Ultrasonic and radiofrequency electromagnetic heating for local drug delivery

描述(申请人提供)：我们已经开发出可以被外源能源激活的脂质体颗粒，从而局部输送药物。对于可以被超声波激活的颗粒，我们发现，24小时内亲水性分子的释放(与免费给药相比)可以增加60倍。为了用超声波温和加热来激活颗粒，必须加入一个短酰基(或单酰基)链--因此，颗粒在循环过程中并不完全稳定。为了提高循环中的稳定性，我们设计了具有较长酰基链的颗粒，可以提供更大的剂量增加，但需要一种新的激活方法。通过将纳米金结合到颗粒的脂双层中(其中~1 nm的金附着在脂头基团上)，这些颗粒可以使用电磁波加热，在体内任何深处释放药物，实现药物累积增加200倍。虽然金颗粒也可以用于直接消融一个区域，但我们认为，使用它们以安全有效的方式局部输送药物在癌症治疗中可能是重要的，因此我们将开发使用电磁能量输送亲水分子的系统和颗粒。作为概念验证，我们将在小鼠肿瘤模型中将亲水性药物装载到颗粒中，并展示其传递和疗效。这项R21建议的具体目的是：量化、改进和增强用于加热纳米金颗粒的RF-EM加热设备，测试和改善使用纳米金颗粒从脂质体中释放货物的热敏性能，比较使用RF-EM方法和超声加热方法在移植肿瘤模型中的亲水药物释放剂量，并根据治疗时间的函数，展示药物在移植肿瘤模型中的释放效果。 与公共卫生相关：目前，美国四分之一的死亡是由癌症引起的。各种药物的毒性特征限制了可供选择的抢先和治疗方法。因此，大量的努力被用于开发基于纳米技术的方法，以提高药物治疗的有效性和降低其毒性。电磁波可以用来从载体中释放药物，甚至可以在大脑或胸部深处释放药物。超声波可以加热组织，间接加热颗粒。在这里，我们已经建立了一种从车辆中释放亲水性药物的装置，并比较了超声波和电磁药物输送方法。

DESCRIPTION (provided by applicant): We have developed liposomal particles that can be activated by exogenous energy sources, thus locally delivering drugs. For particles that can be activated by ultrasound, we have found that a 60 fold increase in delivery of hydrophilic molecules (as compared to free drug administration) can be achieved at 24 hours. In order to activate particles with ultrasound using mild heating, a short acyl (or single acyl) chain must be incorporated-as a result, the particles are not fully stable during circulation. In order to improve stability during circulation, we have designed particles with a longer acyl chain that can deliver a greater dose increase but require a new method for activation. By incorporating nanogold within the lipid bilayer of the particles (where the ~1 nm gold is attached to the lipid head group), these particles can be heated using electromagnetic waves, releasing the drug in any region deep within the body and achieving a 200 fold increase in drug accumulation. Although the gold particles can also be used to directly ablate a region, we feel that their use to locally deliver a drug in a safe and efficacious manner could be important in cancer therapeutics and therefore we will develop the system and particles to deliver hydrophilic molecules using electromagnetic energy. As a proof of concept, we will load the particles with a hydrophilic drug and demonstrate delivery and efficacy in a murine tumor model. The specific aims of this R21 proposal are to: quantify, refine and enhance the RF-EM heating device for heating gold nanoparticles, test and improve thermally- sensitive release of cargo from liposomes using gold nanoparticles, compare delivered dose of hydrophilic drug in implanted tumor models using RF-EM method vs. ultrasound heating and as a function of treatment duration, demonstrate efficacy of drug release in implanted tumor models. PUBLIC HEALTH RELEVANCE: Currently, one in 4 deaths in the United States is due to cancer. Available options for preemption and treatment are limited by the toxicity profiles of various drugs. As a result, substantial efforts have been directed to develop nanotechnology-based methods for increasing the efficacy and decreasing the toxicity of drug therapies. Electromagnetic waves can be used to release drugs from vehicles, even deep within the brain or thorax. Ultrasound waves can heat tissues and indirectly heat particles. Here, we have build a device for releasing hydrophilic drugs from vehicles and compare ultrasound and electromagnetic methods for drug delivery.