Docetaxel Nanoparticles for Prostate Cancer Targeting

描述(申请人提供)：这项拟议项目的目标是开发一种新技术，该技术允许控制配方的多西紫杉醇-聚乳酸纳米粒含有适体靶向配体，可用于体内靶向前列腺特异性膜抗原，以改进前列腺癌治疗。含化疗药物的聚合物纳米粒介导的前列腺癌靶向治疗在临床上的成功有限。仍然存在各种制剂挑战，如提高药物的载药和载药效率，控制纳米粒的尺寸和表面特性，以及消除药物突发释放效应。如果没有对这些处方参数的适当控制，将肿瘤靶向配体引入纳米粒只会增加纳米粒的复杂性，并为所希望的靶向癌症治疗提供有限的益处。在目前为抗癌药物输送而开发的聚合物纳米粒中，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，要么非共价包裹到疏水性聚合物纳米粒中。聚合物-药物结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纳米的范围内，与较大的纳米颗粒相比，可能会使肾脏清除相对较快。另一方面，聚合物纳米颗粒通常在30-300 nm的范围内，因此与聚合物药物结合物相比，具有降低肾脏清除量的作用。然而，低载药量、低载药率和突发性药物释放动力学是通过包封法制备的聚合物/药物纳米粒的典型配方挑战。这些配方挑战大大阻碍了聚合物纳米颗粒用于癌症治疗的临床翻译。我们的目标是通过多西紫杉醇引发的丙交酯开环聚合和纳米沉淀，开发多西紫杉醇-聚乳酸共轭纳米颗粒，或称为纳米共轭化合物。与传统的包封法相比，多西紫杉醇-聚乳酸纳米结合物的载药率为100%，载药量可达30-40wt%，可通过单体/引发剂的比例控制。药物突发释放被消除或大大减少。适体靶向配体将被引入多西紫杉醇-聚乳酸纳米结合物中，以增强抗肿瘤效果并降低全身毒性。 与公共健康相关：目前的聚合物纳米粒具有不受欢迎的配方挑战，如低载药量、低载药率和药物突发释放。这些缺点阻碍了它们被用于靶向抗癌药物的输送。为了解决这些配方挑战，我们的目标是通过定点开环聚合开发高负载聚乳酸-多西紫杉醇纳米颗粒，用于体外和体内前列腺癌靶向。

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.