An amphiphilic hyperbranched polymer containing large amounts of pH sensitive bonds was synthesized by our group. The hydrophobic chains are hyperbranched polyacetals (HBPAs) and the hydrophilic chains are polyethylene glycols. Polyethylene glycols are attached to the hyperbranched polyacetals by the hydrazone bonds. The amphiphilic hyperbranched polymer could be assembled into micelles easily by the dialysis method. The micelles containing large amounts of pH sensitive bonds were quite fragile in pH 5.0 buffer solution but very stable in pH 7.4 buffer solution. DOX-loaded micelles were also prepared by the dialysis method. The sizes of the blanked micelle and DOX-loaded micelle were 30 nm and 35 nm, respectively. The increase of the diameter confirmed that DOX was successfully loaded into the micelle. Drug loading content and drug loading efficiencies were 2.34% and 23.4%, respectively, which was detected by the UV-VIS at the wavelength of 482 nm. The drug release behavior demonstrated that DOX was released faster in pH 5.0 buffer solution than in pH 7.4 buffer solution.
Single chemotherapeutic agent like paclitaxel (PTX) has shown some limitations in anti-tumor treatment, such as undesirable side effects, multidrug resistance, and high toxicity. In order to reduce the toxicity of PTX and increase the anti-tumor effect, folate-modified amphiphilic and biodegradable biomaterial was developed to co-deliver PTX and metformin (MET) for exerting the synergistic effect. PTX was physically entrapped in the hydrophobic inner core of the amphiphilic block copolymer by a solvent evaporation method, whereas MET was chemically conjugated to the hydrophilic terminals of copolymer via a pH-sensitive cis -aconityl linkage (Cis). The in vitro release behaviors of the drugs were analyzed by high-performance liquid chromatography (HPLC), and the synergistic effect of the drugs was evaluated by a Q value method. Results showed that drug-loaded micelles with an average size about 100 nm were successfully constructed. In acidic environments, the chemically conjugated MET was rapidly released after the breakage of sensitive bond between drug and copolymer. In vitro anti-tumor studies demonstrated that MET and PTX had a synergistic effect and co-delivery micelles induced higher cytotoxicity and apoptosis against 4T1 breast cancer cells than free drugs. Furthermore, folate-targeted co-delivery micelles increased the cellular uptake of drugs and were found to be effective for the treatment of solid tumor in vivo . These findings indicated that co-delivery of MET and PTX through the polymeric micelles is a promising strategy for cancer therapy.
Yang Xiao-Guang,Li Yan-Feng,Wang Yan-Jun,Kong Rui-Heng,Wang Dun
Recent studies have shown that monoamine oxidase A (MAOA) is significantly expressed in malignant prostate cancer (PCa) and plays an important role in tumorigenesis indicating its potential to serve as a target for PCa treatment. Here, we choose the small molecule isoniazid as the MAOA
inhibition functionality and incorporated it in the tumor-targeting moiety of heptamethine carbocyanine dyes via a pH sensitive hydrazone bond to design and synthesize novel MAOA inhibitor isoniazid-heptamethine carbocyanine dye conjugates. Cytotoxicity assay in PC-3 cells shows that
all conjugates possessed improved antitumor efficacy compared with isoniazid. The tested compounds also demonstrated a moderate MAOA inhibitory effect. In conclusion, these results indicate that these conjugates exert antitumor effects by delivering the MAOA-inhibiting moiety to PCa cells.
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