Abstract
Polyethylene glycolated (PEGylated)curcumin-grafted-chitosan (PCC) conjugates were synthesized with three PEG/chitosan feed molar ratios (1/5, 1/7.5, and 1/10), namely PCC1, PCC2 and PCC3. Chemical structures of these conjugates were characterized by Fourier transform infrared (FTIR) and proton nuclear magnetic resonance (1H NMR). The degrees of substitution (DS) of PEG were 0.75%, 0.45% and 0.33%, respectively, for PCC1, PCC2 and PCC3by 1H NMR analysis. Self-assembled PCC nanoparticles (NPs) were spherical as observed in transmission electron microscope images. Mitoxantrone (MTO)-loaded PCC NPs were prepared to analyze the particle size, zeta potential, drug loading, drug release and in vitro cytotoxicity. The MTO-loaded PCC3 NP (DS = 0.33%) possessed the smallest size (~183.1 nm), highest zeta potential (~+34.0 mV) and the largest loading capacity of curcumin (CUR, ~16.1%) and MTO (~8.30%). The release results showed that MTO-loaded PCC3 NP demonstrated the lowest percentage of MTO release and increased as pH decreased, but the CUR release could only be detected at pH 4.0. In the cytotoxicity study, MTO-loaded PCC3 NP displayed the highest cytotoxicity in HepG2 cell line and the best synergistic effect among the tested NPs. Our results suggest that the DS of PEG has impacts on the structures and functions of PCC NPs: the smaller DS of PEG was associated with the smaller size, the higher zeta potential, the slower drug release, and the higher cytotoxicity of NPs.
Highlights
Chemotherapy is one of the main strategies for the treatment of late stage of malignant tumors
We have demonstrated the effects of hydrophobicity in formation of NPs using different degrees of substitution (DS) of cholesterol in pullulan nanoparticles and have reported a method for connecting a hydrophobic molecule to produce an amphiphilic conjugate [24,25]
Gref et al [45] described that, in polyethylene glycol (PEG) concentration above 5%, PEG functioned as a “brush” which effectively shielded the surface charge of the nanoparticles, thereby prolonging the retention time of NPs in circulation and stabilizing NPs structure in vivo. These findings suggest that the PEGylated-Chitosan nanoparticles (CS NPs) developed in the current study could be applicable for systemic circulation
Summary
Chemotherapy is one of the main strategies for the treatment of late stage of malignant tumors. The combination chemotherapy of CUR and other drugs has attracted increasing attention on improving therapeutic efficacy by signaling different pathways, and suppressing and reversing drug resistance [3,5,6]. Mitoxantrone (MTO), a chemotherapeutic drug, has curative effect on variety of malignant tumors, but its associated cardiac toxicity and myelosuppression create significant health impairments [7,8]. Studies have shown that the combination of MTO and CUR can enhance the MTO efficacy, may reduce the MTO dose and the side effects [5,9]
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