Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges

重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战

• 批准号: EP/Y001486/1
• 负责人: Alejandro Paredes
• 金额: $ 20.43万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY001486%2F1
• 关键词: Re; thinking; drug; nanocrystals; highly

This collaborative project aims to be the first step towards a paradigm change in the use of nanocrystals (NCs), moving from a simple solubility enhancement technique to their application as highly-loaded "Trojan horses" that can cross biological barriers and produce drug accumulation in target tissues or cells. A wide variety of lipid- and polymer-based nanoparticles have been used to target intracellular organelles and specific organs; however, their low drug loading capacity (frequently lower than 10%) pose a significant barrier to further industrial development and translation to bench side products that can actually benefit patients. Therefore, the need for the development of more efficient, highly loaded, targeted nanoparticles is clear. Here, we propose to develop a novel platform, consisting of NCs entirely made of drug, with specifically tailored properties to deliver therapeutic drug concentration to selective tissues. Well-experienced on the use of NCs for enhancing oral, transdermal, and mucosal drug delivery, both in human and veterinary medicine, the applicant's aim is now to develop the next generation of targeted NCs. To this purpose, a major departure on what we know to date about the technology is required. The surface chemistry of the NCs will have to be fundamentally re-thought. Electrostatic and covalent attachment of polymers and specific ligands to the NCs surface will be necessary in order to achieve internalisation by specific cells and permeation across targeted biological barriers. This will increase drug efficacy, selectivity, and contribute to the development of better medicines for patients. Given the multidisciplinary nature of the idea, collaboration with a suitable partner is critical. Prof Marcelo Calderón, a worldwide recognised macromolecular chemist with an extensive track record on functional nanoparticle synthesis, will bring the complementary expertise required to make this project thrive. If successful, this partnership will set the basis of a new, flexible platform with vast therapeutic applications and industrial potential. Our main hypothesis of work relies on the ability of NCs of poorly soluble drugs to remain in the body as undissolved particles for different periods of time. Specifically tailored in terms of size and surface properties, the novel NCs could act as highly loaded nanovectors which can cross biological barriers and produce drug accumulation in target tissues. The general aim of this collaborative project is to develop a new platform based on highly loaded nanoparticles consisting of NCs decorated with ligands enabling active accumulation in target tissues and cells.

该合作项目旨在成为纳米晶体（NC）使用范式转变的第一步，从简单的溶解度增强技术转变为高负载的“特洛伊木马”，可以跨越生物屏障并在靶组织或细胞中产生药物积累。多种基于脂质和聚合物的纳米颗粒已被用于靶向细胞内细胞器和特定器官;然而，它们的低载药量（通常低于10%）对进一步的工业开发和转化为实际上可以使患者受益的副产品构成了重大障碍。因此，开发更有效、高负载、靶向纳米颗粒的需求是明确的。在这里，我们建议开发一种新的平台，由完全由药物制成的NC组成，具有专门定制的特性，可将治疗药物浓度递送到选择性组织。在人类和兽医学中，申请人在使用NC增强口服、透皮和粘膜药物递送方面经验丰富，现在的目标是开发下一代靶向NC。为此目的，我们需要对迄今为止所知的技术进行重大偏离。NCs的表面化学必须从根本上重新思考。聚合物和特定配体与NC表面的静电和共价连接将是必要的，以便实现特定细胞的内化和穿过靶向生物屏障的渗透。这将提高药物的有效性和选择性，并有助于为患者开发更好的药物。鉴于这一想法的多学科性质，与合适的伙伴合作至关重要。Marcelo Calderón教授是一位全球公认的大分子化学家，在功能性纳米颗粒合成方面拥有广泛的记录，他将带来使该项目蓬勃发展所需的补充专业知识。如果成功，这一合作伙伴关系将为具有巨大治疗应用和工业潜力的新的灵活平台奠定基础。我们工作的主要假设依赖于难溶性药物的NC在不同时间段内作为未溶解颗粒保留在体内的能力。根据尺寸和表面性质进行专门定制，新型NC可以充当高度负载的纳米载体，其可以穿过生物屏障并在靶组织中产生药物积累。该合作项目的总体目标是开发一种基于高负载纳米颗粒的新平台，该纳米颗粒由配体修饰的NC组成，能够在靶组织和细胞中进行活性积累。