Targeting Tumor Vasculature with Aptamer-Functionalized Doxorubicin–Polylactide Nanoconjugates for Enhanced Cancer Therapy

• Published in: ACS nano Vol. 9; no. 5; pp. 5072 - 5081
• Main Authors: Tang, Li, Tong, Rong, Coyle, Virginia J, Yin, Qian, Pondenis, Holly, Borst, Luke B, Cheng, Jianjun, Fan, Timothy M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-05-2015
• Subjects: Animals; Antigens, Surface - metabolism; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - genetics; Base Sequence; Cell Line, Tumor; Delayed-Action Preparations; Dogs; Doxorubicin - chemistry; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Gene Expression Regulation, Neoplastic - drug effects; Glutamate Carboxypeptidase II - metabolism; Hemangiosarcoma - blood supply; Hemangiosarcoma - drug therapy; Hemangiosarcoma - pathology; Humans; Male; Mice; Models, Molecular; Molecular Conformation; Nanoconjugates - chemistry; Nanoconjugates - therapeutic use; Nanoconjugates - toxicity; Nanomedicine - methods; Neovascularization, Pathologic - drug therapy; Polyesters - chemistry; Tissue Distribution; nanoconjugate drug delivery; tumor-associated endothelium; cancer targeting by aptamer; comparative tumor model; prostate-specific membrane antigen
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.5b00166

An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin–polylactide (Doxo-PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt-functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis.