Huynh Loan, Leroux Jean-Christophe, Allen Christine
Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
Org Biomol Chem. 2009 Sep 7;7(17):3437-46. doi: 10.1039/b906862g. Epub 2009 Jul 2.
Computer-based theoretical calculations were employed to direct the design of docetaxel conjugates with enhanced solubility in the internal phase of a nano-emulsion formulation. The theoretically-identified optimal docetaxel conjugates were synthesized by direct attachment of lauroyl moieties through an ester linkage to docetaxel. In comparison to docetaxel, the conjugates exhibited significantly improved solubility in oil, as predicted by our theoretical calculations. This contributed to high drug entrapment efficiencies (up to 97%) and a high drug loading capacity (5.7% w/w) for the docetaxel conjugates. The mono-substitution of an acyl group at C-2' of docetaxel resulted in a conjugate with 37- to 46-fold lower cytotoxicity than that of the parent drug in two human cancer cell lines. Importantly, the activity exerted by the mono-substituted docetaxel on the cancer cells was due in part to the cytotoxicity of the parent drug that was released via hydrolysis of the ester bond between the lauroyl moiety and the drug under biologically relevant conditions. In contrast, di- and tri-substitution of acyl groups at C-2', C-7 and/or C-10 of docetaxel resulted in non-hydrolysable conjugates that were found to be inactive. Overall, our results show that computer-based theoretical calculation is a promising strategy for guiding the enhancement of material-drug compatibility in formulation development. Also, these studies confirm that chemical modification of docetaxel for enhancement of material-drug compatibility should be limited to mono-substitution at C-2' and result in a prodrug that is hydrolysable at a moderate rate under biologically relevant conditions.
采用基于计算机的理论计算来指导多西他赛缀合物的设计，以提高其在纳米乳剂配方内相中的溶解度。通过月桂酰部分经酯键直接连接到多西他赛上，合成了理论上确定的最佳多西他赛缀合物。与多西他赛相比，如我们的理论计算所预测，这些缀合物在油中的溶解度显著提高。这有助于多西他赛缀合物实现高药物包封效率（高达97%）和高载药量（5.7% w/w）。多西他赛C-2'位的酰基单取代产生了一种缀合物，在两种人类癌细胞系中，其细胞毒性比母体药物低37至46倍。重要的是，单取代多西他赛对癌细胞发挥的活性部分归因于母体药物的细胞毒性，该母体药物是在生物相关条件下通过月桂酰部分与药物之间的酯键水解而释放的。相比之下，多西他赛C-2'、C-7和/或C-10位的酰基双取代和三取代产生了不可水解的缀合物，这些缀合物被发现无活性。总体而言，我们的结果表明，基于计算机的理论计算是在制剂开发中指导提高材料-药物相容性的一种有前景的策略。此外，这些研究证实，为提高材料-药物相容性而对多西他赛进行的化学修饰应限于C-2'位的单取代，并产生一种在生物相关条件下能以适度速率水解的前药。
