Claw Shaped Polymeric Micelles-New Opportunities for the Pharmaceutical Sector

爪形聚合物胶束——医药领域的新机遇

• 批准号: GR/T20410/02
• 负责人: Ijeoma Uchegbu
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=GR%2FT20410%2F02
• 关键词: Claw; Shaped; Polymeric; Micelles; New

A number of molecular interactions have been harnessed by the pharmaceutical sector enable valuable drug compounds to be delivered to patients. Some molecular interactions involving water insoluble drugs are aimed at drug solubilisation, thus allowing the drugs to be administered. Despite all these efforts up to 40% of new chemical entities with proven biological activity still fail in development simply because a) they are insoluble in water and b) suitable and biocompatible drug solubilisers are unavailable. Available materials include low molecular weight surfactant solubilisers which have poor biocompatibility as they tend to lyse cells due precisely to their detergent nature and the resulting solutions are unstable to dilution. Block copolymer on the other hand are poor drug solubilisers. The proposal builds on work which has established that biocompatible (do not cause cell lysis) polymeric comb shapedsurfactants, in which soluble polymers bearing water insoluble pendant groups, are abto solubilise water insoluble molecules in aqueous media by specific intermolecularA number of molecular interactions have been harnessed by the pharmaceutical sector to enable valuable drug compounds to be delivered to patients. Some molecular interactions involving water insoluble drugs are aimed at drug solubilisation, thus allowing the drugs to be administered. Despite all these efforts up to 40% of new chemical entities with proven biological activity still fail in development simply because a) they are insoluble in water and b) suitable and biocompatible drug solubilisers are unavailable. Available materials include low molecular weight surfactant solubilisers which have poor biocompatibility as they tend to lyse cells due precisely to their detergent nature and the resulting solutions are unstable to dilution. Block copolymers on the other hand are poor drug solubilisers. The proposal builds on work which has established that biocompatible (do not cause cell lysis) polymeric comb shapedsurfactants, in which soluble polymers bearing water insoluble pendant groups, are able to solubilise water insoluble molecules in aqueous media by specific intermolecular events. Specifically the proposal examines a new polymer architecture - claw shaped polymeric surfactants (as shown in the Figure) in which the water insoluble molecule isheld in a hydrophobic pocket formed by each claw shaped surfactant molecule. The hydrophobic pocket will arise from the aggregation of the separate amphiphilic digits of the claw. At the University of Strathclyde, we have already worked out the tricky part of the synthesis and aim to synthesise a variety of polymeric amphiphiles, identify optimal architectures, using a newly developed high throughput system, and study the claw shaped polymeric surfactant self assembly as well as the molecular interactions between the new polymers and model drug molecules. Suitable candidates will undergo preliminary biological testing in order to establish proof of the delivery concept. Total cost = 213,174. The work fulfils the EPSRC Life Sciences Interface Programme objectives and contributes to the Council's mission to support innovative materials and engineering research.

许多分子相互作用已经被制药部门利用，使有价值的药物化合物能够被递送给患者。一些涉及水不溶性药物的分子相互作用旨在药物增溶，从而允许药物被施用。尽管所有这些努力，高达40%的具有已证实的生物活性的新化学实体仍然未能开发，仅仅是因为a）它们不溶于水和B）合适的和生物相容的药物增溶剂不可用。可用的材料包括低分子量表面活性剂增溶剂，其具有差的生物相容性，因为它们倾向于裂解细胞，这恰恰是由于它们的去污剂性质，并且所得溶液对稀释不稳定。另一方面，嵌段共聚物是差的药物增溶剂。该建议建立在已经确定的生物相容性（不引起细胞溶解）聚合物梳形表面活性剂的工作之上，其中带有水不溶性侧基的可溶性聚合物能够通过特定的分子间相互作用在水性介质中溶解水不溶性分子。许多分子相互作用已经被制药部门利用以使有价值的药物化合物能够被递送给患者。一些涉及水不溶性药物的分子相互作用旨在药物增溶，从而允许药物被施用。尽管所有这些努力，高达40%的具有已证实的生物活性的新化学实体仍然未能开发，仅仅是因为a）它们不溶于水和B）合适的和生物相容的药物增溶剂不可用。可用的材料包括低分子量表面活性剂增溶剂，其具有差的生物相容性，因为它们倾向于裂解细胞，这恰恰是由于它们的去污剂性质，并且所得溶液对稀释不稳定。另一方面，嵌段共聚物是差的药物增溶剂。该建议建立在已经确定的生物相容性（不引起细胞裂解）聚合物梳形表面活性剂的工作上，其中含有水不溶性侧基的可溶性聚合物能够通过特定的分子间事件溶解水不溶性分子。具体而言，该提案研究了一种新的聚合物结构-爪形聚合物表面活性剂（如图所示），其中水不溶性分子隐藏在由每个爪形表面活性剂分子形成的疏水口袋中。疏水袋将由爪的分开的两亲性足趾的聚集而产生。在斯特拉斯克莱德大学，我们已经解决了合成的棘手部分，旨在合成各种聚合物两亲物，确定最佳结构，使用新开发的高通量系统，并研究爪形聚合物表面活性剂自组装以及新聚合物和模型药物分子之间的分子相互作用。合适的候选人将接受初步的生物测试，以建立交付概念的证据。总费用= 213 174美元。这项工作实现了EPSRC生命科学接口计划的目标，并有助于理事会的使命，以支持创新材料和工程研究。

项目成果

Abstract 4519: Lomustine nanoparticles are effective brain cancer treatments.

摘要 4519：洛莫司汀纳米颗粒是有效的脑癌治疗方法。

• DOI: 10.1158/1538-7445.am2013-4519
• 发表时间: 2013
• 期刊: Cancer Research
• 影响因子: 11.2
• 作者: Fisusi F

Down-regulation of GP130 signaling sensitizes bladder cancer to cisplatin by impairing Ku70 DNA repair signaling and promoting apoptosis.

• DOI: 10.1016/j.cellsig.2021.109931
• 发表时间: 2021-01
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Shanshan He;Gang Li-;A. Schätzlein;P. Humphrey;R. Weiss;I. Uchegbu;Darryl T. Martin

It takes more than a vow

这需要的不仅仅是一个誓言

• 发表时间: 2018
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Gewin Virginia

Abstract 5530: Chitosan amphiphile nanoparticles reduced the myelosuppressive effects of lomustine

摘要 5530：壳聚糖两亲纳米粒子降低洛莫司汀的骨髓抑制作用

• DOI: 10.1158/1538-7445.am2015-5530
• 发表时间: 2015
• 期刊: Cancer Research
• 影响因子: 11.2
• 作者: Fisusi F

Nanoparticulate Mycophenolic Acid Eye Drops - Analytical Validation of a High Performance Liquid Chromatography Assay and Stability Studies.

纳米颗粒霉酚酸滴眼液 - 高效液相色谱测定和稳定性研究的分析验证。

• DOI: 10.2174/2211738509666210111161110
• 发表时间: 2021
• 期刊: Pharmaceutical nanotechnology
• 作者: Al-Kulabi A