Mucus Penetrating Nanoparticles for Small Cell Lung Cancer

吸入化疗药物在人类身上显示出在提高肺癌应答率同时减少全身毒性方面的重大前景。我们认为，由于游离药物通过全身吸收和粘液清除机制迅速从呼吸道中清除，吸入化疗的有效性和安全性将通过吸入性延长给药策略得到改善。这一努力潜力的关键是最近开发的粘液穿透纳米颗粒(MPP)平台技术，该平台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输送到肺部呼吸道。虽然传统的纳米颗粒(CP)很容易固定在粘液的最外层，该凝胶层通过纤毛作用迅速从肺中清除，但我们发现，包裹着非粘附性聚合物的颗粒迅速穿透人体粘液屏障。通过穿透表面粘液层，我们假设MPP将：(1)避免从肺部呼吸道迅速消除，(Ii)提供局部长期的化疗药物输送，从而(Iii)显著提高抗小细胞肺癌的药物疗效，(Iv)将全身毒性降至最低，以及(V)与全身化疗方案相结合时提供增强的疗效，其中所需的全身剂量可能被降低。我们将制备用于小细胞肺癌的可生物降解的一线化疗药物MPP，并对其与未包裹的药物和与MPP相同的CP中的药物进行对比评估，不包括非粘附性涂层。在目标1中，我们将制定MPP和“细胞粘附性MPP”，并对纳米颗粒进行彻底的表征，包括颗粒大小、载药量、释放动力学和在新鲜的未稀释的人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内的滞留，并对MPP和细胞黏附MPP释放的药物进行药代动力学分析，并与CPAN未包裹的药物进行比较。在目的3中，我们将评价载药MPP和细胞粘附性MPP与CP和未包裹药物在小鼠小细胞肺癌原位模型中的安全性和有效性。GLP生产和安全/毒性试验将由验证核心与FDA密切协商，在第4年或第5年对主要产品进行。

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.