HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer.

Abstract

PURPOSE:

This study focused on the synthesis and in vitro characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for the delivery of geldanamycin to prostate cancer tumors. Conjugates were modified to incorporate WIFPWIQL peptide, which binds to cell-surface-expressed Glucose-regulated protein 78.

METHODS:

HPMA copolymers containing aminohexylgeldanamycin with and without WIFPWIQL peptide were synthesized and characterized, and stability in pH 7.4 and pH 5.0 buffers, complete cell culture medium, and fetal bovine serum was evaluated. The comparative cell surface expression of GRP78 in DU145 and PC3 cell lines was assessed and competitive binding to cell surface expressed GRP78 evaluated. The ability of the conjugates to inhibit cell growth was also evaluated in vitro.

RESULTS:

HPMA copolymer-aminohexylgeldanamycin conjugates were stable with maximal release observed in fetal bovine serum at 37°C of approximately 10% in 72 h. HPMA copolymers bearing WIFPWIQL peptide bound to cell surface expressed GRP78 with affinities comparable to free WIFPWIQL peptide and demonstrated increased cytotoxicity as compared to untargeted conjugates.

CONCLUSION:

HPMA copolymer aminohexylgeldanamycin conjugates bearing WIFPWIQL peptide have the ability to bind to cell-surface-expressed GRP78 and inhibit the growth of human prostate cancer cells, suggesting that the conjugates have the potential to target solid prostate cancer tumors.

• Authors: Nate Larson, Abhijit Ray, Alexander Malugin, Daniel B Pike, Hamidreza Ghandehari
• Journal: Pharmaceutical research (Pharm Res) Vol. 27 Issue 12 Pg. 2683-93 (Dec 2010) ISSN: 1573-904X [Electronic] United States
• PMID: 20845065 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylic Resins
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• Lactams, Macrocyclic
• Methacrylates
• Oligopeptides
• hydroxypropyl methacrylate

Topics

• Acrylic Resins (chemistry)
• Amino Acid Sequence
• Cell Division
• Cell Line, Tumor
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins (metabolism)
• Humans
• Lactams, Macrocyclic (chemistry)
• Male
• Methacrylates (chemistry)
• Oligopeptides (chemistry, metabolism)
• Prostatic Neoplasms (metabolism, pathology)