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

这一合作项目旨在成为改变纳米晶体(NCs)使用模式的第一步，从简单的溶解性增强技术转向它们的应用，成为可以跨越生物障碍并在目标组织或细胞中产生药物积累的高负载“特洛伊木马”。各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能够真正使患者受益的辅助产品构成了重大障碍。因此，开发更高效、高负载、靶向的纳米粒子的必要性是显而易见的。在这里，我们建议开发一种新的平台，由完全由药物制成的纳米管组成，具有特殊定制的特性，可以将治疗药物浓度输送到选择性组织。申请人在使用NCS增强口服、经皮和粘膜给药方面经验丰富，在人类和兽医方面都是如此，现在的目标是开发下一代靶向NCS。为此，需要对我们迄今所知的这项技术进行重大偏离。NCS的表面化学将不得不从根本上重新考虑。为了实现特定细胞的内化和渗透目标生物屏障，聚合物和特定配体的静电和共价连接到NCS表面将是必要的。这将提高药物的疗效和选择性，并有助于为患者开发更好的药物。鉴于该想法的跨学科性质，与合适的合作伙伴进行合作至关重要。马塞洛·卡尔德龙教授是一位世界知名的大分子化学家，在功能纳米颗粒合成方面有着丰富的记录，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。我们的主要工作假设依赖于难溶药物的NCS在不同时间段以未溶颗粒的形式留在体内的能力。在尺寸和表面性质方面进行了专门定制的新型纳米CS可以作为高负载纳米载体，可以跨越生物屏障，在靶组织中产生药物积累。这一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，该纳米颗粒由修饰有配体的NCs组成，能够在靶组织和细胞中主动积聚。

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.