A poly(γ, L-glutamic acid)-citric acid based nanoconjugate for cisplatin delivery.
A cisplatin-loaded nanoconjugate, poly(γ, L-glutamic acid)-citric acid-cisplatin [γ-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 °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 γ-PGA-CA-CDDP nanoconjugate significantly decreased by comparison to that of unconjugated CDDP. The maximum tolerated dose (MTD) of γ-PGA-CA-CDDP nanoconjugate was about 38 mg/kg versus 8 mg/kg for CDDP. No apathy or acute adverse reactions were observed in γ-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 γ-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 γ-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, γ-PGA-CA-CDDP showed a significantly higher antitumor activity versus CDDP. These results reveal that γ-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.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China pharmaceutical University, 24 Tongjiaxiang, Nanjing, China.
Yerong
Y
Xiong
Weiwei
W
Jiang
Yan
Y
Shen
Huiyi
H
Li
Chunmeng
C
Sun
Ammar
A
Ouahab
Jiasheng
J
Tu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002845:Chromatography / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage*; D019343:Citric Acid / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D006461:Hemolysis; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008027:Light; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008813:Mice, Inbred ICR; D058726:Nanoconjugates / Q000737:chemistry*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012542:Scattering, Radiation; D019265:Spectroscopy, Near-Infrared / Q000379:methods; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D058726:Nanoconjugates; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019343:Citric Acid; D019344:Lactic Acid; D002945:Cisplatin