| Hydroxycamptothecin(HCPT) is an anticancer drug, but there are three problems that limit their clinical applications: the first one, owing to its low solubility in body fluids, it is difficult to achieve effective therapeutic concentrations; the second, the bioactive lactone ring of HCPT is facile to transform into the inactive carboxylate form in basic condition; the last one, it has very significant toxicity and short half life. So the problem is how to improve the stability and develop targeting-controlled release preparation of HCPT.Poly(ethyleneglycol)(PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. After HCPT conjugation with PEG, the water solubility and bioavailability of conjugates will be improved.While, the immunogenicity and antigenicity of conjugates will be reduced, too. Because of the excellent biocompatibility, interbedded anionic exchangeability and sustained release performance, hydrotalcite-like compounds(HTlc) were widely used as pharmaceutical carriers.To solve these problems, in this paper, the preparation and properties of Methoxypolyethylene glycol(MPEG)-conjugated hydroxycamptothecin(HCPT), denoted as MPEG-HCPT, and its hydrotalcite-like compounds nanohybrids were investigated. Meanwhile, the effective ways to improve the solubility, stability of E ring and controlled-release formulations of HCPT was developed, too.The main contents of this paper are as follows:(1)MPEG-HCPT, was synthesized through etherification reaction between terminal hydroxyl of MPEG and 10-hydroxy of HCPT, and was characterized using 1H-NMR, FT-IR. Effect of MPEG conjugation on the solubility and lactone-ring stability of HCPT was determined, and aggregation behavior of the synthesized MPEG-HCPT was investigated particularly. It was showed that the molar ratio of MPEG to HCPT in the derivative was approximated to 1:1, and the mass content of HCPT in the derivative was approximately 33%. The solubilities of the MPEG-HCPT in buffer solutions of pH 4.8 and 7.2 at 37 °C were respectively 5.23 and 7.90 mmol/L, which were significantly higher than those of pristine HCPT(0.0026 and 0.035 mmol/L). The pKah(Kah, the apparent hydrolysis equilibrium constant) of the MPEG-HCPT at 37 °C was determined to be ~7.12, higher than that of pristine HCPT(~6.67), indicating that the MPEG conjugation could enhance the lactone-ring stability of HCPT. The MPEG-HCPT exhibited obvious surface activity, and could form aggregates in water with a critical micelle concentration of 0.46 mmol/L.(2)Nanohybrids of MPEG-HCPT/grapheme oxide(GO)/Zn2-Al HTlc were synthesized. MPEG-HCPT molecules were initially loaded on the surface of GO nanosheets and the resulting negatively charged MPEG-HCPT-loaded GO nanosheets and the positively charged HTlc nanosheets were then assembled to obtain the layered MPEG-HCPT/GO/HTlc nanohybrids. The drug loading of the nanohybrids was 35.6 mg/g. The in vitro release of CPT from the nanohyb rid was examined in pH 7.2 and 4.8 phosphate buffer solutions at 37 ℃. The results showed that the drug release process could be described with pseudo-second order kinetic model, and exhibited strong pH dependence, namely, the release rate and the percentage release in pH 4.8 buffer were evidently higher than those in pH 7.2 buffer. The coassembly method is a simple route for building drug/GO/HTlc nanohybrids, and the nanohybrids have potential applications in drug delivery. |
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