Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 7, Issue 11, Pages 6340-6350Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.5b00962
Keywords
pH-sensitive; nanoparticle; switchable delivery; doxorubicin; tumor treatment
Funding
- National Natural Science Foundation of China [31271073, 81301309, 31470925, 31470963, 81171371]
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To achieve higher therapeutic efficiency with catabatic side effects, desirable nanocarriers should be designed to retain the loaded drug tightly during the systemic circulation, but release the drug rapidly and efficiently upon endocytosis by tumor cells. Herein, to achieve off-on controlled delivery of DOX, novel amphiphilic polyelectrolyte/prodrug nanoparticles (NPs) with cooperative pH-sensitivity were constructed via synergistic electrostatic and hydrophobic interactions between: Slightly positively charged methoxy polyethylene glycol-b-(poly(2-(diisopropylamino) ethyl methacrylate-co-aminopropyl methacrylamide) (PEDPA) copolymer and negatively charged cis-aconityl-doxorubicin (CAD) pro drug (termed as PEDPA/CAD NPs). With polymer-prodrug synergistic noncovalent interactions, the drug loading content of PEDPA/CAD NPs could be improved up to 12.6% With favorable serum stability, and significantly lowered the drug leakage to 2.5% within 24 h at pH 7.4. However, nearly 80% of encapsulated drug could be released at pH 5.0 within 12 h, due to the cooperative effects of the protonation of PDPA blocks resulting in quick disassembly of NPs and the rapid hydrolysis of cis-aconityl linkage leading to charge-reverse of CAD. Moreover, the results of fluorescent microscopy imaging and flow cytometry measurements exhibited that DOX could be recovered and released rapidly from PEDPA/CAD NPs upon endocytosis and then exert therapeutic action in the cell nucleus. Importantly, the PEDPA/CAD NPs exhibited significantly higher antitumor efficiency in vivo with reduced nonspecific toxicity to normal tissues in comparation with free DOX. In summary, the NPs designed in this work, constructed by synergistic electrostatic and hydrophobic interactions with cooperative pH-sensitivity, which potentially resolved the dilemma between systemic stability and rapid intracellular drug release, would provide a promising nanomedicine platform for cancer therapy:
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