Targeting prostate carcinoma by G3-C12 peptide conjugated N-(2-hydroxypropyl)methacrylamide copolymers.

Abstract

Prostate carcinoma is the second leading cause of cancer-related deaths. Increased expression of membrane-bound galectin-3 by prostate carcinoma cell has been found to correlate with more poorly differentiated and increased metastatic potential. In the present study, different amount of galectin-3-binding peptide, G3-C12 (the sequence ANTPCGPYTHDCPVKR), was attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers as targeting moiety. The results of qPCR and competitive binding test indicated that the expression level of galectin-3 in two metastatic prostate carcinoma cell lines (PC-3 and DU145 cells) could be significantly suppressed by the addition of G3-C12-modified HPMA copolymers (PG1 and PG2), demonstrating the high affinity of PG1 and PG2 to galectin-3. Due to the multivalent effects of moieties, the uptake of copolymers was remarkably enhanced with the increasing amount of conjugated G3-C12 peptide. A higher internalization of PG1 and PG2 occurred in PC-3 cells via caveolin- and clathrin-mediated endocytosis, whereas a clathrin-mediated uptake process was involved in DU145 cells. The in vivo biodistribution and pharmacokinetics of nonmodified ((131)I-pHPMA) and G3-C12-modified ((131)I-PG1 and (131)I-PG2) copolymers were estimated on a well-established mice model bearing PC-3 xenografts by (131)I-SPECT-imaging. Higher tumor accumulation of (131)I-PG1 (1.60 ± 0.08% ID/g, p < 0.05) and (131)I-PG2 (1.54 ± 0.06% ID/g, p < 0.05) was observed compared with (131)I-pHPMA (1.19 ± 0.04% ID/g) at 2 h post-intravenous injection. Although the amount of conjugated G3-C12 peptide performed a remarkable in vitro effect on the affinity and internalization of HPMA copolymers to the galectin-3 overexpressed prostate carcinoma cells, the molecular weight and ligand modification all play important roles on their in vivo tumor accumulation.

• Authors: Yang Yang, Lian Li, Zhou Zhou, Qingqing Yang, Chong Liu, Yuan Huang
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 11 Issue 10 Pg. 3251-60 (Oct 06 2014) ISSN: 1543-8392 [Electronic] United States
• PMID: 24955652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Antineoplastic Agents
• Peptides
• Polymers
• N-(2-hydroxypropyl)methacrylamide

Topics

• Acrylamides (chemistry)
• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Cell Line, Tumor
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Peptides (chemistry)
• Polymers (chemistry)
• Prostatic Neoplasms (drug therapy)