Design, Synthesis, Characterization, And Biological Evaluation Of Polv(L-γ-glutamyl-L-Carbocisteine)-Paclitaxel Nanoconjugate

In recent years in developing countries or developed countries, the incidence of cancer continues to rise rapidly. Once the patient was diagnosed with cancer, the patient will suffer both in mental and physical. Paclitaxel (PTX) was a first-line chemotherapeutics of breast cancer and ovarian cancer and lung cancer. Due to its unique mechanism of action, PTX performed the strongest anticancer activity of natural source of taxanes compounds. In the current domestic market, there are only two kind preparation of paclitaxel:paclitaxel injection (Taxotere) and paclitaxel liposome. Paclitarel injections were dissolved in the mixture of polyoxyethylene castor oil and Tween 80. Because the surface active agents polyoxyethylene castor oil and Tween 80 may cause allergization, it limits the use to allergic patients. By contrast, paclitaxel liposomes take the advantage of avoiding the use of surface active agent, and passive targeting to the tumor tissue through the EPR effect. However, the price of liposome was about five times higher than the injection and its stability and loading capacity still needs to be improved.Though developments and results had been accomplished in the field of PTX, there are still many problems:poor water solubility, multidrug resistance, none targeting. To address those problems, conjugation of such drugs to polymers is one of the means of increasing water-solubility. The concepts underlying the development of polymer-drug conjugates are not new and have been comprehensively reviewed. The core principle is that when a poorly soluble drug is linked to a water-soluble polymer, it results in a conjugate with a markedly improved aqueous solubility that also has a prolonged plasma half-life and is passively accumulated in solid tumor tissues via the "enhanced permeability and retention" effect. Since the earliest studies of polymer-drug conjugates in 1975, many groups have investigated the use of polymers for drug delivery. However, there are still shortcomings, such as high cost, complex synthesis process, hard for industrial production, cannot self-assembly into nanoparticles in aqueous solution, low drug loading capacity, none desirable particle size, low drug release rate. Only a few polymers, such as N-(2-hydroxypropyl)methacrylamide, poly(L-glutamic acid) (PGA), and polyethylene glycol, have been systemically examined or have entered clinical trials. Therefore, to design a more smart and effective antitumor drug delivery system has great significance for the treatment of cancer.This thesis reported a novel smart drug delivery system PGSC based on PGA and cysteine. We loaded PGSC with PTX and formed novel nanoconjugate PGSC-PTX with 36%(w/w) loading capacity. PGSC-PTX self-assembles into nanoparticles, whose size remains in the range of 15-20 nm and its water solubility was 60mg/mL, which is much more 2000-fold higher than PTX. PGSC-PTX demonstrated sensitive to acid pH and released PTX rapidly in acid pH. The potency of PGSC-PTX when tested in vitro against the human lung cancer NH460 cell line was comparable to PGG-PTX conjugates. The IC50 for PGSC-PTX was almost equal to PGG-PTX. The maximum tolerated dose of PGSC-PTX was found to be 250 mg PTX/kg. To compare their toxicities in vivo,125 mg/kg PGSC-PTX possesses better efficiency when compared with 250 mg/kg PGG-PTX in mice. This result indicates that PGSC-PTX was substantially more effective in vivo than PGG-PTX.