Docetaxel Nanoparticles for Prostate Cancer Targeting

描述（由申请人提供）：这个项目的目标是开发一种新的技术，允许控制多西紫杉醇-聚乳酸纳米颗粒的配方，这些纳米颗粒含有适配体靶向配体，可用于前列腺特异性膜抗原的体内靶向，以改善前列腺癌的治疗。化疗药物联合聚合纳米颗粒介导的前列腺癌靶向治疗在临床上取得了有限的成功。如何提高载药量和载药效率，如何控制NP大小和表面特性，如何消除药物的爆发释放效应，这些都是目前在配方上面临的挑战。如果没有适当控制这些配方参数，将癌症靶向配体加入纳米颗粒只会增加纳米颗粒的复杂性，并且对预期的靶向癌症治疗提供有限的益处。在目前用于癌症药物递送的聚合物纳米颗粒中，药物分子要么通过偶联化学与亲水性聚合物共价连接，形成单分子聚合物-药物偶联物，要么被非共价封装到疏水性聚合物纳米颗粒中。聚合物-药物缀合物通常具有可控的药物释放。然而，它们相对较小的尺寸，通常在1-5纳米范围内，与较大的纳米颗粒相比，可能会带来相对较快的肾脏清除。另一方面，聚合物纳米颗粒通常在30-300纳米范围内，因此与聚合物药物偶联物相比，其肾脏清除率降低。然而，低载药量、低载药效率和药物释放动力学是通过包封方法制备的聚合物/药物纳米颗粒的典型配方挑战。这些配方方面的挑战显著地阻碍了聚合纳米颗粒用于癌症治疗的临床转化。我们的目标是通过多西他赛引发的丙交酯开环聚合，然后进行纳米沉淀，开发多西他赛-聚丙交酯共轭纳米颗粒，或称为纳米共轭物。与传统包封法制备的纳米粒子相比，多西他赛-聚乳酸纳米缀合物的载药效率为100%，载药量可达30-40 wt%，由单体/引发剂比例控制。药物爆发释放被消除或大大减少。适配体靶向配体将被纳入多西紫杉醇聚乳酸纳米偶联物中，以增强抗肿瘤疗效并降低全身毒性。

DESCRIPTION (provided by applicant): The goal of this proposed project is to develop a new technique that allows controlled formulation of docetaxel- polylactide nanoparticles containing aptamer targeting ligands that can be used for in vivo targeting of Prostate Specific Membrane Antigen for improved prostate cancer therapy. Targeted prostate cancer therapy mediated by chemotherapeutics-incorporated polymeric nanoparticles has limited success in clinic. Various formulation challenges still exist, such as increasing drug loading and loading efficiency, controlling NP size and surface characteristics, and eliminating drug burst release effect. Without proper control of these formulation parameters, incorporating cancer targeting ligand to nanoparticles will only increase the complexity of nanoparticle and provide limited benefit for the desired targeted cancer therapy. In current polymeric nanoparticles developed for cancer drug delivery, drug molecules are either covalently linked to a hydrophilic polymer via coupling chemistry to create a unimolecular polymer-drug conjugate or non-covalently encapsulated into the hydrophobic polymeric nanoparticles. Polymer-drug conjugates usually have controlled drug release. However, their relatively small sizes, typically in a range of 1-5 nm, may render relatively fast renal clearance compared to larger nanoparticles. Polymeric nanoparticles, on the other hand, are typically in a range of 30-300 nm, and therefore have reduced renal clearance compared to polymer-drug conjugates. However, low drug loading, low loading efficiency, and burst drug release kinetics are typical formulation challenges of polymer/drug nanoparticles prepared via encapsulation approaches. These formulation challenges significantly prohibit the clinic translation of polymeric nanoparticles for cancer therapy. We aim to develop docetaxel-polylactide conjugated nanoparticles, or called nanoconjugates, through docetaxel-initiated ring-opening polymerization of lactide followed by nanoprecipitation. Compared to nanoparticles prepared via conventional encapsulation approach, docetaxel-polylactide nanoconjugates can be prepared with 100% drug loading efficiency and drug loading up to 30-40 wt% controlled by monomer/initiator ratio. Drug burst release are eliminated or substantially reduced. Aptamer targeting ligand will be incorporated to docetaxel-polylactid nanoconjugates for enhanced antitumor efficacy and reduced systemic toxicity. PUBLIC HEALTH RELEVANCE: Current polymeric nanoparticles have undesirable formulation challenges such as low drug loading, low loading efficiency and drug burst release. These drawbacks prohibit them from being used for targeted cancer drug delivery. To address these formulation challenges, we aim to develop high loading polylactide-docetaxel nanoparticles via site-specific ring-opening polymerization for in vitro and in vivo prostate cancer targeting.