Abstract
The toxicity and side effects of traditional chemotherapeutic drugs are the main causes of chemotherapy failure. To improve the specificity and selectivity of chemotherapeutic drugs for tumor cells, a novel redox-sensitive polymer prodrug, polyethylene glycol-poly (β-benzyl-L-aspartate) (PEG-PBLA)-SS-paclitaxel (PPSP), was designed and synthesized in this study. The PPSP micelle was manufactured via high-speed dispersion stirring and dialysis. The particle size and zeta potential of this prodrug micelle were 63.77 ± 0.91 nm and −25.8 ± 3.24 mV, respectively. The micelles were uniformly distributed and presented a spherical morphology under a transmission electron microscope. In the tumor physiological environment, the particle size of the PPSP micelles and the release rate of paclitaxel (PTX) were significantly increased compared with those of mPEG-PBLA-CC-PTX (PPCP) micelles, reflecting the excellent redox-sensitive activity of the PPSP micelles. The inhibitory effect of PPSP on HepG2, MCF-7 and HL-7702 cell proliferation was investigated with MTT assays, and the results demonstrated that PPSP is superior to PTX with respect to the inhibition of two tumor cell types at different experimental concentration. Simultaneously PPSP has lower toxicity against HL-7702 cells then PTX and PPCP. Moreover, the blank micelle from mPEG-PBLA showed no obvious toxicity to the two tumor cells at different experimental concentrations. In summary, the redox-sensitive PPSP micelle significantly improved the biosafety and the anti-tumor activity of PTX.
Highlights
Cancer is a major killer that endangers human life and health
To improve the therapeutic effect of paclitaxel in the present study, we describe a new type of PTX self-assembled prodrug, mPEG-PBLA-SS-PTX (PPSP), with disulfide linkages and reduction- responsive release properties, and its molecular structure was characterized by nuclear magnetic spectrogram
Compared with the spectra of PXT, mPEG-PBLA-CC-COOH and mPEG-PBLA-SSCOOH (Figure S2), the peaks of -COOH at δ = 12.14 ppm and δ = 12.36 ppm disappeared and the new proton peaks of PTX appeared in the PTX and mPEG-PBLA-CC-PTX (PPCP) and PPSP spectra, which indicated the PTX was successfully grafted to the -COOH groups of mPEG-PBLACC-COOH and the mPEG-PBLA-SS-COOH
Summary
Cancer is a major killer that endangers human life and health. Its mortality rate is much higher than that of AIDS, tuberculosis and malaria combined [1]. Aside from surgery, chemotherapy is the most important therapeutic approach for cancer treatment [2]. Most chemotherapeutic drugs suffer from intrinsic limitations, such as poor water solubility, low bioavailability, poor selective distribution, rapid blood clearance [3, 4], serious side effects [5], and drug resistance of cancer cells as well [6, 7]. A drug delivery system (DDS) can overcome the above disadvantages of chemotherapy to a certain extent [8,9,10,11,12]. DDS research and development for cancer treatment is valued by
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