Ultrasonic and radiofrequency electromagnetic heating for local drug delivery

描述（由申请人提供）： 我们已经开发出可以被外源性能量源激活的脂质体颗粒，从而局部递送药物。对于可以通过超声激活的颗粒，我们已经发现，在24小时时可以实现亲水性分子的递送增加60倍（与游离药物施用相比）。为了使用温和的加热用超声波激活颗粒，必须使短酰基（或单个酰基）链双链化-因此，颗粒在循环期间不是完全稳定的。为了提高循环过程中的稳定性，我们设计了具有更长酰基链的颗粒，可以提供更大的剂量增加，但需要新的激活方法。通过将纳米金掺入颗粒的脂质双层（其中约1 nm的金附着在脂质头基上），这些颗粒可以使用电磁波加热，在体内任何深处释放药物，并实现药物积累增加200倍。虽然金颗粒也可以用于直接消融一个区域，但我们认为它们以安全有效的方式局部递送药物在癌症治疗中可能很重要，因此我们将开发使用电磁能递送亲水分子的系统和颗粒。作为概念验证，我们将用亲水性药物装载颗粒，并在小鼠肿瘤模型中证明递送和功效。该R21提案的具体目标是：量化、改进和增强用于加热金纳米颗粒的RF-EM加热装置，测试和改善使用金纳米颗粒从脂质体中释放货物的热敏性，比较使用RF-EM方法与超声加热的植入肿瘤模型中亲水性药物的递送剂量，并作为治疗持续时间的函数，证明植入肿瘤模型中药物释放的有效性。 公共卫生相关性： 目前，美国每四个死亡病例中就有一个是由癌症引起的。各种药物的毒性特征限制了可供选择的预防和治疗方法。因此，大量的努力已经指向开发基于纳米技术的方法，用于增加药物治疗的功效和降低毒性。电磁波可用于从载体中释放药物，甚至在大脑或胸腔深处。超声波可以加热组织并间接加热颗粒。在这里，我们已经建立了一个装置，从车辆释放亲水性药物，并比较超声和电磁给药方法。

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.