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

Abstract

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.

Nano/Microparticles Encapsulation Via Covalent Drug Conjugation

“…This may be attributed to the synergistic effects of multiple therapeutic agents [113,114]. Remarkably, to assess the general biosafety of drug conjugates, Ibrahim et al have gone further into in vivo investigation of the drug conjugates developed by their group [115]. The organs of mice exposed to these drug conjugates for 21 days were sliced and analyzed histologically.…”

“…Similarly, more recent studies have further shown that covalent linked prodrugs improve the pharmacokinetics and biodistribution of the conjugated drug as reported by Ibrahim and co-workers. H22 tumor model was induced in BALB/c [115]; the mice were exposed to conjugated drug delivery system and free-drug camptothecin (CPT), respectively. From the results, conjugates had a significantly had better pharmacokinetic profile than the free drug, this also led to increased accumulation of the drug within the tumor tissues and consequently better activity.…”

Smart materials for drug delivery and cancer therapy

“…The multiple endogenous sensitive smart materials were common in many works, such as dual responsive materials to pH and GSH, 273–277 pH and hypoxia, 131 pH and enzyme, 173 ROS and GSH, 60,278,279 GSH and hypoxia, 280,281 as well as GSH and enzyme 183 . There were also examples of triple responsive materials which were sensitive to pH, GSH, and enzyme 161,282 …”

Self-assembled and pH-responsive polymeric nanomicelles impart effective delivery of paclitaxel to cancer cells

“…The size from TEM analysis observed smaller than the DLS measurements which could be due to difference in the dried state and hydrated state of the nanomicelles. 47,50 Fig. 3c and d, illustrates the SAED patterns of the NM-1 and NM-2.…”