Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, Brazil.
Exp Biol Med (Maywood). 2011 Jul;236(7):808-15. doi: 10.1258/ebm.2011.011038. Epub 2011 Jun 17.
Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal cavity.
顺铂（CDDP）是最有效的细胞毒性药物之一，已广泛应用于腹腔内（i.p.）途径治疗腹膜癌病。然而，CDDP 是一种低分子量化合物，在 i.p.腹膜的毛细血管中被迅速吸收，并转移到血液中，导致出现全身副作用，如肾毒性。此外，i.p. CDDP 化疗仅限于在手术减瘤后残余肿瘤结节直径小于 0.5 厘米的患者。i.p. 治疗失败归因于 CDDP 对较大肿瘤的穿透不良。提高腹腔区域药物输送并降低毒性的一种策略是使用药物输送系统。本工作的目的是评估含有顺铂的长循环和 pH 敏感脂质体（SpHL-CDDP）与游离 CDDP 相比，在荷 Ehrlich 腹水瘤小鼠中经 i.p.给药后的生物分布和抗肿瘤作用。在给予游离 CDDP 或 SpHL-CDDP 单次 i.p. 推注 6mg/kg 后，收集腹水（AF）、血液和器官（肾脏、肝脏、脾脏和肺），并分析 CDDP 含量。SpHL-CDDP 给药后获得的 AF 和血液中的 CDDP 浓度-时间曲线下面积（AUC）分别是游离 CDDP 治疗的 3.3 倍和 1.3 倍，表明其在腹腔内的高保留。确定每个组织与血液之间 AUC 的比值（Kp）表明 SpHL-CDDP 治疗后肾脏中 CDDP 的积累较低。SpHL-CDDP 治疗导致肝脏和脾脏的摄取增加。SpHL-CDDP 治疗导致初始或播散性腹膜癌病小鼠的存活率高于 CDDP 治疗。这些结果表明，SpHL-CDDP 可能因其在腹腔内的更高浓度而对 i.p. 化疗有用。
