In Vivo Antitumor Activity of Folate-Conjugated Cholic Acid-Polyethylenimine Micelles for the Codelivery of Doxorubicin and siRNA to Colorectal Adenocarcinomas

Muhammad Wahab Amjad, Mohd Cairul Iqbal Mohd Amin, Haliza Katas, Adeel Masood Butt, Prashant Kesharwani, Arun K. Iyer

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.

Original languageEnglish
Pages (from-to)4247-4258
Number of pages12
JournalMolecular Pharmaceutics
Volume12
Issue number12
DOIs
Publication statusPublished - 14 Nov 2015

Fingerprint

Cholic Acid
Polyethyleneimine
Micelles
Folic Acid
Doxorubicin
Small Interfering RNA
Adenocarcinoma
Multiple Drug Resistance
Vascular Endothelial Growth Factor A
Nanoconjugates
Neoplasms
Dihydrouracil Dehydrogenase (NADP)
Particle Size
Polymers
Necrosis
Cell Count
X-Rays
Apoptosis
Liver
Growth

Keywords

  • cytotoxicity
  • drug delivery
  • electron microscopy
  • in vivo tumor targeting
  • micelle
  • nanoparticle

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

In Vivo Antitumor Activity of Folate-Conjugated Cholic Acid-Polyethylenimine Micelles for the Codelivery of Doxorubicin and siRNA to Colorectal Adenocarcinomas. / Amjad, Muhammad Wahab; Mohd Amin, Mohd Cairul Iqbal; Katas, Haliza; Butt, Adeel Masood; Kesharwani, Prashant; Iyer, Arun K.

In: Molecular Pharmaceutics, Vol. 12, No. 12, 14.11.2015, p. 4247-4258.

Research output: Contribution to journalArticle

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abstract = "Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7{\%}, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25{\%} doxorubicin was released within 24 h at pH 7.4, while more than 30{\%} release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.",
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AU - Kesharwani, Prashant

AU - Iyer, Arun K.

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