New Nanoscale Drug Delivery Systems and their Application to HIV/AIDS treatment

艾滋病毒/艾滋病被世界卫生组织描述为一种全球流行病。据估计，自1981年以来，已有2 500多万人死亡，目前有3 300多万人（包括成人和儿童）患有这种疾病。2005年，艾滋病夺去了全球约330万人的生命，其中包括57万多名儿童。艾滋病毒/艾滋病的流行率继续上升，预计仅在非洲，最终将有9 000多万人受到感染。在2001年至2007年期间，英国是西欧艾滋病毒/艾滋病感染增长最快的国家，增长了64%。艾滋病毒治疗面临许多问题，包括患者需要遵守非常严格的药物治疗制度。HIV突变会导致对现有治疗方法产生耐药性，但是针对体内HIV的治疗方法的能力对药物的成功至关重要。艾滋病毒存在于身体的各个部位，但细胞和组织部位都是药物难以到达的。这些所谓的“避难所”有可能成为药物颗粒的目标，而不是溶解的药物分子。癌症研究已经显示了颗粒纳米药物递送方法的好处。使用纳米级聚合物载体作为运输和递送难溶性药物到所需作用部位的载体，对肿瘤靶向治疗是有益的，因为纳米药物的颗粒性质驱动了肿瘤组织中的积累。HIV感染中的细胞和组织庇护点也被广泛推测为基于颗粒的方法的理想候选者，但在这一领域的工作有限。支链聚合物可以作为颗粒状药物递送载体，许多已被证明具有治疗优势。然而，最好的材料在合成方面非常昂贵，并且在撒哈拉以南地区（超过2000万艾滋病毒感染者）等人群中不可行，在这些地区，成本是治疗选择的关键组成部分。利物浦大学已经开发出一种新型材料——多枝性聚合物，它具有最复杂的支链聚合物的许多优点，但生产成本相对较低。在早期的工作中，原型材料已经生产出粒径为bbb - 40nm并具有封装能力的材料。这些材料是独特的，仍处于非常早期的发展阶段。本研究将同时探索多枝花的合成及其干预HIV治疗的能力。它们将作为特定大小、形状和表面功能的药物载体进行研究，并建立它们在避难所靶向HIV的能力。在全球制药公司和艾滋病毒临床医生的投入下，化学、分子和临床药理学部门之间建议进行为期4.5年的合作。这种综合药理学的材料合成方法将大大加速潜在新疗法的发展，使英国处于领先地位，这将适用于癌症、结核病和丙型肝炎等其他健康问题。

HIV/AIDS is described by the World Health Organisation as a global pandemic. Estimates show that over 25 million people have died since 1981 and over 33 million people including adults and children are currently living with the disease. In 2005, AIDS claimed an estimated 3.3 million lives globally, including more than 570,000 children. The prevalence of HIV/AIDS continues to increase and it is expected that over 90 million will ultimately be infected in Africa alone. The UK had the highest growth in HIV/AIDS infection in western Europe in the period between 2001 - 2007 with a 64% increase. HIV treatment suffers from many issues including the need for patient compliance with a very strict regime of medication. HIV mutation leads to resistance to existing therapies but the ability of therapies to target HIV in the body is critical to the success of medication. HIV resides in various sites throughout the body but there are both cellular and tissue sites which are particularly difficult for drugs to reach. These so called 'sanctuary sites' have the potential to be targeted by particles of drug, rather than dissolved drug molecules. Cancer research has shown the benefits of particulate nanomedicine drug delivery approaches. The use of nanoscale polymer carriers which act as vehicles to transport and deliver poorly soluble drugs to the desired site of action, has been beneficial for tumour targeting as the particle nature of the nanomedicine drives the accumulation in tumour tissues. Cellular and tissue sanctuary sites in HIV infection have been widely speculated to also be ideal candidates for particle-based approaches but there has been limited work in this area.Branched polymers may operate as particle-like drug delivery vehicles and many have been shown to have therapeutic advantages. The best materials are however very expensive to synthesise and would not be viable for treatments in populations such as the sub-Saharan regions (over 20 milllion HIV infections) where cost is a critical component of treatment choice. The University of Liverpool has developed a new class of materials, Polydendrons, that offer many of the benefits of the most sophisticated branched polymers, but can be produced relatively cheaply. In early work, prototype materials have been produced with particle sizes of >40nm and encapsulation capabilities. These materials are unique and still at a very early stage of development. This proposal will simultaneously explore the synthesis of Polydendrons and their ability to intervene in HIV treatments. They will be studied as drug carriers of specific size, shape and surface functionality and their ability to target HIV in sanctuary sites will be established. A collaboration between the departments of Chemistry and Molecular and Clinical Pharmacology over 4.5 years is proposed with input from global pharmaceutical companies and HIV clinicians. This approach of material synthesis with integrated pharmacology will considerably accelerate the development of potential new therapies leading to a leading position for the UK that will be applicable to other health issues such as cancer, tuberculosis and hepatitis C.