Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, United States.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, United States.
Mol Pharm. 2021 Mar 1;18(3):1093-1101. doi: 10.1021/acs.molpharmaceut.0c01012. Epub 2021 Jan 13.
Nanocarriers (NCs) are an attractive class of vehicles for drug delivery with the potential to improve drug efficacy and safety, particularly for intravenous parenteral delivery. Many therapeutics remain challenging to formulate in NCs due to their intrinsic solubilities that frustrate NC loading or result in too rapid release . Therapeutic conjugate approaches that alter the solubility of a conjugate "prodrug" have been used to enable NC formation and controlled release from NCs using labile linker chemistry. A limitation of this approach has been that a different linker chemistry must be used to produce an adjustable release rate for a single therapeutic. We report on a new approach where the therapeutic conjugate hydrolysis rates are varied by adjusting the excipient formulation of the NC core, not the conjugate linker chemistry. A hydrophobic therapeutic conjugate of camptothecin (PROCPT) is synthesized by conjugating camptothecin (CPT) with an acid derivative of α-tocopherol (vitamin E). The PROCPT compound can be loaded to 50% wt in poly(lactic acid)--poly(ethylene glycol) (PLA--PEG)-stabilized NCs produced by Flash NanoPrecipitation with particle diameters between 60 and 80 nm. Co-loading a zwitterionic lipid, 1-palmitoyl-2-oleoyl--3-phosphocholine, from 0 to 67% core loading tunes the PROCPT hydrolysis from no observable therapeutic release over 200 h to therapeutic conjugate half-life times of 31 h. For a single therapeutic conjugate molecule, the hydrolysis rate can be tuned by modifying the NC formulation with different excipient concentrations. NCs containing a 50% core loading of PROCPT were lyophilized and encapsulated in a PEG hydrogel matrix to make microparticles for depot delivery with an average diameter of 65 ± 10 μm that provide a sustained, first-order release of CPT with a therapeutic conjugate half-life of 240 h. These results demonstrate a new approach to the formulation of therapeutic NCs with variable release profiles using a single molecular entity therapeutic conjugate.
纳米载体（NCs）是一类很有吸引力的药物输送载体，具有提高药物疗效和安全性的潜力，特别是在静脉内给药方面。许多治疗药物由于其内在的溶解度而难以用 NCs 进行配方，这阻碍了 NC 的负载或导致药物过快释放。为了使 NC 形成并通过不稳定的连接化学从 NC 中进行控制释放，已经使用改变缀合物“前药”溶解度的治疗性缀合物方法。这种方法的一个局限性是，必须使用不同的连接化学来为单个治疗药物产生可调节的释放速率。我们报告了一种新方法，其中通过调整 NC 核的赋形剂配方而不是缀合物连接化学来改变治疗性缀合物的水解速率。喜树碱（CPT）的疏水治疗性缀合物是通过将 CPT 与 α-生育酚（维生素 E）的酸衍生物缀合而合成的。PROCPT 化合物可以负载到聚乳酸-聚乙二醇（PLA-PEG）稳定的 NC 中，负载量为 50wt%，通过 Flash NanoPrecipitation 制备，粒径为 60-80nm。共负载两性离子脂质 1-棕榈酰基-2-油酰基-3-磷酰胆碱，从 0 到 67%的核心载药量，将 PROCPT 的水解从 200 小时内没有观察到治疗性释放调整为治疗性缀合物半衰期为 31 小时。对于单个治疗性缀合物分子，可以通过用不同的赋形剂浓度修饰 NC 配方来调整水解速率。含有 50%核心负载量的 PROCPT 的 NC 被冻干并封装在 PEG 水凝胶基质中，制成用于 depot 给药的微球，平均直径为 65±10μm，提供 CP 的持续一级释放，治疗性缀合物半衰期为 240h。这些结果表明，使用单一分子实体治疗性缀合物，用可变释放谱的治疗性 NC 进行配方的新方法。
