EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer

Goutam Mondal, Saud Almawash, Amit Kumar Chaudhary, Ram I Mahato

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)3121-3133
Number of pages13
JournalMolecular Pharmaceutics
Volume14
Issue number9
DOIs
StatePublished - Sep 5 2017

Fingerprint

gemcitabine
Micelles
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Triethylenephosphoramide
Dodecanol
Neoplasms
Ethylene Glycol
Cetuximab
Fluorescent Dyes

Keywords

  • C225
  • EGFR
  • gemcitabine
  • miR-205
  • pancreatic cancer
  • polymeric mixed micelles
  • targeted drug delivery

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer. / Mondal, Goutam; Almawash, Saud; Chaudhary, Amit Kumar; Mahato, Ram I.

In: Molecular Pharmaceutics, Vol. 14, No. 9, 05.09.2017, p. 3121-3133.

Research output: Contribution to journalArticle

@article{fda0d6bfb0014414a57aff53c2a45e2f,
title = "EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer",
abstract = "Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.",
keywords = "C225, EGFR, gemcitabine, miR-205, pancreatic cancer, polymeric mixed micelles, targeted drug delivery",
author = "Goutam Mondal and Saud Almawash and Chaudhary, {Amit Kumar} and Mahato, {Ram I}",
year = "2017",
month = "9",
day = "5",
doi = "10.1021/acs.molpharmaceut.7b00355",
language = "English (US)",
volume = "14",
pages = "3121--3133",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "9",

}

TY - JOUR

T1 - EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer

AU - Mondal, Goutam

AU - Almawash, Saud

AU - Chaudhary, Amit Kumar

AU - Mahato, Ram I

PY - 2017/9/5

Y1 - 2017/9/5

N2 - Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.

AB - Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.

KW - C225

KW - EGFR

KW - gemcitabine

KW - miR-205

KW - pancreatic cancer

KW - polymeric mixed micelles

KW - targeted drug delivery

UR - http://www.scopus.com/inward/record.url?scp=85028865181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028865181&partnerID=8YFLogxK

U2 - 10.1021/acs.molpharmaceut.7b00355

DO - 10.1021/acs.molpharmaceut.7b00355

M3 - Article

C2 - 28719220

AN - SCOPUS:85028865181

VL - 14

SP - 3121

EP - 3133

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 9

ER -