Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of cd44-positive and drug-resistant tumors

Xin Wei, Thulani H. Senanayake, Galya Warren, Serguei V. Vinogradov

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diameter 20-40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2-7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to that of free drugs and nonmodified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to that in nonmodified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed a higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids.

Original languageEnglish (US)
Pages (from-to)658-668
Number of pages11
JournalBioconjugate Chemistry
Volume24
Issue number4
DOIs
StatePublished - Apr 17 2013

Fingerprint

Hyaluronic acid
Hyaluronic Acid
Tumors
Pharmaceutical Preparations
Cells
Neoplasms
Stem cells
Glycoproteins
Neoplastic Stem Cells
Cholesterol
Cell membranes
Cytotoxicity
Cellular Spheroids
Hydrolysis
Esters
NanoGel
Membranes
Biological Availability
Curcumin
Drug Design

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of cd44-positive and drug-resistant tumors. / Wei, Xin; Senanayake, Thulani H.; Warren, Galya; Vinogradov, Serguei V.

In: Bioconjugate Chemistry, Vol. 24, No. 4, 17.04.2013, p. 658-668.

Research output: Contribution to journalArticle

Wei, Xin ; Senanayake, Thulani H. ; Warren, Galya ; Vinogradov, Serguei V. / Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of cd44-positive and drug-resistant tumors. In: Bioconjugate Chemistry. 2013 ; Vol. 24, No. 4. pp. 658-668.
@article{5fc000390beb4268a62d92f790fa09ec,
title = "Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of cd44-positive and drug-resistant tumors",
abstract = "Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diameter 20-40 nm) with a hydrophobic core and high drug loads (up to 20{\%}) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2-7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to that of free drugs and nonmodified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to that in nonmodified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed a higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids.",
author = "Xin Wei and Senanayake, {Thulani H.} and Galya Warren and Vinogradov, {Serguei V.}",
year = "2013",
month = "4",
day = "17",
doi = "10.1021/bc300632w",
language = "English (US)",
volume = "24",
pages = "658--668",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of cd44-positive and drug-resistant tumors

AU - Wei, Xin

AU - Senanayake, Thulani H.

AU - Warren, Galya

AU - Vinogradov, Serguei V.

PY - 2013/4/17

Y1 - 2013/4/17

N2 - Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diameter 20-40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2-7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to that of free drugs and nonmodified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to that in nonmodified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed a higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids.

AB - Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diameter 20-40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2-7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to that of free drugs and nonmodified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to that in nonmodified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed a higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids.

UR - http://www.scopus.com/inward/record.url?scp=84876484728&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876484728&partnerID=8YFLogxK

U2 - 10.1021/bc300632w

DO - 10.1021/bc300632w

M3 - Article

C2 - 23547842

AN - SCOPUS:84876484728

VL - 24

SP - 658

EP - 668

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 4

ER -