title: 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: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors: Yang
authors: Y
authors: Yang
authors: Lian
authors: L
authors: Li
authors: Zhou
authors: Z
authors: Zhou
authors: Qingqing
authors: Q
authors: Yang
authors: Chong
authors: C
authors: Liu
authors: Yuan
authors: Y
authors: Huang
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy*
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D010455:Peptides; D011108:Polymers; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: G3-C12 peptide; HPMA copolymers; galectin-3; prostate carcinoma