Enhancing tumor penetration and targeting using size-minimized and zwitterionic nanomedicines

• Published in: Journal of controlled release 2016-09, Vol.237, p.115-124
• Main Authors: Zhang, Yajun, Chen, Weizhi, Yang, Chenchen, Fan, Quli, Wu, Wei, Jiang, Xiqun
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Betaine - analogs & derivatives; Boronic Acids - chemistry; Cell Line, Tumor; Delayed-Action Preparations - chemistry; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug delivery; Drug Delivery Systems - methods; Humans; Hydrogen-Ion Concentration; Mice; Multiarm block copolymer; Nanomedicine; Neoplasms - drug therapy; Neoplasms - pathology; Polyethylene Glycols - chemistry; Polymers - chemistry; Polyzwitterion; Size effect; Surface chemistry; Tumor penetration
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.07.011

We report a strategy to significantly improve tumor penetration of nanomedicines by using size-minimized and zwitterionic nanocarriers. We synthesized a series of 21-arm star block copolymers with the hydrodynamic diameter of 10–40nm and conjugated doxorubicin to the copolymers through pH-sensitive acylhydrazone linkages. The zwitterionic poly(carboxybetaine) (PCB), nonionic polyethylene glycol (PEG) and phenylboronic acid-incorporated PCB were selected as the peripherial hydrophilic blocks of the copolymers, respectively. We demonstrated that the size-minimized multiarm copolymer with PCB surface showed stronger tumor permeability when compared to the copolymers with PEG surface or larger size. The drug-conjugated multiarm copolymer that has the longest blood circulation time did not achieve the highest tumor accumulation. The incorporation of phenylboronic acid group into the peripherial block of the drug-conjugated multiarm copolymer significantly enhanced their cytotoxicity, cellular uptake, tumor accumulation, tumor permeability and antitumor activity. The effects of size, hydrophilic block and targeting moiety on tumor accumulation and tumor penetration of the 21 arm star block copolymers were investigated in cellular and tissue levels. [Display omitted]