Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy.
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.
Li
L
Tang
Rong
R
Tong
Virginia J
VJ
Coyle
Qian
Q
Yin
Holly
H
Pondenis
§Department of Population Health and Pathobiology, North Carolina State University, Raleigh, North Carolina 27607, United States.
Luke B
LB
Borst
Jianjun
J
Cheng
Timothy M
TM
Fan
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D004285:Dogs; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D006394:Hemangiosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058726:Nanoconjugates / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D050997:Nanomedicine / Q000379:methods*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011091:Polyesters / Q000737:chemistry*; D014018:Tissue Distribution
D000954:Antigens, Surface; D052157:Aptamers, Nucleotide; D003692:Delayed-Action Preparations; D058726:Nanoconjugates; D011091:Polyesters; C033616:poly(lactide); D004317:Doxorubicin; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
cancer targeting by aptamer; comparative tumor model; nanoconjugate drug delivery; prostate-specific membrane antigen; tumor-associated endothelium