正电化修饰的HPMA聚合物-阿霉素接合物的制备表征及对肿瘤细胞摄取的影响

目的:制备2种正电化修饰的N-(2-羟丙基)甲基丙烯酰胺(HPMA)聚合物-阿霉素接合物并表征,分别考察2种接合物的正电基团含量对肿瘤细胞摄取的影响。方法:制备侧链带伯胺基的HPMA聚合物-阿霉素接合物(pHPMA-DOX-APMA)和侧链带胍基的HPMA聚合物-阿霉素接合物(pHPMA-DOX-GPMA),对其药剂学性质如正电基团含量,载药量,Zeta电位和分子量进行表征,进一步考察不同正电基团含量的接合物对MCF-7细胞摄取和毒性的影响。结果:通过自由基聚合反应,2种接合物成功合成。其中pHPMA-DOX-APMA伯胺基含量为0.44~1.57 mmol·g^-1,载药量为7.15%~9.25%;pHPMA-DOX-GPMA胍基含量为0.11~0.54 mmol·g^-1,载药量为7.55%~9.07%;相对分子质量分别为33~38 kDa和32~37 kDa。通过BCA法和MTT法研究分别发现在pHPMA-DOX-APMA中的伯胺基团含量为1.570 mmol·g^-1及pHPMA-DOX-GPMA中的胍基含量为0.260 mmol·g^-1时,肿瘤细胞对阿霉素的摄取量显著增加,二者的IC₅₀与pHPMA-DOX相比显著降低(P<0.05)。结论:成功制备了2种正电化修饰的HPMA聚合物-阿霉素接合物;适当的正电化修饰对阿霉素的肿瘤细胞摄取有促进作用。

Doxorubicin-loaded,positively charged HPMA copolymer conjugates: synthesis,characterization and influences on cellular uptake in tumor cells

OBJECTIVE To synthesize doxorubicin-loaded HPMA copolymer conjugates with two kinds of positive charged groups and investigate their characteristics and influences of copolymers with different densities of positive charged groups on uptake of tumor cells.METHODS Two kinds of doxorubicin-loaded, positively charged HPMA copolymer conjugates were synthesized. Characteristics such as drug loading capacity, Zeta potential, molecular weight were investigated. Furthermore, influences of positive charged groups on MCF-7 cell uptake were also studied.RESULTS Conjugates were synthesized via radical solution polymerization. Drug loading capacity of conjugates modified with primary amine and guanidine were 7.15%-9.25% and 7.55%-9.46%, and contents of primary amine and guanidine were 0.44-1.57 mmol·g^-1 and 0.11-0.54 mmol·g^-1, respectively. Molecular weights of two conjugates were 33-38 kDa and 32-37 kDa. Furthermore, influences of copolymer with different densities of positive charged groups were analyzed by BCA method and MTT method. Cellular-uptake and cytotoxicity results showed a notable increase with 1.570 mmol·g^-1 in primary amine and 0.260 mmol·g^-1 in guanidine.CONCLUSION Doxorubicin-loaded, positively charged HPMA copolymer conjugates have been successfully synthesized. Cellular uptake of doxorubicin-loaded HPMA copolymer conjugates are improved by rational modification of positive charged groups.