Sustained-release Properties And Targeted Modification Analysis Of γ-poly (Glutamic Acid) As A Targeted Drug Delivery System

Cisplatin is one of the most widely used antitumor drugs for the clinic treatment of many malignancies.A major obstacle to more widespread use of cisplatin is the persistence of severe toxic side effects including acute nephrotoxicity and chronic neurotoxity also a heavy burden towards to the tissue of the kidney and liver.In this study,poly(γ-glutamic acid)-D-galactose esterifiable derivative-DDP complex compound(γ-D⁺-DDP) were prepared by target-oriented drug formulation and emulsion polymerization.The hydrolyzedγ-PGA has a molecular weight between 20 and 70 kDa, and is a water-soluble,biodegradable,and nontoxic polymer.γ-PGA was used as the carrier, and DDP as the sample,for the potential of targeting liver cancer cells D-galactose was conjugated on the preparedγ-PGA.The drug loading efficacy of theγ-D⁺-DDP compound. and its release profile also cytotoxicity on BEL-7402 cells(a liver cancer cell line) were investigated in vitro.Additionally,biodistributions of theγ-D⁺-DDP were studied in vivo in normal KM mice and H₂₂ hepatocellular carcinoma-tumor-bearing KM mice.The antitumor efficacy of theγ-D⁺-DDP in H₂₂-tumor-bearing KM mice was also examined.A clinically available cisplatin formulation was used as a control.As expected,DDP could be easily incorporated into poly(γ-glutamic acid)-D-galactose esterifiable derivative through a covalent bond.The yield of DDP incorporation into theγ-PGA was 9.4%-9.8%,more than that of CPT incorporation into theγ-PGA.The DDP was released in the initial 8h in a burst manner,and thereafter in a sustained manner.The pharmacokinetics of DDP release was thus very similar to other clinically used drugs.The results were the observations that the conjugation of DDP to poly(γ-glutamic acid)-D-galactose esterifiable derivative not only reduced the toxicity of the DDP but also enhanced antitumor and the targeting activity.Both in vitro and in vivo experiments conclusively demonstrated that theγ-D⁺-DDP compound was much less toxic to both normal cell lines and animals than DDP alone.A direct evaluation showed that H₂₂ hepatocellular carcinoma-tumor-bearing mice treated withγ-D⁺-DDP compound at a dose of 7.5mg/kg displayed significant tumor regression.Furthermore,the implanted solid tumors in 35%of the H₂₂ tumor-bearing mice disappeared completely afterγ-D⁺-DDP compound administration.It is concluded that theγ-D⁺-DDP was a promising complex for avoiding the toxicity of platinous drugs,while retaining antitumor activity.The aforementioned results of biodistributions of theγ-D⁺-DDP compound in various organs in normal mice demonstrated that the compound had a specific interaction with liver's parenchymal cells and H₂₂ hepatocellular carcinoma tumor cells via specific binding. Therefore,it is reasonable to speculate that theγ-D⁺-DDP compound may be explored as a potential drug delivery system for the control of liver cancers or other liver diseases.