Non Invasive Ultrasound Assisted Delivery of Drug Loaded Intact Liposomes: A Combined Experimental and Modeling Approach

本研究的总体目标是开发一种新的药物递送技术，提供一种可穿戴、非侵入性、可定制的透皮给药平台，这是目前尚无的。该技术的优点是允许完整的药物封装在囊泡中，通过皮肤层输送。这样可以在体循环中持续、稳定地释放，并满足明确定义的临床需求，从而改善健康结果并降低医疗保健成本。其中一种被测试的药物用于关节炎和癌症治疗，通过非侵入性的递送途径减少副作用并提高其生物利用度是迫在眉睫的重要问题。据估计，关节炎影响着2700万美国人，每年的总成本接近550亿美元。此外，每年有150多万新患者被诊断患有癌症，导致每年930亿美元的直接治疗费用。这种跨学科的方法结合了生物化学和非侵入性、非电离的方式，如超声波，可以在没有注射器或针头的情况下安全输送任何药物，降低了感染的风险，消除了患者的不适。此外，由于它提供了一种可行的临床替代传统的针刺经皮递送，它将立即产生社会影响。与目前的透皮给药方法相比，完整的给药方案提供了另一个显著的优势，因为每次给药时，不同的药物化学成分不需要新的配方。提出的技术是真正的变革，因为它适用于各种各样的药物和生物制剂（si-RNA，抗体，蛋白质，疏水或亲水分子）。这可能会导致整个行业对透皮给药技术的重新评估，并允许任何临床疗效和毒性水平非常接近的药物的临床相关毒性降低。除了非侵入性、定制化的药物输送外，所提出的可穿戴贴片涂抹器可用于诸如骨愈合和神经刺激等应用。这种方法的新颖性被一个独立的、轻量级的（100克，包括电池和驱动电子设备）、扁平的（10毫米厚）和完全便携式创可贴的设计进一步放大了。类似超声波涂抹器。结合理论建模和实验（体外）方法将有助于确定优化的物理化学和生理参数集，并阐明声场、囊泡和皮肤层之间相互作用的机制。这些机制的知识对于改进非侵入性透皮给药方法和设计针对患者的个体化治疗是必不可少的，并将用于可穿戴贴片的最终设计。该项目针对明确的临床需求，并允许患者在家中给药。这将减少多次看医生的需要，从而减少医疗费用。消除了频繁运送病人的需要。同时，治疗的有效性将通过最大限度地提高患者？这反过来将改善健康结果。

1064802PapazoglouThe overarching goal of this research is to develop a novel drug delivery technology that provides a wearable, non-invasive, customizable transdermal delivery platform that is not currently available. The technology has the advantage of allowing the intact drug encapsulated in a vesicle to be delivered through the skin layers. This enables sustained, stable release in the systemic circulation and addresses a well-defined clinical need that can lead to improved health outcomes and reduced health care costs. One of the drugs to be tested is used in arthritis and cancer treatment and reducing the side effects and improving its bioavailability with a non-invasive delivery route is of immediate importance. Arthritis affects an estimated 27 million Americans with total costs approaching $55 billion annually. Also, each year over 1.5 million new people are diagnosed with cancer, resulting in direct costs of treatment of $93 billion annually. The interdisciplinary approach combining biochemistry and a non-invasive, non-ionizing modality such as ultrasound to safely deliver any drug without syringes or needles, reduces risk of infection and eliminates patient discomfort. In addition, as it provides a viable clinical alternative to the conventional needle-enabled transcutaneous delivery, it will have an immediate societal impact. The intact drug delivery scheme offers yet another notable advantage over current transdermal delivery methods in that different drug chemistries will not necessitate a new formulation each time a new drug is administered. The proposed technology is truly transformative because it is applicable to a diverse array of drugs and biologics (si-RNA, antibodies, proteins, hydrophobic or hydrophilic molecules). It could lead to industry-wide reevaluation of transdermal delivery techniques and allow clinically relevant toxicity reduction with any drug where clinical efficacy and toxicity levels are very close. In addition to non-invasive, customized drug delivery the proposed wearable patch applicator implementation can be used in applications such as bone healing and nerve stimulation. The novelty of the approach is further amplified by the design of a self-contained, lightweight (100g including battery and driving electronics), flat (10mm in thickness) and fully portable Band-Aid?-like ultrasound applicator. The combined theoretical modeling and experimental (in vitro) approach will aid in determining the optimized set of physico-chemical- and physiological parameters and elucidate the mechanisms that underlie the interaction between the acoustic field, the vesicles and the skin layers. Knowledge of these mechanisms is indispensable in refining the non-invasive transdermal drug delivery methods and designing patient specific individual treatments and will be used in the final design of the wearable patch. The project addresses a well-defined clinical need and will allow drug administration by the patient at home. This will reduce the healthcare expenses by limiting the need for multiple visits at the physician?s office and eliminating the need for frequent patient transportation. At the same time the effectiveness of the treatment will be enhanced by maximizing the patient?s compliance, which in turn will improve health outcomes.