Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).     

Improvement of anti-tumor abilities on human non-small cell lung carcinoma by micellization and cross-linking of N-(2-hydroxypropyl) methacrylamide copolymers

Non-small cell lung carcinoma is one of the most frequently occurred cancers with a very high rate of recurrence. Self-assembly N-(2-hydroxypropyl) methacrylamide (HPMA) micelles and cross-linked micelles were developed to improve antitumor ability of linear HPMA copolymer. The characters of HPMA micelles were investigated and compared using human non-small cell lung carcinoma 3-D culture model and nude mice xenograft model. Cross-linked micelles showed highest cytotoxicity on A549 cell monolayers after a short time treatment in vitro. Moreover, both of the two micelles exhibited better in vitro anti-tumor activity on A549 tumor spheroids than linear HPMA conjugates especially the cross-linked micelles. On BALB/c nude mice bearing A549 xenograft tumors, the cross-linked micelles exhibited the greatest tumor accumulation and the best anti-tumor activity due to the highly improved stabilities and the more pronounced enhanced permeability and retention (EPR) effect, which were followed by the non-cross-linked micelles. Meanwhile, neither the two micelles nor the linear HPMA copolymers showed significant toxicity on the main organs of mice while free doxorubicin (DOX) showed obvious cardiac toxicity. All the results suggested that micellization improved the anti-tumor activity of HPMA copolymers on A549 human non-small cell lung carcinoma, furthermore, cross-linked HPMA copolymer micelles with pH-sensitivity and biodegradability showed more excellent anti-tumor activity.     

Cellulose-Based Hydrogels as Sustained Drug-Delivery Systems

Hydrogels, three-dimensional (3D) polymer networks, present unique properties, like biocompatibility, biodegradability, tunable mechanical properties, sensitivity to various stimuli, the capacity to encapsulate different therapeutic agents, and the ability of controlled release of the drugs. All these characteristics make hydrogels important candidates for diverse biomedical applications, one of them being drug delivery. The recent achievements of hydrogels as safe transport systems, with desired therapeutic effects and with minimum side effects, brought outstanding improvements in this area. Moreover, results from the utilization of hydrogels as target therapy strategies obtained in clinical trials are very encouraging for future applications. In this regard, the review summarizes the general concepts related to the types of hydrogel delivery systems, their properties, the main release mechanisms, and the administration pathways at different levels (oral, dermal, ocular, nasal, gastrointestinal tract, vaginal, and cancer therapy). After a general presentation, the review is focused on recent advances in the design, preparation and applications of innovative cellulose-based hydrogels in controlled drug delivery.     

Sericin nanomicelles with enhanced cellular uptake and pH-triggered release of doxorubicin reverse cancer drug resistance

Drug resistance is the major challenge facing cancer chemotherapy and nanoscale delivery systems based on natural materials, such as sericin, are a promising means of overcoming drug resistance. Yet, no attempt of introducing synthetic poly(γ-benzyl-L-glutamate) (PBLG) onto sericin polypeptide to fabricate a facile biocompatible and biodegradable micelle has been tried. Here, we prepared a polypeptide-based amphiphilic polymer containing hydrophilic sericin polypeptide backbone and PBLG side chains via ring-opening polymerization (ROP) strategy. The introduction of PBLG side chains remarkably enhances the stability of sericin micelles in water. Meanwhile, the micelles exhibited a high loading capacity and pH-responsive release ability for antitumor drug doxorubicin (DOX), called sericin-PBLG-DOX. Owing to the excellent cell membrane penetration of sericin-PBLG, the cellular uptake of DOX when loaded into micelles was improved. Subsequently, sericin-PBLG-DOX was transferred into perinuclear lysosomes, where the release rate of DOX was accelerated. Compared to the same dose of DOX, sericin-PBLG-DOX could induce a more efficient anti-tumor effect both in vitro and in vivo, and these micelles have promise for future clinical applications in overcoming cancer drug resistance with good biosafety, enhanced cellular uptake, pH-triggered drug release, efficient anti-tumor effects, and minimized systemic toxicity.     

Effective intracellular delivery and Th1 immune response induced by ovalbumin loaded in pH-responsive polyphosphazene polymersomes

A polymersome system for delivering protein antigen ovalbumin (OVA) based on amphiphilic polyphosphazene grafting with N,N-diisopropylethylenediamine (DPA) and poly(ethylene glycol) (PEG) groups (poly[(DPA)_m (PEG)_n phosphazene], PEDP) was designed and constructed. The 200-240?nm-size OVA-loaded polymersomes displayed high stability at physiological pH, slow internalization through clathrin-mediated endocytosis pathway, and then a pH-triggered sustained OVA release in acidic environment, leading to extensive antigen access to cytosol. Prime-boost vaccine kept high antibody titers for 8?weeks and the subcutaneous vaccine of OVA polymersomes biased the immune response towards a type 1?T helper (Th1) response. Animal experiment results showed that the antigen-specific prophylactic vaccination by PEDP polymersomes delivery was much more rapid and efficient in depressing tumor growth and progress when compared with the therapeutic vaccination. These results suggested that PEDP-based polymersomes are very promising in controlled cytosolic delivery of protein antigens, and enhanced Th1 specific immune response.     

Hybrid polymeric micelles based on bioactive polypeptides as pH-responsive delivery systems against melanoma

The bioactive polymer poly(l-glutamic acid)_n-b-poly(d, l-lactic acid)_m was synthesized and used to form doxorubicin-loaded hybrid polymeric micelles to treat melanoma. These polymers exhibited pH-responsive changes in conformation, which controlled the diverse functionalities of the micelles. During circulation, poly(l-glutamic acid)_n-b-poly(d, l-lactic acid)_m protected Tat peptides on the micelles from proteolysis. Under tumor-acidic conditions, polymers with shorter poly(l-glutamic acid) blocks underwent a conformational change to form channels that accelerated the release of doxorubicin. The conformational change also exposed the Tat peptides to tumor cells, thereby promoting cellular internalization of the micelles. Enhanced cellular uptake of the micelles induced significant apoptosis of A375 melanoma cells in tumor-acidic conditions. In vivo studies demonstrated that the micelles with shorter poly(l-glutamic acid) blocks could effectively accumulate in tumor tissues, suppress tumor growth and help maintain the body weight of tumor-bearing mice. However, micelles with longer poly(l-glutamic acid) blocks did not undergo a conformational change under acidic conditions and performed poorly in both in vitro and in vivo evaluations. Our work provides a strategy for applying bioactive polymers to the rational construction of pH-responsive delivery systems for solid tumors and lends insight into possible conformational effects on the bioactivity of drug carriers.     

智能纳米材料在药物传递系统中的应用研究现状

目前,对某些环境刺激可产生特定响应的新型智能纳米材料已越来越多地被应用于药物传递系统,以实现靶向给药,提高药物疗效,减少药物不良反应。分类综述对pH、温度、光照、酶和氧化还原等刺激敏感的智能纳米材料在药物传递系统中的应用研究现状。     

基于聚赖氨酸的星形嵌段共聚物对胰岛素的装载与控制释放研究

目的：研究合成的星形嵌段共聚物（PEI-PLL-b-mPEG）对胰岛素的装载以及pH敏感释放。方法：将PEI-PLL-b-mPEG与胰岛素混合体系对水溶液进行充分透析以测定装载量;将PEI-PLL-b-mPEG-胰岛素复合体对不同pH值的缓冲溶液进行透析,测定胰岛素的释放速率。结果：PEI-PLL-b-mPEG可实现对胰岛素的快速有效俘获并显示明显的pH敏感释放,同时能保持胰岛素的结构完整和生物活性。结论：合成的PEI-PLL-b-mPEG可用作酸度敏感释放的胰岛素载体。     

Reversion of multidrug resistance by a pH-responsive cyclodextrin-derived nanomedicine in drug resistant cancer cells

Multidrug resistance (MDR) is one of the major problems responsible for inefficiency of cancer chemotherapy. Currently, there is still unmet demand for innovative strategies as well as effective and safe sensitizers to overcome MDR. In this study, we developed a nanosensitizer based on a pH-responsive nanoparticle (NP) derived from acetalated α-cyclodextrin (Ac-aCD). This pH-responsive NP could be effectively endocytosed by MDR cancer cells, and intracellularly transported by endolysosomal compartments. Ac-aCD NP was able to dramatically potentiate the activity of anticancer drugs including paclitaxel, docetaxel, cis-diamminedichloroplatinum, camptothecin, and doxorubicin. This sensitizing capability of Ac-aCD NP on MDR cells was resulted from the combined effects of decreased Pgp expression, attenuated Pgp ATPase activity, and the reduced intracellular ATP level. Ac-aCD NP exerted these diverse biological functions by intracellularly released α-cyclodextrin molecules, which were produced due to hydrolysis of Ac-aCD in acidic subcellular organelle. On the other hand, treatment with Ac-aCD NP showed no significant effects on the integrity of the plasma membrane, cytoskeleton, cell cycle, mitochondrial membrane potential, and apoptosis. These findings suggest that this pH-responsive NP has great potential for effective therapy of resistant cancers by combining with chemotherapeutic agents. It may also serve as a pharmacologically active nanocarrier for intracellular delivery of a plethora of antitumor drugs.     

The efficiency of tumor-specific pH-responsive peptide-modified polymeric micelles containing paclitaxel

The acidic pH in tumor tissues could be used for targeting solid tumors. In the present study, we designed a tumor-specific pH-responsive peptide H₇K(R₂)₂, which could respond to the acidic pH in tumor tissues, and prepared H₇K(R₂)₂-modified polymeric micelles containing paclitaxel (PTX-PM-H₇K(R₂)₂) in order to evaluate their potential targeting of tumor cells and tumor endothelial cells and their anti-tumor activity in mice with tumor cells. PTX-PM-H₇K(R₂)₂ was prepared by a thin-film hydration method. The in vitro release of PTX from PTX-PM-H₇K(R₂)₂ was tested. The in vitro targeting characteristics of H₇K(R₂)₂-modified polymeric micelles on HUVEC (human umbilical vein endothelial cells) and MCF-7 (human breast adenocarcinoma cells) were evaluated. The in vivo targeting activity of H₇K(R₂)₂-modified polymeric micelles and the in vivo anti-tumor activity of PTX-PM-H₇K(R₂)₂ were also investigated in MCF-7 tumor-bearing mice. The released PTX from the PTX-PM-H₇K(R₂)₂ was not affected by the pH. The targeting activity of the H₇K(R₂)₂-modified polymeric micelles was demonstrated by in vitro flow cytometry and confocal microscopy as well as in vivo biodistribution. PTX-PM-H₇K(R₂)₂ produced very marked anti-tumor and anti-angiogenic activity in MCF-7 tumor-bearing mice in vivo.