The amphiphilic block copolymer anticancer drug nanocarriers clinically used or in the progress of clinical trials frequently suffer from modest final therapeutic efficacy due to a lack of intelligent features. For example, the biodegradable amphiphilic block copolymer, poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PDLLA) has been approved for clinical applications as a paclitaxel (PTX) nanocarrier (Genexol-PM) due to the optimized pharmacokinetics and biodistribution; however, a lack of intelligent features limits the intracellular delivery in tumor tissue. To endow the mediocre polymer with smart properties via a safe and facile method, we introduced a matrix metalloproteinase (MMP)-responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG-GPLGVRGDG-PDLLA (P1). P1 was further self-assembled into micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered dePEGylation due to cleavage of the peptide linkage. Moreover, the residual VRGDG sequences are retained on the surface of the NPs after dePEGylation, which can serve as ligands to facilitate the cellular uptake. The cytotoxicity of PTX loaded in P1 NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG-GPLGVRG-PDLLA (P2) and PEG-PDLLA (P3) NPs. In vivo studies confirmed that PTX-loaded P1 NPs show prolonged blood circulation, which are similar to P2 and P3 NPs but exhibit more-efficient accumulation in the tumor site. Ultimately, PTX-loaded P1 NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration. Therefore, the strategy by facile incorporation of a responsive peptide linkage between PEG and PDLLA is a promising approach to improving the therapeutic efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles.
Therapeutic nanoreactors have been proposed as nanoplatforms to treat diseases through in situ production of therapeutic agents. When this treatment strategy is applied in cancer therapy, it can efficiently produce highly toxic anticancer drugs in situ from low-toxic prodrugs or some biomolecules in tumor tissues, which can maximize the therapeutic efficacy with a significantly low systemic toxicity. An ideal therapeutic nanoreactor can provide the reaction space, protect the loaded fragile catalysts, target the desired pathological site, and be selectively activated. In this minireview, we highlight the recent advances concerning the applications of therapeutic nanoreactors as in vivo nanoplatforms particularly in cancer therapy. Herein, the therapeutic nanoreactors are discussed on the basis of treatment strategies and various nanoparticles. Specifically, the treatment strategies of nanoreactors including single enzyme, single enzyme with chemodrugs, and multienzymes, as well as varying types of engineered nanoparticle-loaded active catalysts, primarily including liposomes, polymersomes, polymeric micelles, inorganic nanoparticles, and metal-organic framework (MOF) architectures, are documented and briefly discussed. Finally, we elucidate the current challenges to be addressed toward further development and translation into clinical applications of these therapeutic nanoreactors in cancer therapy.
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