepsin B were recorded. The fluorescence intensity of TPE-GEM-RGD increased steadily with time in the presence of cathepsin B, which might be ascribed to the cleavage of GFLG sequence by cathepsin B. The reduction-responsive GEM release was studied by incubating TPE-GEM-RGD prodrug with 10 mM of GSH. According to HPLC analysis, upon treating with GSH, GEM was released owing to the appearance of the peak at 4.3 min, which was the characteristic peak of free GEM. Therefore, GEM can be released upon treating with GSH. Since cathepsin B is overexpressed in pancreatic cancer cells, the capability of TPE-GEM-RGD as cancer cell specific fluorescent light-up probe was studied for live cell imaging [4]. As shown in Figure 2, strong blue fluorescence was observed after BxPC-3 cells were incubated with 50 μM TPE-GEM-RGD. However, when BxPC-3 cells were pretreated with cathepsin B inhibitor CA-074-Me, only very weak blue fluorescence was observed. Moreover, TPE-GEM-RDG prodrug without RGD targeting was used as a negative control. The fluorescent intensity of BxPC-3 cells incubated with TPE-GEM-RDG was much weaker than that incubated with TPE-GEM-RGD. These results demonstrated that the intracellular fluorescence light-up can be achieved. Figure 2. Fluorescent microscopy images of BxPC-3 cells (a) incubated with TPE-GEM-RGD; (b) pretreated with CA-074-Me and incubated with TPE-GEM-RGD; (c) incubated with TPE-GEM-RDG. In order to identify the reduction-responsive release of GEM, the in vitro cell proliferation inhibition behavior was studied by MTT. The GSH level in BxPC-3 cells can be enhanced or inhibited by pretreating the cells with GSH promoterGSH-OEt or GSH inhibitor BSO [5]. As shown in Figure 3,the BxPC-3 cells pretreated with GSH-OEt or BSO exhibited lowest or highest cell viability, which proved the GSH-responsive behavior of TPE-GEM-RGD prodrug. Figure 3. Cell viability of BxPC-3 cells incubated with TPE-GEM-RGD prodrug. BxPC-3 cells were pretreated with BSO or GSH-OEt. In summary, we have successfully synthesized a theranostic TPE-GEM-RGD prodrug with AIE-based intracellular light-up properties. The TPE-GEM-RGD prodrug was used for targeted light-up imaging and selective inhibition of the proliferation of pancreatic cancer cells.

Zwitterionic nanoparticles constructed from bioreducible RAFT–ROP double head agent for shell shedding triggered intracellular drug delivery

Nanomedicines have emerged as indispensable platforms for cancer theranostics, however, the therapeutic outcomes were often compromised not only by the multiple biological barriers during the itinerary from the initial injection site to the intracellular action site but also the insufficient drug release at the pathological site. Herein, novel bioreducible double head agent, combining reversible addition-fragmentation chain transfer agent and ring opening polymerization initiator through disulfide linkage, was firstly prepared. Well-defined cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone block copolymers (termed as cRGD-PCSSL) were facilely synthesized using this initiator. Subsequently, shell sheddable and drug-encapsulated zwitterionic nanoparticles were constructed by one-step self-assembly with doxorubicin (DOX) (termed as cRGD-PCSSL/DOX NPs). The reduction-responsive shedding of PCB shells resulted in the rapid loss of cRGD-PCSSL/DOX NPs stability in the presence of glutathione, facilitating the rapid DOX release. Results of flow cytometry and fluorescence microscopy demonstrated that cRGD-PCSSL/DOX NPs could be internalized by HepG2 cells via receptor-mediated endocytosis with fast intracellular drug release, leading to considerable cytotoxicity in comparison with free DOX. Importantly, the low protein adsorption and excellent serum stability properties of cRGD-PCSSL/DOX NPs translated into prolonged systemic circulation and enhanced tumor accumulation. Furthermore, intravenous injection of cRGD-PCSSL/DOX NPs in tumor-bearing mice exhibited significantly higher antitumor efficiency and lower systemic toxicity compared to free DOX. Consequently, the novel zwitterionic NPs, which facilely overcome the dilemma between multifunctionality and complexity by programmatically circumventing the multiple biological barriers, would represent a promising platform for enhanced anticancer drug delivery. Statement of significanceHerein, novel bioreducible RAFT and ROP double-head agent was first reported for the synthesis of cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone zwitterionic block copolymers (cRGD-PCB-SS-PCL, termed as cRGD-PCSSL) through controllable polymerization methods. Firstly, this synthetic route surmounted the major disadvantage of most current used methods, which required thiol exchange reaction between active disulfide bond and free thiol groups at the chain ends. Secondly, the prepared cRGD-PCSSL/DOX NPs reasonably integrated cRGD for active tumor targeting and receptor-mediated endocytosis, zwitterionic PCB with nonfouling property for prolonged systemic circulation, disulfide linkage for reduction-responsive drug release, biodegradable PCL for hydrophobic anticancer drug loading. Finally, the systematic evaluation fully verified that the in vitro optimized cRGD-PCSSL/DOX NPs translated into significantly better therapeutic efficiency with reduced side effects in vivo.

A reduction-degradable polymer prodrug for cisplatin delivery: Preparation, in vitro and in vivo evaluation

We describe the development of novel reduction-sensitive therapeutic micelles consisting of polyethylene glycol-poly-(l-glutamic acid) (PEG-PLG), and conjugate with dithiodipropionic-Pt (IV) (DTDP-Pt). The drug delivery polymeric micelles lie in the covalent conjugation of each cisplatin drug to the PLG chains through a disulfide bond. The resulting micelles show well-controlled cisplatin loading yield, excellent reduction-responsive drug release kinetics, and enhanced in vitro cytotoxicity against cancer cells. The in vivo studies on the subcutaneous human ovarian carcinoma SKOV-3 xenograft model confirmed that PEG-P(LG-DTDP-Pt) micelles showed significant antitumor activity and reduced side effects, compared with free cisplatin. This characteristic drug release profile holds the promise to suppress cancer cell by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.