LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer

Di Wen, Deepak Chitkara, Hao Wu, Michael Danquah, Renukadevi Patil, Duane Miller, Ram I. Mahato

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Methods: LHRH-PEG-b-p(CB-co-LA) was synthesized by opening polymerization of carbonate (CB), lactide (LA), and HOOC-PEG-OH followed by conjugation with LHRH analogue. Bicalutamide analogue CBIDV17 loaded micelles were formulated by film hydration method, and characterized for critical micelle concentration (CMC), drug loading and in vitro drug release. Formulations were tested on LNCaP and C4-2 cells for cellular uptake, induction of apoptosis, viability and dowregulation of androgen receptor (AR). In vivo studies were performed in ectopic tumor bearing athymic nude mice after tail vein injection at a dose of 10 mg/kg. Tumor volume and body weight were measured for 25 days followed by immunohistochemistry (IHC) of tumor samples for Ki-67, caspase-3, and prostate specific antigen (PSA).

Purpose: Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer.

Results: HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co-LA) were characterized by 1HNMR and used for preparing micelles, which had a mean particle size of 75.60∈±∈2.25 and 72.64∈±∈1.15 nm, respectively and CBDIV17 loading of 4.6% w/w. LHRH conjugated micelles showed higher cellular uptake, cytotoxicity, and apoptosis in LNCaP and C4-2 cells compared to non-targeted micelles. CBDIV17 loaded LHRH micelles more efficiently inhibited the proliferation and induced apoptosis of tumor cells according to Ki-67, caspase-3, and PSA expression. There was significant inhibition of tumor growth with the treatment of CBDIV17 loaded LHRH-conjugated micelles.

Conclusion: These results demonstrated that LHRH-b-PEG-p(CB-co-LA) micelles have the potential for targeted delivery of CBDIV17 to treat advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)2784-2795
Number of pages12
JournalPharmaceutical Research
Volume31
Issue number10
DOIs
StatePublished - May 2 2014

Fingerprint

Androgen Antagonists
Micelles
Gonadotropin-Releasing Hormone
Prostatic Neoplasms
Carbonates
Polyethylene glycols
Tumors
Prostate-Specific Antigen
Apoptosis
Tumor Burden
Nude Mice
Caspase 3
Neoplasms
Bearings (structural)
Critical micelle concentration
Androgen Receptors
Cytotoxicity
Particle Size
Polymerization
Hydration

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer. / Wen, Di; Chitkara, Deepak; Wu, Hao; Danquah, Michael; Patil, Renukadevi; Miller, Duane; Mahato, Ram I.

In: Pharmaceutical Research, Vol. 31, No. 10, 02.05.2014, p. 2784-2795.

Research output: Contribution to journalArticle

Wen, Di ; Chitkara, Deepak ; Wu, Hao ; Danquah, Michael ; Patil, Renukadevi ; Miller, Duane ; Mahato, Ram I. / LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer. In: Pharmaceutical Research. 2014 ; Vol. 31, No. 10. pp. 2784-2795.
@article{705cea507b4b40c8b435640bf4673604,
title = "LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer",
abstract = "Methods: LHRH-PEG-b-p(CB-co-LA) was synthesized by opening polymerization of carbonate (CB), lactide (LA), and HOOC-PEG-OH followed by conjugation with LHRH analogue. Bicalutamide analogue CBIDV17 loaded micelles were formulated by film hydration method, and characterized for critical micelle concentration (CMC), drug loading and in vitro drug release. Formulations were tested on LNCaP and C4-2 cells for cellular uptake, induction of apoptosis, viability and dowregulation of androgen receptor (AR). In vivo studies were performed in ectopic tumor bearing athymic nude mice after tail vein injection at a dose of 10 mg/kg. Tumor volume and body weight were measured for 25 days followed by immunohistochemistry (IHC) of tumor samples for Ki-67, caspase-3, and prostate specific antigen (PSA).Purpose: Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer.Results: HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co-LA) were characterized by 1HNMR and used for preparing micelles, which had a mean particle size of 75.60∈±∈2.25 and 72.64∈±∈1.15 nm, respectively and CBDIV17 loading of 4.6{\%} w/w. LHRH conjugated micelles showed higher cellular uptake, cytotoxicity, and apoptosis in LNCaP and C4-2 cells compared to non-targeted micelles. CBDIV17 loaded LHRH micelles more efficiently inhibited the proliferation and induced apoptosis of tumor cells according to Ki-67, caspase-3, and PSA expression. There was significant inhibition of tumor growth with the treatment of CBDIV17 loaded LHRH-conjugated micelles.Conclusion: These results demonstrated that LHRH-b-PEG-p(CB-co-LA) micelles have the potential for targeted delivery of CBDIV17 to treat advanced prostate cancer.",
author = "Di Wen and Deepak Chitkara and Hao Wu and Michael Danquah and Renukadevi Patil and Duane Miller and Mahato, {Ram I.}",
year = "2014",
month = "5",
day = "2",
doi = "10.1007/s11095-014-1375-6",
language = "English (US)",
volume = "31",
pages = "2784--2795",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "10",

}

TY - JOUR

T1 - LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer

AU - Wen, Di

AU - Chitkara, Deepak

AU - Wu, Hao

AU - Danquah, Michael

AU - Patil, Renukadevi

AU - Miller, Duane

AU - Mahato, Ram I.

PY - 2014/5/2

Y1 - 2014/5/2

N2 - Methods: LHRH-PEG-b-p(CB-co-LA) was synthesized by opening polymerization of carbonate (CB), lactide (LA), and HOOC-PEG-OH followed by conjugation with LHRH analogue. Bicalutamide analogue CBIDV17 loaded micelles were formulated by film hydration method, and characterized for critical micelle concentration (CMC), drug loading and in vitro drug release. Formulations were tested on LNCaP and C4-2 cells for cellular uptake, induction of apoptosis, viability and dowregulation of androgen receptor (AR). In vivo studies were performed in ectopic tumor bearing athymic nude mice after tail vein injection at a dose of 10 mg/kg. Tumor volume and body weight were measured for 25 days followed by immunohistochemistry (IHC) of tumor samples for Ki-67, caspase-3, and prostate specific antigen (PSA).Purpose: Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer.Results: HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co-LA) were characterized by 1HNMR and used for preparing micelles, which had a mean particle size of 75.60∈±∈2.25 and 72.64∈±∈1.15 nm, respectively and CBDIV17 loading of 4.6% w/w. LHRH conjugated micelles showed higher cellular uptake, cytotoxicity, and apoptosis in LNCaP and C4-2 cells compared to non-targeted micelles. CBDIV17 loaded LHRH micelles more efficiently inhibited the proliferation and induced apoptosis of tumor cells according to Ki-67, caspase-3, and PSA expression. There was significant inhibition of tumor growth with the treatment of CBDIV17 loaded LHRH-conjugated micelles.Conclusion: These results demonstrated that LHRH-b-PEG-p(CB-co-LA) micelles have the potential for targeted delivery of CBDIV17 to treat advanced prostate cancer.

AB - Methods: LHRH-PEG-b-p(CB-co-LA) was synthesized by opening polymerization of carbonate (CB), lactide (LA), and HOOC-PEG-OH followed by conjugation with LHRH analogue. Bicalutamide analogue CBIDV17 loaded micelles were formulated by film hydration method, and characterized for critical micelle concentration (CMC), drug loading and in vitro drug release. Formulations were tested on LNCaP and C4-2 cells for cellular uptake, induction of apoptosis, viability and dowregulation of androgen receptor (AR). In vivo studies were performed in ectopic tumor bearing athymic nude mice after tail vein injection at a dose of 10 mg/kg. Tumor volume and body weight were measured for 25 days followed by immunohistochemistry (IHC) of tumor samples for Ki-67, caspase-3, and prostate specific antigen (PSA).Purpose: Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer.Results: HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co-LA) were characterized by 1HNMR and used for preparing micelles, which had a mean particle size of 75.60∈±∈2.25 and 72.64∈±∈1.15 nm, respectively and CBDIV17 loading of 4.6% w/w. LHRH conjugated micelles showed higher cellular uptake, cytotoxicity, and apoptosis in LNCaP and C4-2 cells compared to non-targeted micelles. CBDIV17 loaded LHRH micelles more efficiently inhibited the proliferation and induced apoptosis of tumor cells according to Ki-67, caspase-3, and PSA expression. There was significant inhibition of tumor growth with the treatment of CBDIV17 loaded LHRH-conjugated micelles.Conclusion: These results demonstrated that LHRH-b-PEG-p(CB-co-LA) micelles have the potential for targeted delivery of CBDIV17 to treat advanced prostate cancer.

UR - http://www.scopus.com/inward/record.url?scp=84931083218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931083218&partnerID=8YFLogxK

U2 - 10.1007/s11095-014-1375-6

DO - 10.1007/s11095-014-1375-6

M3 - Article

VL - 31

SP - 2784

EP - 2795

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 10

ER -