Developing Clinically Applicable, Cancer-Targeting Polymeric Nanoconjugates

描述(由申请人提供) 摘要：金属催化剂通过定量引发和单体转化实现了可控的活性聚合反应，有利于制备多分散性窄、分子量可控的聚合物材料。然而，这些控制良好的化学成分对聚合物纳米药物的配方几乎没有影响。目前的聚合物纳米药物仍然依赖于传统的偶联或包封法进行药物的包合，这导致了纳米药物在制备过程中不可避免的异质性。这些制剂在颗粒大小、粒度分布、药物分布以及不同批次之间的载药量和包封率的差异给这些纳米药物载体的临床翻译带来了巨大的问题。我们建议研究一种前所未有的方法，以弥合现代聚合化学提供的控制与当前纳米药物配方缺乏控制之间的差距。更具体地说，我们的目标是开发聚合物-药物纳米结合物，这是一种新的给药纳米药物范例，具有与目前的聚合物纳米粒(纳米胶囊)截然不同的特性。在聚合物-药物纳米结合物的制备中，我们使用含羟基的药物分子作为引发剂，在镁(II)催化剂的存在下，催化丙交酯的开环聚合。得到的聚乳酸-药物结合物随后被纳米沉淀，形成尺寸均匀的亚100 nm纳米颗粒。与目前的纳米微囊相比，我们的初步研究表明，聚合物纳米结合物具有100%的药物掺入效率，并可根据LA/药物比例预先定义载药量。此外，纳米结合物不会表现出突发性药物释放，这是聚合物纳米胶囊通常存在的一个缺点。以吡喃乙醇为模型药物，我们证明了克或更大规模、高负载的纳米结合物可以在几个小时内形成。制备具有可控加载和释放特性的大规模纳米结合物的简单性表明其在临床翻译方面具有巨大的潜力。为了研究纳米结合物在体内的适用性，我们建议开发具有整合适体配体的聚乳酸-多西紫杉醇纳米结合物，用于靶向治疗晚期前列腺癌。 公共卫生相关性：聚合物纳米胶囊作为药物输送载体已经被研究了30多年，但只有少数几种药物进行了临床测试，更少的药物被食品和药物管理局批准用于临床应用。我们建议通过金属催化剂介导的、药物引发的开环聚合策略和随后的纳米沉淀来开发纳米偶联物。

DESCRIPTION (Provided by the applicant) Abstract: Metal catalysts mediate well-controlled, living polymerizations with quantitative initiation and monomer conversion, which facilitates the preparation of polymeric materials with narrow polydispersities and well-defined molecular weights. These well-controlled chemistries, however, show little impact on the formulation of polymeric nanomedicine. Current polymeric nanomedicine still relies on conventional conjugation or encapsulation for drug incorporation, which results in inevitable heterogeneity during nanomedicine formulation. These formulation heterogeneity in particle size, size distribution, drug distribution and variation between batch-to- batch for the drug loading and incorporation efficiency creates tremendous problems for the clinical translations of these nanomedicine delivery vehicles. We propose to study an unprecedented approach to bridge the gap between the control offered by modern polymerization chemistry and the lack of control of current nanomedicine formulation. More specifically, we aim to develop polymer-drug nanoconjugate, a new paradigm of drug delivery nanomedicine with characteristics distinctly different from the current polymeric nanoparticles (nanoencapsulates). In the preparation of polymer-drug nanoconjugates, we use hydroxyl- containing drug molecules as the initiators to mediate a ring-opening polymerization of lactide in the presence of a Mg(II) catalyst. The resulting polylactide-drug conjugate is subsequently nanoprecipitated to form sub-100 nm nanoparticles in uniform size. Compared to current nanoencapsulates, our preliminary study demonstrated that polymeric nanoconjugates show 100% drug incorporation efficiency with pre-definable drug loading by LA/drug ratio. Moreover, nanoconjugates do not show burst drug release, a drawback commonly associated with polymeric nanoencapsulates. Using pyrenemethanol as the model drug, we demonstrated that gram- or larger-scale, highly loaded nanoconjugates can be formulated with several hours. The simplicity for the preparation of large-scale nanoconjugates with controlled loading and release characteristics suggests its great potential for clinical translation. To study the in vivo applicability of nanoconjugates, we propose to develop polylactide-docetaxel nanoconjugates with integrated aptamer ligand for the targeted treatment of the advanced prostate cancer. Public Health Relevance: Polymeric nanoencapsulate as drug delivery vehicles have been investigated for more than 30 years, but only a few of them have been tested clinically and even less been approved by the Food and Drug Administration for clinical applications. We propose to develop nanoconjugates via metal-catalysts mediated, drug-initiated ring-opening polymerization strategy followed by nanoprecipitation.