Biodistribution of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer drug delivery.
Biodistribution of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer drug delivery.
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DOI：
10.1021/mp900134c
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发表时间：
2009-11
影响因子：
4.9
通讯作者：
Ghandehari H
中科院分区：
文献类型：
--
作者：
Borgman MP;Aras O;Geyser-Stoops S;Sausville EA;Ghandehari H
N-(2-羟丙基甲基丙烯酰胺)共聚物-精氨酸-甘氨酸-天冬氨酸(Arg-Gly-Asp)靶向αvβ3整合素的结合物存在于血管新生血管和某些肿瘤类型中，已显示出在实体肿瘤中蓄积增加，并具有用于部位特异性给药的特性。格尔达那霉素(GDM)是一种与热休克蛋白90(HSP90)结合的苯喹类阿萨霉素，对治疗包括前列腺癌在内的多种癌症类型有效，但具有剂量限制的细胞毒性。我们最近报道了含有RGDfK的HPMA共聚物-氨基己基-格尔达霉素(AH-GDM)结合物的合成，该结合物具有良好的药物释放性能、与αvβ3整合素的体外结合、对人前列腺癌细胞的细胞毒性以及在裸鼠体内的耐受性超过相当自由药物剂量的2倍。本研究评价了~(125)I-放射性标记的HPMA共聚物-AH-GDM结合物与RGDfK结合物在荷瘤裸鼠和DU145前列腺癌裸鼠体内的分布。在非荷瘤小鼠中，在60 mg/kg药物当量聚合物剂量下，这两种结合物都显示出从血液中快速消除，并减少在所有其他器官中的蓄积。肾积聚占主导地位，且以含RGDfK的结合物较高。在荷瘤小鼠中，与不含RGDfK的结合物相比，微量的含有RGDfK的结合物显示肿瘤聚集增加。还评估了前列腺癌移植瘤中30和60 mg/kg药物当量共聚物结合物(含和不含RGDfK)治疗后的游离药物浓度，并与30 mg/kg游离AH-GDM治疗进行了比较。总体而言，与所有其他处理相比，60 mg/kg的RGDfK结合物处理组显示出显著更高的肿瘤药物浓度(p<；0.001)。与非靶向系统相比，靶向结合物可以有效地将更多量的格尔达那霉素输送到肿瘤。
N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-RGD (Arg-Gly-Asp) conjugates targeting the αvβ3 integrin present on angiogenic blood vessels and some tumor types have shown increased accumulation in solid tumors and possess properties that suggest their use for site-specific drug delivery. Geldanamycin (GDM) is a benzoquinoid ansamycin that binds to heat-shock protein 90 (HSP90), effective for the treatment of multiple cancer types including prostate, but has dose-limiting cytotoxicity. We recently reported the synthesis of HPMA copolymer-aminohexyl-geldanamycin (AH-GDM) conjugates containing RGDfK that demonstrated favorable properties of drug release, in vitro binding to the αvβ3 integrin, cytotoxicity in human prostate cancer cells, and tolerability in nude mice greater than 2-fold equivalent free drug doses. In this study the biodistribution of 125I-radiolabeled HPMA copolymer-AH-GDM conjugates with and without RGDfK in both non-tumor and DU145 prostate tumor xenograft-bearing nude mice was evaluated. At 60 mg/kg drug equivalent polymer doses in non-tumor bearing mice both conjugates showed fast elimination from blood and decreasing accumulation in all other organs. Kidney accumulation predominated and was higher for the conjugate containing RGDfK. In tumor bearing mice, trace quantities of the conjugate containing RGDfK showed increased tumor accumulation as compared to the conjugate without RGDfK. Also evaluated were free drug concentrations in prostate tumor xenografts following treatments of 30 and 60 mg/kg drug-equivalent copolymer-conjugates (with and without RGDfK) compared with 30 mg/kg free AH-GDM. Overall, 60 mg/kg treatment of RGDfK-containing conjugate showed significantly higher (p<0.001) tumor drug concentrations compared with all other treatments. The targetable conjugates can effectively deliver higher amounts of geldanamycin to the tumor compared to non-targetable systems.
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影响因子：
10.8
作者：
Julyan, PJ;Seymour, LW;Kerr, DJ
通讯作者：
Kerr, DJ
影响因子：
10.8
作者：
Mitra, A;Mulholland, J;Line, BR
通讯作者：
Line, BR
影响因子：
11.5
作者：
Nowakowski, Grzegorz S.;McCollum, Andrea K.;Erlichman, Charles
通讯作者：
Erlichman, Charles
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
DOI：
10.1034/j.1399-3011.1999.00052.x
发表时间：
1999-05-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Bogdanowich-Knipp, SJ;Chakrabarti, S;Siahaan, TJ
通讯作者：
Siahaan, TJ