Journal
JOURNAL OF CONTROLLED RELEASE
Volume 220, Issue -, Pages 704-714Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2015.08.058
Keywords
Chimaeric polymersomes; pH-responsive; Protein delivery; PSMA targeting; Prostate cancer
Funding
- National Natural Science Foundation of China [NSFC 51273139, 51473111]
- National Science Fund for Distinguished Young Scholars [NSFC 51225302]
- Ph.D. Programs Foundation of Ministry of Education of China [20133201110005]
- Natural Science Foundation of Jiangsu Province [14KJA150008]
- Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions
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Protein drugs as one of the most potent biotherapeutics have a tremendous potential in cancer therapy. Their application is, nevertheless, restricted by absence of efficacious, biocompatible, and cancer-targeting nanosystems. In this paper, we report that 2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (Acupa)-decorated pH-responsive chimaeric polymersomes (Acupa-CPs) efficiently deliver therapeutic proteins into prostate cancer cells. Acupa-CPs had a unimodal distribution with average sizes ranging from 157-175 nm depending on amounts of Acupa. They displayed highly efficient loading of both model proteins, bovine serum albumin (BSA) and cytochrome C (CC), affording high protein loading contents of 9.1-24.5 wt.%. The in vitro release results showed that protein release was markedly accelerated at mildly acidic pH due to the hydrolysis of acetal bonds in the vesicular membrane. CLSM and MTT studies demonstrated that CC-loaded Acupa10-CPs mediated efficient delivery of protein drugs into PSMA positive LNCaP cells leading to pronounced antitumor effect, in contrast to their non-targeting counterparts and free CC. Remarkably, granzyme B (GrB)-loaded Acupa10-CPs caused effective apoptosis of LNCaP cells with a low half-maximal inhibitory concentration (IC50) of 1.6 nM. Flow cytometry and CLSM studies using MitoCapture (TM) revealed obvious depletion of mitochondria membrane potential in LNCaP cells treated with GrB-loaded Acupa10-CPs. The preliminary in vivo experiments showed that Acupa-CPs had a long circulation time with an elimination phase half-life of 3.3 h in nude mice. PSMA-targeted, pH-responsive, and chimaeric polymersomes have appeared as efficient protein nanocarriers for targeted prostate cancer therapy. (C) 2015 Elsevier B.V. All rights reserved.
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