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

世界卫生组织将艾滋病毒/艾滋病描述为一种全球流行病。据估计，自1981年以来，已有超过2500万人死亡，目前有超过3300万人患有这种疾病，其中包括成人和儿童。2005年，全球估计有330万人死于艾滋病，其中包括57万多名儿童。艾滋病毒/艾滋病的流行继续增加，预计最终仅在非洲就会有9000多万人受到感染。在2001年至2007年期间，英国是西欧艾滋病毒/艾滋病感染人数增长最快的国家，的增幅为%。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用药制度。艾滋病毒突变会导致对现有疗法的抵抗力，但疗法针对体内艾滋病毒的能力对药物的成功至关重要。艾滋病毒存在于全身的不同部位，但细胞和组织部位都是药物特别难以到达的部位。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微粒纳米药物给药方法的好处。使用纳米级聚合物载体作为载体将难于溶解的药物运输和输送到所需的作用部位，这对肿瘤靶向是有利的，因为纳米药物的颗粒性质推动了肿瘤组织的积聚。HIV感染中的细胞和组织避难所被广泛认为也是基于颗粒的方法的理想候选者，但在这一领域的工作一直有限。支化聚合物可能作为颗粒状药物输送载体，许多已被证明具有治疗优势。然而，最好的材料合成非常昂贵，对于撒哈拉以南地区(超过2000万艾滋病毒感染)等人群的治疗是不可行的，在这些地区，成本是治疗选择的关键组成部分。利物浦大学开发了一种新的材料--多枝状聚合物，这种材料具有最复杂的支化聚合物的许多优点，但生产成本相对较低。在早期的工作中，已经生产出了颗粒尺寸为&gt；40 nm、具有封装能力的原型材料。这些材料是独一无二的，仍处于非常早期的开发阶段。这项提议将同时探索多树形化合物的合成及其干预艾滋病毒治疗的能力。将把它们作为特定大小、形状和表面功能的药物载体进行研究，并将确定它们在避难所针对艾滋病毒的能力。建议在全球制药公司和艾滋病毒临床医生的参与下，在化学、分子和临床药理学系之间进行长达4.5年的合作。这种材料合成和综合药理学的方法将大大加快潜在新疗法的开发，从而使英国处于领先地位，适用于其他健康问题，如癌症、结核病和丙型肝炎。

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.