LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer.
OBJECTIVE
Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer.


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).


RESULTS
HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co-LA) were characterized by (1)HNMR 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.


CONCLUSIONS
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.
College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
Di
D
Wen
Deepak
D
Chitkara
Hao
H
Wu
Michael
M
Danquah
Renukadevi
R
Patil
Duane D
DD
Miller
Ram I
RI
Mahato
D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D000813:Anilides / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D006885:Hydroxybutyrates / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008819:Mice, Nude; D008823:Micelles; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D000813:Anilides; D004337:Drug Carriers; D006885:Hydroxybutyrates; D008823:Micelles; C576344:N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-cyanophenyl)(methyl)amino)-2-hydroxy-2-methylpropanamide; D007987:Gonadotropin-Releasing Hormone