Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs

Serguei V. Vinogradov, Arin D. Zeman, Elena V. Batrakova, Alexander V. Kabanov

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5′-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5′-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33% by weight of the drug-Nanogel formulation. In vitro 35% of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90% of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)143-157
Number of pages15
JournalJournal of Controlled Release
Volume107
Issue number1
DOIs
StatePublished - Sep 20 2005

Fingerprint

Drug Compounding
Nucleosides
Pharmaceutical Preparations
Polyethyleneimine
Folic Acid
Neoplasms
NanoGel
Transcytosis
Polyphosphates
Caco-2 Cells
Ethylene Glycol
MCF-7 Cells
Drug Delivery Systems
Cultured Cells
Polymers
Breast Neoplasms

Keywords

  • Caco-2
  • Cytotoxicity
  • Fludarabine
  • Folate vector
  • MCF-7
  • Nanogel
  • Nucleoside 5′-triphosphate

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs. / Vinogradov, Serguei V.; Zeman, Arin D.; Batrakova, Elena V.; Kabanov, Alexander V.

In: Journal of Controlled Release, Vol. 107, No. 1, 20.09.2005, p. 143-157.

Research output: Contribution to journalArticle

Vinogradov, Serguei V. ; Zeman, Arin D. ; Batrakova, Elena V. ; Kabanov, Alexander V. / Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs. In: Journal of Controlled Release. 2005 ; Vol. 107, No. 1. pp. 143-157.
@article{60c99b757ae54a5da9cefb218cd086f5,
title = "Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs",
abstract = "Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5′-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5′-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33{\%} by weight of the drug-Nanogel formulation. In vitro 35{\%} of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90{\%} of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.",
keywords = "Caco-2, Cytotoxicity, Fludarabine, Folate vector, MCF-7, Nanogel, Nucleoside 5′-triphosphate",
author = "Vinogradov, {Serguei V.} and Zeman, {Arin D.} and Batrakova, {Elena V.} and Kabanov, {Alexander V.}",
year = "2005",
month = "9",
day = "20",
doi = "10.1016/j.jconrel.2005.06.002",
language = "English (US)",
volume = "107",
pages = "143--157",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs

AU - Vinogradov, Serguei V.

AU - Zeman, Arin D.

AU - Batrakova, Elena V.

AU - Kabanov, Alexander V.

PY - 2005/9/20

Y1 - 2005/9/20

N2 - Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5′-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5′-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33% by weight of the drug-Nanogel formulation. In vitro 35% of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90% of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.

AB - Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5′-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5′-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33% by weight of the drug-Nanogel formulation. In vitro 35% of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90% of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.

KW - Caco-2

KW - Cytotoxicity

KW - Fludarabine

KW - Folate vector

KW - MCF-7

KW - Nanogel

KW - Nucleoside 5′-triphosphate

UR - http://www.scopus.com/inward/record.url?scp=24344467910&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24344467910&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2005.06.002

DO - 10.1016/j.jconrel.2005.06.002

M3 - Article

C2 - 16039001

AN - SCOPUS:24344467910

VL - 107

SP - 143

EP - 157

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

IS - 1

ER -