Mucus Penetrating Nanoparticles for Small Cell Lung Cancer

吸入化疗药物在提高肺癌反应率同时降低全身毒性方面已显示出在人类中的显著前景。我们认为，吸入化疗的有效性和安全性将通过可吸入的延长递送策略来改善，因为游离药物通过全身吸收结合粘液清除机制从气道中快速清除。这项努力的潜力的关键是最近开发的一种粘液穿透纳米颗粒（MPP）平台技术，该技术能够在比以前可能的传统纳米技术更持续的时间内将受控浓度的药物局部递送到肺气道。虽然传统的纳米颗粒（CP）很容易固定在粘液的最外层凝胶层，通过纤毛作用从肺中迅速清除，但我们发现，涂覆有非粘膜粘附聚合物的颗粒迅速穿透人类粘液屏障。通过穿透表面粘液层，我们假设MPP将：（1）避免从肺气道快速消除，（ii）提供化疗药物的局部延长递送，从而（iii）显著改善针对SCLC的药物功效，（iv）最小化全身毒性，以及（v）当与全身化疗方案组合时提供增强的功效，其中所需的全身剂量可能会降低。我们将制备装载有用于SCLC的一线化疗剂的可生物降解MPP，并针对与MPP相同的未包封药物和CP中装载的药物（不包括非粘膜粘附涂层）对其进行评价。在目标1中，我们将配制MPP和“细胞粘附MPP”，并对纳米颗粒进行全面表征，包括粒径、载药量、释放动力学和在新鲜未稀释的人粘液和小鼠气管粘液中的扩散速度。在目标2中，我们将研究纳米颗粒在小鼠肺气道中的滞留，并进行从MPP和细胞粘附MPP释放的药物与CPan未包封药物相比的药代动力学分析。在目标3中，我们将在原位小鼠SCLC模型中评价载药MPP和细胞粘附MPP与CP和未包封药物相比的体内安全性和有效性。验证中心将与FDA密切协商，在第4年或第5年对主导产品进行GLP生产和安全性/毒性研究。

Inhalation of chemotherapeutics has shown significant promise in humans in enhancing lung cancer response rates while reducing systemic toxicity. We h3^othesize that the efficacy and safety of inhaled chemo will be improved by an inhalable prolonged delivery strategy, since free drug is rapidly cleared from the airways by systemic absorption combined with mucus clearance mechanisms. Key to the potential of this effort is the recent development ofa mucus-penetrating nanoparticle (MPP) platform technology capable of providing delivery of controlled concentrations of drug locally to the lung airways over more sustained periods than previously possible viith conventional nanotechnologies. While conventional nanoparticles (CP) are easily immobilized in the outermost gel layer of mucus that is cleared rapidly from the lung by ciliary action, we discovered that particles coated with non-mucoadhesive polymers rapidly penetrate human mucus barriers. By penetrating the surface mucus layer, we hypothesize that MPP will; (1) avoid rapid elimination from the lung airways, (ii) provide prolonged delivery of chemotherapeutics locally and, thereby, (iii) significantly improve drug efficacy against SCLC, (iv) minimize systemic toxicity, and (v) provide enhanced efficacy when combined with systemic chemo regimens, where the systemic dose required may potentially be reduced. We will prepare biodegradable MPP loaded with frontline chemotherapeutic agents for SCLC, and evaluate them against unencapsulated drug and drug loaded in CP that are identical to the MPP, excluding the non-mucoadhesive coatings. In Aim 1, we will formulate MPP and "cell-adhesive MPP" and perform thorough characterization of the nanoparticles, including particle size, drug loading, release kinetics, and diffusion speeds in fresh undiluted human mucus and mouse tracheal mucus. In Aim 2, we will investigate nanoparticle retention in the lung airways of mice, and perform pharmacokinetic analysis of drugs released from MPP & cell-adhesive MPP as compared to CPan unencapsulated drug. In Aim 3, we will evaluate the in vivo safety and efficacy of drug-loaded MPP and cell-adhesive MPP compared to CP and unencapsulated drug in an orthotopic mouse SCLC model. GLP manufacture and safety/tox will be performed on the lead product by year 4 or 5 by the Validation Core in close consultation with the FDA.