Targeted delivery of irinotecan to colon cancer cells using epidermal growth factor receptor-conjugated liposomes.

BACKGROUND: CPT-11 (irinotecan) is one of the most efficient agents used for colorectal cancer chemotherapy. However, as for many other chemotherapeutic drugs, how to minimize the side effects of CPT-11 still needs to be thoroughly described. OBJECTIVES: This study aimed to develop the CPT-11-loaded DSPE-PEG 2000 targeting EGFR liposomal delivery system and characterize its targeting specificity and therapeutic effect on colorectal cancer (CRC) cells in vitro and in vivo. RESULTS: The synthesized liposome exhibited spherical shapes (84.6 ± 1.2 nm to 150.4 nm ± 0.8 nm of estimated average sizes), good stability, sustained release, and enough drug loading (55.19%). For in vitro experiments, SW620 cells treated with CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome showed lower survival extended level of intracellular ROS production. In addition, it generated an enhanced apoptotic cell rate by upregulating the protein expression of both cleaved-caspase-3 and cleaved-caspase-9 compared with those of SW620 cells treated with free CPT-11. Importantly, the xenograft model showed that both the non-target and EGFR-targeted liposomes significantly inhibited tumor growth compared to free CPT-11. CONCLUSIONS: Compared with the non-target CPT-11-loaded DSPE-PEG2000 liposome, CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome treatment showed much better antitumor activity in vitro in vivo. Thus, our findings provide new assets and expectations for CRC targeting therapy.

Flexible Single-Chain-Heteropolymer-Derived Transmembrane Ion Channels with High K+ Selectivity and Tunable pH-Gated Characteristics.

A series of single-chain random heteropolymer (RHP)-derived artificial ion channels with both high K+ selectivity and controllable pH-gated behaviors were fabricated by a facile "one-pot" polymerization method. The benzo-18-crown-6 moieties appended on lateral chains of RHPs can form ion-permeable nanopores and transport K+ over Na+ through the lipid bilayers. The ion permeation selectivity was significantly enhanced by incorporating a cholesterol group to serve as a membrane anchor. Interestingly, similar to natural gated protein channels, on-off switchable characteristics were also realized by integrating an additional acid-sensitive alkylamine group into the RHP-derived channel. The unique design strategies have endowed the RHP-derived ion channels with facile synthetic procedures, desirable membrane compatibility, high K+ selectivity, and tunable pH-gated properties. This work provides an entry point for future design of novel functional nanochannels.

Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.

The selective disruption of nutritional supplements and the metabolic routes of cancer cells offer a promising opportunity for more efficient cancer therapeutics. Herein, a biomimetic cascade polymer nanoreactor (GOx/CAT-NC) was fabricated by encapsulating glucose oxidase (GOx) and catalase (CAT) in a porphyrin polymer nanocapsule for combined starvation and photodynamic anticancer therapy. Internalized by cancer cells, the GOx/CAT-NCs facilitate microenvironmental oxidation by catalyzing endogenous H2O2 to form O2, thereby accelerating intracellular glucose catabolism and enhancing cytotoxic singlet oxygen (1O2) production with infrared irradiation. The GOx/CAT-NCs have demonstrated synergistic advantages in long-term starvation therapy and powerful photodynamic therapy (PDT) in cancer treatment, which inhibits tumor cells at more than twice the rate of starvation therapy alone. The biomimetic polymer nanoreactor will further contribute to the advancement of complementary modes of spatiotemporal control of cancer therapy.

pH- and Amylase-Responsive Carboxymethyl Starch/Poly(2-isobutyl-acrylic acid) Hybrid Microgels as Effective Enteric Carriers for Oral Insulin Delivery.

Oral delivery of insulin has the potential to revolutionize diabetes care since it is regarded as a noninvasive therapeutic approach without the side effects caused by frequent subcutaneous injection. However, the insulin delivery efficiency through oral route was still limited, likely due to the chemical, enzymatic and absorption barriers. In this study, a novel type of pH- and amylase-responsive microgels as an insulin drug carrier for oral administration was developed to improve the drug delivery efficiency. The microgels were prepared via aqueous dispersion copolymerization of acrylate- grafted-carboxymethyl starch (CMS- g-AA) and 2-isobutyl-acrylic acid ( iBAA). The resulting hybrid microgels with the P iBAA contents of 13.6-45.3 wt% exhibited sharp pH-sensitivity, which was revealed by the changes in particle size of the microgels and the transmittance of the microgel aqueous solution. The accelerated decomposition of the CMS-containing microgels in response to amylase was demonstrated by chromogenic reaction and morphology change. Insulin was loaded into the microgels by swelling-diffusion method, and the insulin release from the insulin-loaded microgels in vitro was found to be triggered by pH change and addition of amylase, which was highly dependent on the microgel component. Cytotoxicity assay was performed to show the good biocompatibility of the microgels. In addition, the tests of cellular uptake by Caco-2 cells and transmembrane transport through the Caco-2 cell monolayers were carried out to confirm the intestinal absorption ability of the insulin-loaded microgels. Finally, the oral administration of insulin-loaded microgels to STZ-induced diabetic rats led to a continuous decline in the fasting blood glucose level within 2 to 4 h, and the hypoglycemic effect maintained over 6 h in vivo. The relative pharmacological availability of the insulin-loaded microgels was enhanced 23-38 times compared to free-form insulin solution through oral route. Therefore, the novel starch-based microgels may have potential as an efficient platform for oral insulin delivery.

Injectable Thermosensitive Polypeptide-Based CDDP-Complexed Hydrogel for Improving Localized Antitumor Efficacy.

In this study, a type of novel thermosensitive polypeptide-based hydrogel with tunable gelation behavior through changing the content of carboxyl groups was developed for the purpose of improving the cisplatin (CDDP) release behavior and enhancing the localized antitumor efficiency. The introduction of carboxyl groups in methoxy-poly(ethylene glycol)-b-(poly(γ-ethyl-l-glutamate-co-l-glutamic acid) (mPEG-b-P(ELG-co-LG)) not only led to adjustable mechanical properties of the hydrogel but also significantly reduced the burst release of the drug through the complexation between the carboxyl groups of polypeptide and CDDP. Furthermore, both the good biocompatibility and the biodegradable properties of mPEG-b-P(ELG-co-LG) hydrogel were observed in vivo. Interestingly, the CDDP-complexed mPEG-b-P(ELG-co-LG) hydrogel exhibited significantly enhanced antitumor efficacy in vivo compared to the mPEG-b-PELG hydrogel loaded with CDDP without complexation, although a lower cytotoxicity and IC50 of the CDDP-complexed hydrogel was observed in vitro. Overall, the new type of injectable CDDP-complexed hydrogel may serve as an efficient platform for sustained CDDP delivery in localized tumor therapy.

Fighting bacteria with bacteria: A biocompatible living hydrogel patch for combating bacterial infections and promoting wound healing.

Bacterial infections are among the most critical global health challenges that seriously threaten the security of human. To address this issue, a biocompatible engineered living hydrogel patch was developed by co-embedding engineered photothermal bacteria (EM), photosensitizer (porphyrin) and reactive oxygen species amplifier (laccase) in a protein hydrogel. Remarkably, the genetice engineered bacteria can express melanin granules in vivo and this allows them to exhibit photothermal response upon being exposed to NIR-II laser (1064 nm) irradiation. Besides, electrostatically adhered tetramethylpyridinium porphyrin (TMPyP) on the bacterial surface and encapsulated laccase (Lac) in protein gel can generate highly toxic singlet oxygen (1O2) and hydroxyl radical (·OH) in the presence of visible light and lignin, respectively. Interestingly, the engineered bacteria hydrogel patch (EMTL@Gel) was successfully applied in synergistic photothermal, photodynamic and chemodynamic therapy, in which it was able to efficiently treat bacterial infection in mouse wounds and enhance wound healing. This work demonstrates the concept of "fighting bacteria with bacteria" combining bacterial engineering and material engineering into an engineered living hydrogel path that can synergistically boost the therapeutic outcome. STATEMENT OF SIGNIFICANCE: Genetically engineered bacteria produce melanin granules in vivo, exhibiting remarkable photothermal properties. These bacteria, along with a photosensitizer (TMPyP) and a reactive oxygen species amplifier (laccase), are incorporated into a biocompatible protein hydrogel patch. Under visible light, the patch generates toxic singlet oxygen (1O2) and hydroxyl radical (·OH), demonstrates outstanding synergistic effects in photothermal, photodynamic, and chemodynamic therapy, effectively treating bacterial infections and promoting wound healing in mice.

A Nanocomposite Vehicle Based on Metal-Organic Framework Nanoparticle Incorporated Biodegradable Microspheres for Enhanced Oral Insulin Delivery.

Oral insulin delivery has revolutionized diabetes treatment, but challenges including degradation in the gastrointestinal environment and low permeation across the intestinal epithelium remain. Herein, to overcome these barriers, we developed a novel biodegradable nanocomposite microsphere embedded with metal-organic framework (MOF) nanoparticles. An iron-based MOF nanoparticle (NP) (MIL-100) was first synthesized as a carrier with an insulin loading capacity of 35%. The insulin-loaded MIL-100 nanoparticles modified with sodium dodecyl sulfate (Ins@MIL100/SDS) promoted insulin permeation across Caco-2 monolayer models in vitro. To improve resistance to the gastric acid environment, Ins@MIL100/SDS nanoparticles were embedded into a biodegradable microsphere to construct the nanocomposite delivery system (Ins@MIL100/SDS@MS). The microspheres effectively protected the MOF NPs from rapid degradation under acidic conditions and could release insulin-loaded MOF NPs in the simulated intestinal fluid. After the oral administration of Ins@MIL100/SDS@MS into BALB/c nude mice, increased intestinal absorption of the insulin was detected compared to the oral administration of free insulin or Ins@MIL100/SDS. Furthermore, significantly enhanced plasma insulin levels were obtained for over 6 h after oral administration of Ins@MIL100/SDS@MS into diabetic rats, leading to a remarkably enhanced effect in lowering blood glucose level with a relative pharmacological availability of 7.8%. Thus, the MOF-nanoparticle-incorporated microsphere may provide a new strategy for effective oral protein delivery.

Engineering Thermo-pH Dual Responsive Hydrogel for Enhanced Tumor Accumulation, Penetration, and Chemo-Protein Combination Therapy.

PURPOSE: Combined chemotherapeutic drug and protein drug has been a widely employed strategy for tumor treatment. To realize both tumor accumulation and deep tumor penetration for drugs with different pharmacokinetics, we propose a structure-transformable, thermo-pH dual responsive co-delivery system to co-load granzyme B/docetaxel (GrB/DTX). METHODS: Thermo-sensitive hydrogels based on diblock copolymers (mPEG-b-PELG) were synthesized through ring opening polymerization. GrB/DTX mini micelles (GDM) was developed by co-loading these two drugs in pH-sensitive mini micelles, and the GDM-incorporated thermo-sensitive hydrogel (GDMH) was constructed. The thermo-induced gelation behavior of diblock copolymers and the physiochemical properties of GDMH were characterized. GDMH degradation and deep tumor penetration of released mini micelles were confirmed. The pH-sensitive disassembly and lysosomal escape abilities of released mini micelles were evaluated. In vitro cytotoxicity was studied using MTT assays and the in vivo antitumor efficacy study was evaluated in B16-bearing C57BL/6 mice. RESULTS: GDMH was gelatinized at body temperature and can be degraded by proteinase to release mini micelles. The mini micelles incorporated in GDMH can achieve deep tumor penetration and escape from lysosomes to release GrB and DTX. MTT results showed that maximum synergistic antitumor efficacy of GrB and DTX was observed at mass ratio of 1:100. Our in vivo antitumor efficacy study showed that GDMH inhibited tumor growth in the subcutaneous tumor model and in the post-surgical recurrence model. CONCLUSION: The smart-designed transformable GDMH can facilitate tumor accumulation, deep tumor penetration, and rapid drug release to achieve synergistic chemo-protein therapy.

Tissue-engineered nerve grafts using a scaffold-independent and injectable drug delivery system: a novel design with translational advantages.

OBJECTIVE: Currently commercially available nerve conduits have demonstrated suboptimal clinical efficacy in repairing peripheral nerve defects. Although tissue-engineered nerve grafts (TENGs) with sustained release of neurotrophic factors (NTFs) are experimentally proved to be more effective than these blank conduits, there remains a lack of clinical translation. NTFs are typically immobilized onto scaffold materials of the conduit via adsorption, specific binding or other incorporation techniques. These scaffold-based delivery strategies increase complexity and cost of conduit fabrication and lack flexibility in choosing different drugs. Therefore, to facilitate clinical translation and commercialization, we construct a TENG using a scaffold-independent drug delivery system (DDS). APPROACH: This study adopted a scaffold-independent DDS based on methoxy-poly (ethylene glycol)-b-poly(γ-ethyl-L-glutamate) (mPEG-PELG) thermosensitive hydrogels that undergo sol-to-gel transition at body temperature. In addition, TENG, a chitosan scaffold filled with nerve growth factor (NGF)-loaded mPEG-PELG that gel in the lumen upon injection during surgery and function as a drug-releasing conduit-filler, was designed. Subsequently, the efficacy of DDS and therapeutic effects of TENG were assessed. MAIN RESULTS: The results demonstrated that NGF-loaded mPEG-PELG controllably and sustainably released bioactive NGF for 28 d. When bridging a 10 mm rat sciatic nerve gap, the morphological, electrophysiological, and functional analyses revealed that NGF-releasing TENG (Scaffold + NGF/mPEG-PELG) achieved superior regenerative outcomes compared to plain scaffolds and those combined with systemic delivery of NGF (daily intramuscular injection (IM)), and its effects were relatively similar to autografts. SIGNIFICANCE: This study has proposed a TENG using thermosensitive hydrogels as an injectable implant to controllably release NGF, which has promising therapeutic potential and translatability. Such TENGs obviate the need for conduit modification, complex preloading or binding mediators, therefore they allow the ease of drug switching in clinical practice and greatly simplify the manufacturing process due to the independent preparation of drug delivery system.

Enhanced local cancer therapy using a CA4P and CDDP co-loaded polypeptide gel depot.

Cancer combination therapy based on drug co-delivery systems provides an effective strategy for enhancing treatment efficacy and reducing side effects. In this work, a new strategy through co-delivery of combretastatin A4 disodium phosphate (CA4P) and cisplatin (CDDP) was developed for the local treatment of colon cancer, through an in situ thermo-gelling hydrogel (mPEG-b-PELG). The results indicated that this material possessed concentration-dependent thermogelling properties and tunable in vivo biodegradability. Also, the drug loaded gel could regulate the in vitro drug release behaviors of both CDDP and CA4P, which promoted the in vivo vessel disrupting effects of CA4P compared with a free drug after local treatment for 48 h. Although the drug co-loaded gel induced less in vitro cell death compared with the free drug co-treated group, this drug co-loaded gel depot showed the highest antitumor efficacy compared with the other experimental groups after peritumoral injection toward C26 tumor bearing mice.

Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics-Based Combination Antitumor Therapy.

Different strategies of chemotherapeutics-based combination cancer therapy have presented enhanced antitumor efficiency and are widely used in clinical cancer treatments. However, several drawbacks of the systems for systemic administration, including low drug accumulation at tumor sites and significant systemic side effects limit their efficacy and application in the clinic. Local drug co-delivery systems based on injectable hydrogels may have considerable advantages, such as a facile drug-delivery procedure, targeted delivery of antitumor agents to tumor sites in a sustained manner, and markedly reduced systemic toxicities. Thus, in recent years, these systems have received increasing attention and consequently various injectable hydrogels have been tested as platforms for local chemotherapeutics-based combination antitumor therapy. In this review, the focus is on recent advances in injectable hydrogel-based drug co-delivery systems for local combination antitumor therapy, including multiple chemotherapeutics combination therapy, chemo-immunotherapy, chemo-radiotherapy, and hyperthermia-chemotherapy. Moreover, the rationale and preparation of local co-delivery systems are summarized and discussed.

The effect of PLGA-based hydrogel scaffold for improving the drug maximum-tolerated dose for in situ osteosarcoma treatment.

Although hydrogel-based therapeutic agents have shown great potential for localized cancer treatments, the maximum tolerated dose (MTD) of these methods remains uncertain. To confirm this, doxorubicin (DOX) loaded PLGA-PEG-PLGA hydrogel was employed to investigate the MTD of DOX for localized osteosarcoma treatment. This hydrogel showed good injectable and biodegradable properties in vivo. And the drug remaining time was also obviously prolonged in the tumor site. Different doses of DOX (5.0, 15, 30 mg/kg) with/without hydrogel were adopted to the treatment of tumor-bearing mice. Despite both localized administrations of 5.0 mg/kg DOX showing no obvious systemic toxicity, this dose failed to control the persistent growth of tumors or prolong the survival time in comparison with the control groups. Localized administration of 30 mg/kg DOX showed a high efficacy for suppressing tumor growth, but exhibited obvious body weight losing at the same time. Correspondingly, the DOX-loaded hydrogel with the dose of 15 mg/kg achieved significantly improved anti-tumor efficacy and prolonged mean survival time compared with both the free DOX (15 mg/kg) and other control groups. Furthermore, during the whole therapeutic process, the mice showed no obvious body weight loss, major organs damage or death in this group. The MTD of DOX-loaded agent based on the PLGA-PEG-PLGA hydrogel gave a 2-fold increase compared to the MTD of free DOX (7.5 mg/kg, intravenous injection) for the mouse without significant systemic toxicity.

In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy.

Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti-PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)-degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.

Interleukin-15 and cisplatin co-encapsulated thermosensitive polypeptide hydrogels for combined immuno-chemotherapy.

In situ-forming thermosensitive hydrogels based on poly(ethylene glycol)-poly(γ-ethyl-l-glutamate) diblock copolymers (mPEG-b-PELG) were prepared for the co-delivery of interleukin-15 (IL-15) and cisplatin (CDDP). The polypeptide-based hydrogels as local drug delivery carriers could reduce the systemic toxicity, degrade thoroughly within 3weeks after subcutaneous injection into rats and display an acceptable biocompatibility. When incubated with mouse melanoma B16 cells, only the CDDP-treated groups had significant effects on the S phase cell-cycle arrest in melanoma cells. After a single peritumoral injection of the hydrogel containing IL-15/CDDP in C57BL/6 mice inoculated with B16F0-RFP melanoma cells, the dual drug-loaded hydrogels displayed synergistic anticancer efficacy, which was resulted from a combination of CDDP-mediated S arrest and IL-15/CDDP-induced recovery of CD8+ T cell and NK cell populations to reduce immunosuppression and enhance antitumor immunity. Hence, the as-prepared thermosensitive polypeptide hydrogels for localized and sustained co-delivery of IL-15 and CDDP may have potential for efficient treatment of melanoma.

pH-Triggered Charge-Reversal Polyurethane Micelles for Controlled Release of Doxorubicin.

A series of pH-triggered charge-reversal polyurethane copolymers (PS-PUs) containing methoxyl-poly(ethylene glycol) (mPEG), carboxylic acid groups, and piperazine groups is presented in this work. The obtained PS-PUs copolymers can form into stable micelles at pH 7.4, which response to a narrow pH change (5.5-7.5) and show a tunable pH-triggered charge-reversal property. Doxorubicin (DOX) is encapsulated into the PS-PU micelles as a model drug. The drug release of DOX-loaded PS-PU micelles shows an obviously stepped-up with reducing the pH. Meanwhile, it is found that the charge-reversal property can improve the cellular uptake behavior and intracellular drug release in both HeLa cells and MCF-7 cells. Additionally, the time-dependent cytotoxicity of the DOX-loaded PS-PU micelles is confirmed by MTT assay. Attributed to the tunable charge-reversal property through changing the molar ratio of piperazine/carboxyl, the PS-PU micelles will be a potential candidate as an intelligent drug delivery system in future studies.

pH-Responsive Poly(ethylene glycol)/Poly(L-lactide) Supramolecular Micelles Based on Host-Guest Interaction.

pH-responsive supramolecular amphiphilic micelles based on benzimidazole-terminated poly(ethylene glycol) (PEG-BM) and ß-cyclodextrin-modified poly(L-lactide) (CD-PLLA) were developed by exploiting the host-guest interaction between benzimidazole (BM) and ß-cyclodextrin (ß-CD). The dissociation of the supramolecular micelles was triggered in acidic environments. An antineoplastic drug, doxorubicin (DOX), was loaded into the supramolecular micelles as a model drug. The release of DOX from the supramolecular micelles was clearly accelerated as the pH was reduced from 7.4 to 5.5. The DOX-loaded PEG-BM/CD-PLLA supramolecular micelles displayed an enhanced intracellular drug-release rate in HepG2 cells compared to the pH-insensitive DOX-loaded PEG-b-PLLA counterpart. After intravenous injection into nude mice bearing HepG2 xenografts by the tail vein, the DOX-loaded supramolecular micelles exhibited significantly higher tumor inhibition efficacy and reduced systemic toxicity compared to free DOX. Furthermore, the DOX-loaded supramolecular micelles showed a blood clearance rate markedly lower than that of free DOX and comparable to that of the DOX-loaded PEG-b-PLLA micelles after intravenous injection into rats. Therefore, the pH-responsive PEG-BM/CD-PLLA supramolecular micelles hold potential as a smart nanocarrier for anticancer drug delivery.

Disulfide cross-linked polyurethane micelles as a reduction-triggered drug delivery system for cancer therapy.

Nanoscale carriers that stably load drugs in blood circulation and release the payloads in desirable sites in response to a specific trigger are of great interest for smart drug delivery systems. For this purpose, a novel type of disulfide core cross-linked micelles, which are facilely fabricated by cross-linking of poly(ethylene glycol)/polyurethane block copolymers containing cyclic disulfide moieties via a thiol-disulfide exchange reaction, are developed. A broad-spectrum anti-cancer drug, doxorubicin (DOX), is loaded into the micelles as a model drug. The drug release from the core cross-linked polyurethane micelles (CCL-PUMs) loaded with DOX is suppressed in normal phosphate buffer saline (PBS), whereas it is markedly accelerated with addition of an intracellular reducing agent, glutathione (GSH). Notably, although DOX-loaded CCL-PUMs display lower cytotoxicity in vitro compared to either free DOX or DOX-loaded uncross-linked polyurethane micelles, the drug-loaded CCL-PUMs show the highest anti-tumor efficacy with reduced toxicity in vivo. Since enhanced anti-tumor efficacy and reduced toxic side effects are key aspects of efficient cancer therapy, the novel reduction-responsive CCL-PUMs may hold great potential as a bio-triggered drug delivery system for cancer therapy.

Intracellular pH-sensitive PEG-block-acetalated-dextrans as efficient drug delivery platforms.

Intracellular pH-sensitive micelles of PEG-block-acetalated-dextran (PEG-b-AC-Dex) were prepared and used for acid-triggered intracellular release of anticancer drug. The hydrodynamic radii (Rh) of PEG-b-AC-Dex micelles could increase after incubation in PBS solution at pH 5.5. Based on the pH-responsive Rh variation behavior, it was expected that the PEG-b-AC-Dex micelles should be interesting for intracellular drug delivery. Thus, doxorubicin (DOX), a wide-spectrum anticancer drug, was loaded into the micelles and the pH-dependent release of the payload DOX was tested in vitro. The in vitro drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at pH 7.4, while up to about 90% of the loaded DOX could be quickly released in PBS solution at pH 5.5. Compared to pH-insensitive PEG-PLA micelles, the PEG-b-AC-Dex micelles displayed a faster drug release behavior in tumor cells. Moreover, higher cellular proliferation inhibition efficacy was achieved toward tumor cells. These features suggested that DOX could be efficiently loaded and delivered into tumor cells in vitro by the intracelluar pH-sensitive micelles, leading to enhanced inhibition of tumor cell proliferation. Therefore, the pH-sensitive micelles may provide a promising carrier for acid-triggered drug release for cancer therapy.

Construction of a hyperbranched supramolecular polymer as a bifunctional antioxidative enzyme model.

A HBSP has been designed as a novel bifunctional enzyme model with SOD and GPx activity by host/guest-directed self-assembly of MnTPyP-M-Ad and 6-Te-diCD. The structure of the host/guest complex was elucidated by (1) H NMR spectra, and the HBSP was characterized by SEM, DLS and measurement of catalytic properties. In the bifunctional enzyme model, the Mn(III) porphyrins act as efficient SOD active sites and the tellurol moieties endow GPx activity. The SOD-like activity (IC(50) ) of this new supramolecular catalyst was found to be 1.05 × 10(-7) M, which corresponds to 2.82% of the activity of the native SOD enzyme. Besides this, the hyperbranched supramolecular polymer also shows a higher GPx activity (ν(0 ) = 21.7 × 10(-6) M · min(-1) ) than other supramolecular enzyme models.

Construction of an artificial glutathione peroxidase active site on copolymer vesicles.

To construct an efficient GPx mimic, a novel method for preparing polymer-based vesicles carrying GPx-active sites was developed. A series of block copolymers loaded with recognition and catalytic sites were synthesized based on polystyrene-block-poly[tri(ethylene glycol) methyl ether acrylate]s (PS-PMEO(3) MAs). By altering the molar ratio of the functional copolymers, vesicles with GPx activity were obtained by self-assembly of these functional copolymers through blending. The optimum GPx mimic constructed by the blending process exhibited high catalytic activity and acted as a real catalyst with typical saturation kinetics behavior. The method may be of benefit for designing other enzyme mimics and may cast a light on constructing other biologically related functional nanoparticles.