Ning Wang,Chenyu Liu,Weihe Yao,Hengjun Zhou,Simiao Yu,Hailiang Chen,Weihong Qiao
Constructing highly efficient and multifunctional nanoparticles to overcome the multiple challenges of targeted drug delivery is a new strategy urgently needed in tumor therapy. Here, we synthesized pH-responsive prodrug ( PEG 2K -NH -N- DOX ), GSH-responsive prodrug ( PEG 2K -S-S-CPT ), folate-receptor targeting polymers ( FA-PEG 2K -L8 , FA-PEG 2K -TOS) and T1-enhanced magnetic resonance imaging contrast agents ( Gd-DTPA-N16−16) , used to encapsulate combrestatinA4 (CA4) to prepare multifunctional nanoparticles ( FTDCAG NPs). Unlike other nanoparticles, FTDCAG NPs contains three drugs with the ability to control the release in time and space, which can maximize the effectiveness of precise cancer chemotherapy. We first confirmed that specific binding between FTDCAG NPs and overexpressed folate-receptor cells by flow cytometry and confocal laser scanning microscopy. We then investigated the spatiotemporally controlled release ability of FTDCAG NPs loaded with doxorubicin (DOX), CA4 and camptothecin (CPT). Relative to pH = 7.4, the release efficiency of CA4 in the pH = 6.5 increased by 63.4 %. The first released CA4 is able to destroy the angiogenesis and help tumor cells to be exposed to the remaining FTDCG NPs. After being internalized into the tumor cells, FTDCG NPs is disassembled and the CPT and DOX were released due to the increase of intracellular GSH concentration and the decrease of pH value. Besides, the relaxation time of FTDCAG NPs is 3.86 times that of clinical Gd-DTPA, and the in vitro and vivo T1-weighted imaging is brighter, which can be used to trace the nanoparticles by MRI. Therefore, FTDCAG NPs provide an efficient strategy for the design of multifunctional drug delivery systems for enhancing antitumor efficacy.
Cheng Gao,Fan Tang,Guiyi Gong,Jianxiang Zhang,Maggie P. M. Hoi,Simon M. Y. Lee,Ruibing Wang
In order to realize a combination of chemotherapy and selective drug release into tumor cells, novel pH-sensitive prodrugnanoparticles were designed and prepared via the self-assembly of a synthetic amphiphilic macromolecular prodrug for the selective co-delivery of doxorubicin (Dox) and curcumin (Cur). Dox was covalently conjugated to the oxidized sodium alginate through a Schiff base reaction to produce an amphiphilic macromolecular prodrug, and the prodrug was subsequently self-assembled into nanoparticles (Dox-NPs) in an aqueous solution, which were responsive to the acidic environment in tumor cells. Additionally, a second chemotherapeutic agent, Cur, was encapsulated in the core of nanoparticles (Cur–Dox-NPs) via hydrophobic effects, with a significant drug loading capacity. Cur–Dox-NPs exhibited an efficient release of both Dox and Cur in acidic media and further studies of their intracellular uptake and drug release confirmed that Dox-NPs were easily taken up by cells and selectively released the drug into the human breast cancer cell line MCF-7. In vitro cytotoxicity studies of the NPs showed a remarkable efficacy against MCF-7 cell lines, whereas an improved safety profile was observed in the human breast epithelial cell line MCF-10A. Furthermore, in vivo studies in zebrafish further confirmed an efficient absorption of Dox-NPs. In vivo cardiotoxicity experiments on a zebrafish model showed that Dox-NPs exhibited an improved cardiotoxicity profile in comparison with free Dox. This study demonstrated that this novel pH-sensitive prodrug-nanoparticle system may provide a simple and efficient platform for the selective co-delivery of multiple drugs to tumor cells.
Because of the severe antibiotic resistance , photodynamic therapy is considered as a potent method for the treatment of bacterial infection with bare drug resistance. However, its therapeutic efficacy is not always satisfactory in practical treatment. In this study, pH-responsive prodrug micelles were prepared by conjugation of chlorin e6 to polyethylene glycol- b -poly(2-(hexamethyleneimino) ethyl methacrylate- co -aminoethyl methacrylate) for improving the antimicrobial activity of photodynamic therapy. The micelles were negatively charged in normal physiological environment, which was very important for long blood circulation. However, the micelles could turn to be positively charged in bacterial infection microenvironment and then adhere to negatively charged bacterial membranes, which could significantly improve their antibacterial activity against both methicillin-resistant Staphylococcus aureus and Escherichia coli after laser irradiation. The in vivo experiment showed excellent antibacterial effect of pH-sensitive micelles in a subcutaneous infection model. The micelles showed great potential in the photodynamic therapy of stubborn bacterial infections.
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