Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy

Li Tang, Rong Tong, Virginia J. Coyle, Qian Yin, Holly Pondenis, Luke B. Borst, Jianjun Cheng, Timothy M Fan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5072-5081
Number of pages10
JournalACS Nano
Volume9
Issue number5
DOIs
StatePublished - May 26 2015

Fingerprint

Nanoconjugates
Doxorubicin
Tumors
therapy
tumors
cancer
Endothelial cells
antigens
Antigens
mice
membranes
Membranes
Bearings (structural)
endothelium
poly(lactide)
necrosis
Cell death
profiles
cultured cells
death

Keywords

  • cancer targeting by aptamer
  • comparative tumor model
  • nanoconjugate drug delivery
  • prostate-specific membrane antigen
  • tumor-associated endothelium

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Cite this

Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy. / Tang, Li; Tong, Rong; Coyle, Virginia J.; Yin, Qian; Pondenis, Holly; Borst, Luke B.; Cheng, Jianjun; Fan, Timothy M.

In: ACS Nano, Vol. 9, No. 5, 26.05.2015, p. 5072-5081.

Research output: Contribution to journalArticle

Tang, Li ; Tong, Rong ; Coyle, Virginia J. ; Yin, Qian ; Pondenis, Holly ; Borst, Luke B. ; Cheng, Jianjun ; Fan, Timothy M. / Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy. In: ACS Nano. 2015 ; Vol. 9, No. 5. pp. 5072-5081.
@article{4a4fd543fd4c421eb8ffb3ffd1d9293e,
title = "Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy",
abstract = "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.",
keywords = "cancer targeting by aptamer, comparative tumor model, nanoconjugate drug delivery, prostate-specific membrane antigen, tumor-associated endothelium",
author = "Li Tang and Rong Tong and Coyle, {Virginia J.} and Qian Yin and Holly Pondenis and Borst, {Luke B.} and Jianjun Cheng and Fan, {Timothy M}",
year = "2015",
month = "5",
day = "26",
doi = "10.1021/acsnano.5b00166",
language = "English (US)",
volume = "9",
pages = "5072--5081",
journal = "ACS Nano",
issn = "1936-0851",
publisher = "American Chemical Society",
number = "5",

}

TY - JOUR

T1 - Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy

AU - Tang, Li

AU - Tong, Rong

AU - Coyle, Virginia J.

AU - Yin, Qian

AU - Pondenis, Holly

AU - Borst, Luke B.

AU - Cheng, Jianjun

AU - Fan, Timothy M

PY - 2015/5/26

Y1 - 2015/5/26

N2 - 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.

AB - 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.

KW - cancer targeting by aptamer

KW - comparative tumor model

KW - nanoconjugate drug delivery

KW - prostate-specific membrane antigen

KW - tumor-associated endothelium

UR - http://www.scopus.com/inward/record.url?scp=84930221698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930221698&partnerID=8YFLogxK

U2 - 10.1021/acsnano.5b00166

DO - 10.1021/acsnano.5b00166

M3 - Article

C2 - 25938427

AN - SCOPUS:84930221698

VL - 9

SP - 5072

EP - 5081

JO - ACS Nano

JF - ACS Nano

SN - 1936-0851

IS - 5

ER -