Peptide-mimetic hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention

艾滋病毒/艾滋病是全世界育龄妇女死亡的主要原因。由于缺乏有效的女性避孕选择，艾滋病毒和意外怀孕在发展中国家普遍存在。艾滋病毒/艾滋病仍然是英国面临的主要挑战之一（2017年有428人死于艾滋病相关疾病），我们的意外怀孕率是西欧最高的（六分之一的怀孕）。其中一个关键问题是，患者很难坚持复杂的艾滋病毒和避孕治疗方案，这通常需要每天在非常特定的时间多次给药。最近的战略重点是通过使用长效注射技术来解决患者依从性问题。然而，这些产品有几个重大问题，限制了它们作为艾滋病毒和避孕联合疗法的广泛使用，如:水不溶性药物的使用限制药物的类型可以被纳入产品意义双重HIV-contraceptive技术难以实现摄入快速药物释放后插入导致潜在的毒性问题/关注剂量收到了需要手术植入大针头插入和删除——要求稳定性问题在储存和运输的发展中国家会导致堵塞的注射器和不完整的剂量药物。我们的项目旨在通过创造一种具有增强稳定性的可溶性注射剂来克服这些问题，以改善皮肤下给药的便利性。这将形成一种水凝胶植入物，以响应皮肤内存在的酶，长期释放药物，从而无需每天给药。我们的可注射植入物由类似肽的分子组成，这些分子能够形成类似组织的水凝胶，这种水凝胶可以根据需要逐渐释放药物至少28天。这将消除患者每天遵守复杂药物给药方案的需要，并提高他们对药物的依从性。天然多肽构成了蛋白质和组织的基石。由于其高生物相容性，它们作为药物释放水凝胶植入物用于皮下给药是有希望的，但由于它们在人体中存在的酶在几小时内迅速降解而受到限制。该项目通过研究模拟肽来克服稳定性问题，它保留了肽的积极特性（例如生物相容性，易于药物附着），并且能够形成水凝胶，在治疗期间保持稳定。模拟肽可以在体内经过几个月的时间降解成无毒成分，并从患者体内清除，这意味着不需要手术切除。我们的肽模拟物具有高化学通用性（即广泛的化学官能团选择）。因此，多种药物可以直接附着在肽模拟水凝胶上，从而使大量药物被纳入体内，以满足至少28天的体内治疗需要。在生理条件下，水凝胶在注射后形成药物快速爆发释放的还原电位后，药物脱离发生。药物释放研究将评估持续给药的潜力，以尽量减少药物浓度的药代动力学高峰和低谷。在这个项目中研究的肽模拟物是有目的的小分子，制造成本低廉，提高了它们在临床转化为药物产品的潜力，并有效地利用在医疗保健预算中，为患者和社会带来利益。所获得的数据将允许这种肽模拟水凝胶方法的实际效用，以长期注射给药进行评估。该平台具有很高的潜力，可作为一种新型植入物，用于患者难以坚持服药的情况（如阿尔茨海默氏症、结核病、抑郁症、精神分裂症、疟疾）的持续药物输送。

HIV/AIDS is the leading cause of death in women of reproductive age worldwide. HIV and unintended pregnancies are prevalent in developing nations due to the lack of effective female contraceptive choice. HIV/AIDs remains one of the key challenges facing the UK (428 deaths from AIDS-related illnesses in 2017) and our rate of unintended pregnancies are the highest in Western Europe (one in six pregnancies). One of the key issues is that patients struggle to adhere to the complex regimens of HIV and contraceptive therapies, which often require multiple dosing at very specific times each day. Recent strategies have focused on solving patient adherence issues by using long-acting injectable technologies. However, such products have several significant issues that limit their wider use as combined HIV and contraceptive therapies, such as:-the use of water-insoluble drugs that limit the type of drugs that can be incorporated into the product meaning a dual HIV-contraceptive technology is difficult to achieve -fast drug release after insertion leading to potential toxicity issues/concerns over dose received-a need for surgery for implant insertion and removal -a requirement for large needles -stability issues upon storage/transport to the developing world which can result in clogging of syringes and incomplete dosing of drugs. Our project aims to overcome these issues by creating a soluble injection of enhanced stability, for improved ease of administration under the skin. This will form a hydrogel implant in response to enzymes present within the skin to release drugs long-term, removing the need for daily dosing. Our injectable implant is composed of peptide-like molecules which are capable of forming tissue-like hydrogels that can be tailored to gradually release drugs for at least 28 days. This will remove the need for patients to comply with complex drug dosing regimens on a daily basis and improve their adherence to medication. Natural peptides form the building blocks of proteins and tissues. Their use as a drug releasing hydrogel implant for administration under the skin is promising due to their high biocompatibility, but limited by their rapid degradation within hours by enzymes present in the human body. This project overcomes stability issues by studying peptide-mimetics, which retain the positive properties of peptides (e.g. biocompatibility, easy drug attachment) with the ability to form hydrogels that will be stable for the duration of therapy. Peptide-mimetics can be tailored to degrade within the body over months into non-toxic components that are eliminated from the patient, meaning surgical removal is not necessary.Our peptide-mimetics possess high chemical versatility (i.e. wide choice of chemical functional groups). Therefore multiple drugs can be attached directly to the peptide-mimetic hydrogel enabling large quantities of drug to be incorporated to meet in vivo therapeutic need for at least 28 days. Drug detachment proceeds in physiological conditions after the hydrogel forms reducing potential for rapid burst release of drug upon injection. Drug release studies will assess the potential for sustained drug administration in a bid to minimise pharmacokinetic peaks and troughs in drug concentrations. The peptide-mimetics studied in this project are purposefully small molecules that are cheap to manufacture, improving their potential to be clinically translated as a pharmaceutical product and effectively utilised within healthcare budgets for patient and societal benefit.The data obtained will allow the practical utility of this peptide-mimetic hydrogel approach to long-acting injectable administration of drugs to be assessed. This platform has high potential to be adopted as a novel implant for the sustained delivery of drugs for conditions where patients have difficulty adhering to their medicines (e.g. Alzheimer's, tuberculosis, depression, schizophrenia, malaria).