A series of pH-responsive random copolymer poly(l-glutamic acid-co-l-lysine) [P(Glu-co-Lys)] were synthesized through the ring-opening polymerization (ROP) of γ-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA) and 3-benzyloxycarbonyl-l-lysine N-carboxyanhydride (ZLys-NCA) and the subsequent deprotection. The chemical structure of the P(Glu-co-Lys)s was confirmed by NMR. Critical aggregation concentration and transmission electron microscopy measurements indicated that the P(Glu-co-Lys)s could self-assemble into aggregates in phosphate buffer. The surface charge of P(Glu-co-Lys) aggregates was greatly affected by the solution’s pH and l-glutamic acid/l-lysine ratio because the carboxyl and amino groups present on the P(Glu-co-Lys) aggregates could be protonated or deprotonated to become charged. The pH value of the solution at which the surface charge of the P(Glu-co-Lys) aggregates reversed could be manipulated by the feed ratio of BLG-NCA and ZLys-NCA. In vitro methyl thiazolyl tetrazolium assays demonstrated that negatively charged P(Glu-co-Lys)s were nontoxic and biocompatible. Positive charged P(Glu-co-Lys)s showed some cytotoxicity to Hela cells. Cisplatin (CDDP) was used as a model anticancer drug to evaluate the charge-reversal drug delivery system. By the manipulation of CDDP loading content, the surface charge of the CDDP/P(Glu-co-Lys) nanoparticles could be reversed to positive from negative at tumor extracellular pH (pHe 6.5–7.2). An enhanced drug uptake and inhibition of cancer cell proliferation were observed for the tumoral pHe triggered charge-reversal CDDP/P(Glu-co-Lys) drug delivery system. These indicated that the CDDP/P(Glu-co-Lys) nanoparticles could be used as intelligent drug delivery systems for cancer therapy.
Cisplatin (CDDP) is a potent anti-carcinogen that is widely used for various solid tumors; however, its clinical application is limited by its severe nephrotoxicity. Novel platinum–bisphosphonate polymer–metal complex nanoparticles (Pt–bp NPs), based on platinum–bisphosphonate coordination, have been established. Three polymer carriers bearing alendronate (ALN) ligands, while containing different lengths of alkyl hydrophobic chains, were synthesized. Their structures were characterized by 1H NMR, 31P NMR and FTIR. The ALN was used to coordinate to the CDDP precursor [Pt(NH3)2(OSO3)(OH2)], and the Pt–bp NPs were formed spontaneously. The Pt–bp NPs formed by the polymer carrier, ALN-PEG2k-ASAC18, which contained the poly(ethylene glycol) chain with ALN on one side and the octadecyl hydrophobic chain on the other side, was denoted as ALN-ASAC18-CDDP; its diameter was within 200 nm. CDDP was released in a Cl− or pH-dependent manner. The cytotoxic effects to the HeLa, A549 and MCF-7 cell lines were relatively weak, compared to CDDP. However, ALN-ASAC18-CDDP showed significantly prolonged blood circulation time and tumor accumulation of platinum of 2.5-fold, compared to CDDP at 8 h. Besides, ALN-ASAC18-CDDP was demonstrated to remarkably reduce systemic toxicity without compromising in vivo antitumor activity. These results indicate that the facilely prepared ALN-ASAC18-CDDP has great utilization potential for CDDP delivery in a clinical setting.
Yiwen Xie,Yuwei Shi,Zhihui Li,Sumei Xu,Zhiyun Chen,Xuxia Ye,Wenxi Yan
Introduction Chemotherapy remains the primary treatment modality for advanced and unresectable tumors; however, its antitumor efficacy is limited, and it has significant toxic effects on normal tissues.Methods To address these challenges, cell carrier- and nanomaterial-based strategies were employed in this study to engineer macrophages into functional “Trojan horses” loaded with ICG–CDDP mesoporous silicon nanoparticles, yielding an intelligent cell carrier chemotherapeutic drug delivery system with controlled light responsiveness and “on-demand” nanophotothermolysis capabilities.Results Our findings demonstrate that the intelligent macrophage drug delivery system actively homes to tumor sites and that indocyanine green (ICG) fluorescence can be used to visualize exogenous macrophages at the tumor site. In response irradiation of the delivery area with exogenous near-infrared (NIR) light, ICG generates a thermal effect, resulting in the lysis of macrophages and facilitating spatiotemporally controlled burst release of intracellular cisplatin, thereby precisely targeting tumor cells. Simultaneously, ICG can trigger immunogenic cell death (ICD) under NIR irradiation, transforming “cold tumors” into “hot tumors” and eliciting a prolonged antitumor immune response, thereby overcoming the limitations associated with chemotherapeutic drugs.Conclusion This collaborative trimodal strategy successfully represents a triple breakthrough in precise delivery, spatiotemporally controlled drug release, and immune activation. It is an innovative solution for the precise treatment of advanced tumors and has substantial potential for clinical translation.
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