Pharmaceutical Research

, Volume 26, Issue 6, pp 1407–1418

Targetable HPMA Copolymer–Aminohexylgeldanamycin Conjugates for Prostate Cancer Therapy

  • Mark P. Borgman
  • Abhijit Ray
  • Rohit B. Kolhatkar
  • Edward A. Sausville
  • Angelika M. Burger
  • Hamidreza Ghandehari
Research Paper

DOI: 10.1007/s11095-009-9851-0

Cite this article as:
Borgman, M.P., Ray, A., Kolhatkar, R.B. et al. Pharm Res (2009) 26: 1407. doi:10.1007/s11095-009-9851-0

Abstract

Purpose

This study focuses on the synthesis and characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–cyclo-RGD (Arg-Gly-Asp) conjugates for delivery of geldanamycin to prostate tumors.

Materials and Methods

HPMA copolymers containing aminohexylgeldanamycin (AH-GDM) with and without the targeting peptide RGDfK were synthesized and characterized. Drug release from copolymers was evaluated using cathepsin B. Competitive binding of copolymer conjugates to αvβ3 integrin was evaluated in prostate cancer (PC-3) and endothelial (HUVEC) cell lines and in vitro growth inhibition was assessed. The maximum tolerated dose for single i.v. injections of free drug and the conjugates was established in nude mice.

Results

HPMA copolymers containing AH-GDM and RGDfK showed active binding to the αvβ3 integrin similar to that of free peptide. Similarly, growth inhibition of cells by conjugates was comparable to that of the free drug. Single intravenous doses of HPMA copolymer–AH-GDM–RGDfK conjugates in mice were tolerated at 80 mg/kg drug equivalent, while free drug caused morbidity at 40 mg/kg. No signs of toxicity were present in mice receiving HPMA copolymer-AH-GDM-RGDfK over the 14-day evaluation period.

Conclusion

Results of in vitro activity and in vivo tolerability experiments hold promise for the utility of HPMA copolymer–AH-GDM–RGDfK conjugates for treatment of prostate cancer with greater efficacy and reduced toxicity.

KEY WORDS

geldanamycin HPMA copolymer prostate cancer RGDfK targeted delivery 

Abbreviations

17-AAG

17-allylamino-17-demethoxygeldanamycin

17-DMAG

17-dimethylaminoethylamino-17-demethoxygeldanamycin

AH

6-aminohexylamino

AH-GDM

17-(6-aminohexylamino)-17-demethoxygeldanamycin

CPB

cathepsin B

DCM

dichloromethane

DMSO

dimethyl sulfoxide

EtOAc

ethyl acetate

GDM

geldanamycin (GDM)

HPLC

high performance liquid chromatography

HPMA

N-(2-hydroxypropyl) methacrylamide

MA-GFLG-AH-GDM

N-methacryloylglycylphenylalanylleucylglycl-17-(6-aminohexylamino)-17-demethoxygeldanamycin

MeOH

methanol

RGDfK

cyclo-(arginine-glycince- aspartic acid-d-phenylalanine-lysine)

THF

tetrahydrofuran

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Mark P. Borgman
    • 1
    • 2
  • Abhijit Ray
    • 4
    • 6
  • Rohit B. Kolhatkar
    • 1
    • 2
  • Edward A. Sausville
    • 2
    • 3
  • Angelika M. Burger
    • 2
    • 3
    • 7
  • Hamidreza Ghandehari
    • 4
    • 5
    • 6
  1. 1.Department of Pharmaceutical SciencesUniversity of MarylandBaltimoreUSA
  2. 2.Center for Nanomedicine and Cellular DeliveryUniversity of MarylandBaltimoreUSA
  3. 3.Greenebaum Cancer CenterUniversity of MarylandBaltimoreUSA
  4. 4.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA
  5. 5.Department of BioengineeringUniversity of UtahSalt Lake CityUSA
  6. 6.Center for Nanomedicine, Nano Institute of UtahUniversity of UtahSalt Lake CityUSA
  7. 7.Barbara Ann Karmanos Cancer Institute and Department of PharmacologyWayne State UniversityDetroitUSA

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