A Poly(gamma, L-glutamic acid)-citric acid based nanoconjugate for cisplatin delivery

作者：Xiong, Yerong; Jiang, Weiwei; Shen, Yan^*; Li, Huiyi; Sun, Chunmeng; Ouahab, Ammar; Tu, Jiasheng

来源：Biomaterials, 2012, 33(29): 7182-7193.

DOI：10.1016/j.biomaterials.2012.06.071

• Drug delivery
• Cisplatin
• Poly-L-glutamic acid
• Anti-tumor activity
• Pharmacokinetics
• Biodistribution

A cisplatin-loaded nanoconjugate, poly(gamma, acid)-citric acid-cisplatin [gamma-PGA-CA-CDDP], as a tumor-targeted drug delivery system with sustained release capacity was successfully synthesized and characterized, and its antitumor activity was evaluated. The particle size (107 +/- 6.3 nm) and average molecular weight (66 kDa) were determined by dynamic light scattering (DLS) and gel permeation chromatography (GPC), respectively. The nanoconjugate delivery system released platinum in a sustained manner in PBS at 37 degrees C with an initial burst release during the first 8 h and 50% cumulative release within 48 h. Both in-vitro and in-vivo studies showed that the toxicity of gamma-PGA-CA-CDDP nanoconjugate significantly decreased by comparison to that of unconjugated CDDP. The maximum tolerated dose (MTD) of gamma-PGA-CA-CDDP nanoconjugate was about 38 mg/kg versus 8 mg/kg for CDDP. No apathy or acute adverse reactions were observed in gamma-PGA-CA-CDDP nanoconjugate groups while mice expressed apathy at all dose levels with CDDP treatment. In ICR mice, the area under the curve and total body clearance values for gamma-PGA-CA-CDDP nanoconjugate were 9-fold and one-twentieth of the values for CDDP, respectively. With the aid of near-infrared fluorescence (NIRF) imaging system, it was demonstrated that gamma-PGA-CA-CDDP nanoconjugate gradually accumulated at the tumor site within 15 min postinjection and exhibited prolonged retention for more than 8 h. In H22-implanted mice, gamma-PGA-CA-CDDP showed a significantly higher antitumor activity versus CDDP. These results reveal that gamma-PGA-CA-CDDP nanoconjugate with improved stability, reduced toxicity and prolonged in-vivo retention time holds great potential in terms of clinical application to cancer therapy.

• 出版日期2012-10
• 单位中国药科大学; 天然药物活性组分与药效国家重点实验室