Developing Clinically Applicable, Cancer-Targeting Polymeric Nanoconjugates

开发临床适用的癌症靶向聚合物纳米缀合物

• 批准号: 7981969
• 负责人: Jianjun Cheng
• 金额: $ 237.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981969
• 关键词: Characteristics; Chemistry; Clinical; Drug Delivery Systems; Drug Formulations; Heterogeneity; Hour; Hydroxyl Radical; Life; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metals; Modeling; Molecular Weight; Nanoconjugate; Particle Size; Pharmaceutical Preparations; Polymers; Preparation; Translations; Variant; aptamer; catalyst; docetaxel; drug distribution; in vivo; monomer; nanomedicine; nanoparticle; poly(lactide); polymerization

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.

描述（由申请人提供） 摘要：金属催化剂介导具有定量引发和单体转化的良好控制的活性聚合，这有利于制备具有窄多分散性和明确分子量的聚合物材料。然而，这些良好控制的化学物质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缀合或包封用于药物掺入，这导致在纳米药物制剂过程中不可避免的异质性。这些制剂在粒度、尺寸分布、药物分布以及批次间载药量和掺入效率的变化方面的异质性为这些纳米药物递送载体的临床转化造成了巨大的问题。我们建议研究一种前所未有的方法来弥合现代聚合化学提供的控制和当前纳米药物制剂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-药物纳米缀合物，一种新的药物递送纳米医学的范例，其特征明显不同于当前的聚合物纳米颗粒（纳米胶囊）。在聚合物-药物纳米缀合物的制备中，我们使用含羟基的药物分子作为引发剂以在Mg（II）催化剂的存在下介导丙交酯的开环聚合。随后将所得聚丙交酯-药物缀合物纳米沉淀，形成尺寸均匀的亚100纳米纳米颗粒。与目前的纳米胶囊相比，我们的初步研究表明，聚合物纳米缀合物显示出100%的药物掺入效率，具有通过LA/药物比率预定义的药物负载。此外，纳米缀合物不显示突释药物，这是通常与聚合物纳米胶囊相关的缺点。使用芘甲醇作为模型药物，我们证明了克级或更大规模的高负载纳米缀合物可以在几个小时内配制。制备大规模纳米复合物的简单性和控制负载和释放特性表明其具有巨大的临床转化潜力。为了研究纳米缀合物的体内适用性，我们建议开发具有整合适体配体的聚乳酸-多西他赛纳米缀合物，用于晚期前列腺癌的靶向治疗。 公共卫生相关性：聚合物纳米胶囊作为药物载体已经研究了30多年，但只有少数几种药物进行了临床试验，更少的药物被美国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，然后通过纳米沉淀来开发纳米缀合物。

项目成果

Dynamic urea bond for the design of reversible and self-healing polymers.

• DOI: 10.1038/ncomms4218
• 发表时间: 2014
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ying, Hanze;Zhang, Yanfeng;Cheng, Jianjun
• 通讯作者: Cheng, Jianjun

Chain-shattering polymeric therapeutics with on-demand drug-release capability.

• DOI: 10.1002/anie.201300497
• 发表时间: 2013-06-17
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Zhang, Yanfeng;Yin, Qian;Yin, Lichen;Ma, Liang;Tang, Li;Cheng, Jianjun
• 通讯作者: Cheng, Jianjun

Polypeptides with quaternary phosphonium side chains: synthesis, characterization, and cell-penetrating properties.

• DOI: 10.1021/bm5001026
• 发表时间: 2014-04-14
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Song, Ziyuan;Zheng, Nan;Ba, Xiaochu;Yin, Lichen;Zhang, Rujing;Ma, Liang;Cheng, Jianjun
• 通讯作者: Cheng, Jianjun

Supramolecular self-assembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation.

• DOI: 10.1002/anie.201209991
• 发表时间: 2013-05-27
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Yin, Lichen;Song, Ziyuan;Qu, Qiuhao;Kim, Kyung Hoon;Zheng, Nan;Yao, Catherine;Chaudhury, Isthier;Tang, Haoyu;Gabrielson, Nathan P.;Uckun, Fatih M.;Cheng, Jianjun
• 通讯作者: Cheng, Jianjun

Biodegradable micelles capable of mannose-mediated targeted drug delivery to cancer cells.

• DOI: 10.1002/marc.201400650
• 发表时间: 2015-03
• 期刊: MACROMOLECULAR RAPID COMMUNICATIONS
• 影响因子: 4.6
• 作者: Yin, Lichen;Chen, Yongbing;Zhang, Zhonghai;Yin, Qian;Zheng, Nan;Cheng, Jianjun
• 通讯作者: Cheng, Jianjun