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能量激活的脂质体颗粒，从而局部递送药物。对于可以通过超声波激活的颗粒，我们发现在24小时内亲水分子的递送量（与自由给药相比）可以增加60倍。为了用温和加热的超声波激活颗粒，必须加入短酰基（或单酰基）链——因此，颗粒在循环过程中不是完全稳定的。为了提高循环过程中的稳定性，我们设计了具有更长的酰基链的颗粒，可以提供更大的剂量增加，但需要一种新的激活方法。通过在颗粒的脂质双分子层中加入纳米金（其中约1nm的金附着在脂质头组上），这些颗粒可以使用电磁波加热，在身体深处的任何区域释放药物，从而使药物积累增加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是重要的，因此我们将开发利用电磁能递送亲水性分子的系统和颗粒。作为概念验证，我们将在颗粒上装载一种亲水性药物，并在小鼠肿瘤模型中演示其递送和功效。本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，使用金纳米颗粒测试和改善脂质体的热敏释放，使用RF-EM方法比较植入肿瘤模型中亲水药物的给药剂量与超声加热并作为治疗时间的函数，证明植入肿瘤模型中药物释放的功效。

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.