Polymeric micelles coated with hybrid nanovesicles enhance the therapeutic potential of the reversible topoisomerase inhibitor camptothecin in a mouse model

Nanoparticles with longer blood circulation, high loading capacity, controlled release at the targeted site, and preservation of camptothecin (CPT) in its lactone form are the key characteristics for the effective delivery of CPT. In this regard, natural membrane-derived nanovesicles, particularly those derived from RBC membrane, are important. RBC membrane can be engineered to form vesicles or can be coated over synthetic nanoparticles, without losing their basic structural features and can have prolonged circulation time. Here, we developed a hybrid system to encapsulate CPT inside the amphiphilic micelle and coat it with RBC membrane. Thus, it uses the dual ability of polymeric micelles to preserve CPT in its active form, while maintaining its stealth effect due to conserved RBC membrane coating. The hybrid system stabilized 60% of the drug in its active form even after 30 h of incubation in serum, in contrast to 15% active form present in free drug formulation after 1 h of incubation. It showed strong retention inside the Ehrlich Ascites Carcinoma (EAC) mice models for at least 72 h, suggesting camouflaging ability conferred by RBC membrane. Additionally, the nano formulation retarded the tumor growth rate more efficiently than free drug, with no evident signs of necrotic skin lesions. Histopathological analysis showed a significant reduction in cardiac atrophy, hepato-renal degeneration, and lung metastasis, which resulted in the increased overall survival of mice treated with the nano formulation. Hence, CPT-loaded polymeric micelles when coated with RBC membrane can prove to be a better system for the delivery of poorly soluble drug camptothecin. Statement of significance RBC-derived nanovesicles have the ability to evade host's immune response and act as an alternative to synthetic analogues for personalized chemotherapy. Topoisomerase inhibitors, specifically camptothecin and its analogues, show optimum antitumor activity, but their therapeutic potential is limited due to their water insolubility and hydrolysis at physiological pH before cell uptake. Although most of the previous studies have focused on using RBC-derived nanovesicles for the delivery of water-soluble therapeutics, we could not find much studies where such a system has been used to deliver insoluble and hydrolytically labile camptothecin. Here, we report polymeric micelles coated with hybrid nanovesicles derived from erythrocytes that protect CPT against hydrolysis and act as a long-time circulating nanoparticle system, thus limiting its side effects. (c) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

A hybrid system was developed to encapsulate CPT inside amphiphilic micelles and coat it with RBC membrane, achieving stabilization of drug activity and prolonged circulation time, leading to enhanced efficacy in tumor treatment.