Mucus penetrating nanoparticles for early stage cervical cancer

全身给药通常以非常低的浓度到达宫颈阴道(CV)。因此，对影响心血管系统的疾病的药物治疗通常会出现疗效不佳和严重的不良全身副作用。通过全身吸收与粘液清除机制相结合的方式，CV途径中的局部给药(以团剂或凝胶形式)通常能迅速清除。因此，全身化疗是宫颈癌手术后或放疗后最后或严格同时进行的选择；局部化疗目前不是患者的选择。为了满足宫颈癌治疗对局部和持续药物输送的需求，我们开发了粘液穿透颗粒(MPP)，这是一种基于聚合物的纳米颗粒技术，适用于将化疗药物(和其他药物)局部持续输送到CV通道。虽然常规颗粒(CP)很容易固定在最外层的粘液中，这些粘液迅速从CV通道中脱落，但我们发现，用非粘附性聚合物包裹药物递送颗粒可以使直径长达500 nm的颗粒快速穿透人体CV粘液屏障。通过穿透快速脱落的表面粘液层，我们假设MPP将：(I)避免从CV道中快速消除，(Ii)实现更均匀的分布，以及(Iii)提供局部持续的化疗药物输送，从而，(Iv)显著提高抗CV肿瘤的药物疗效，同时(V)将全身毒性降至最低。我们将制备和评估装载一线化疗药物的可生物降解的MPP，并测试它们与MPP在所有方面都相同的颗粒，但没有粘液惰性涂层。在目标1中，我们将研制由生物可降解聚合物组成的MPP和细胞粘附型MPP，我们已经证明这些聚合物能够持续输送广泛的生物活性分子。我们将对纳米颗粒进行彻底的物理化学表征，包括载药量、释放动力学和纳米颗粒在新鲜、未稀释的人CV粘液中的扩散速度。在目标2中，我们将研究MPP和细胞黏附性MPP释放的药物在小鼠体内的滞留和分布，并与CP进行比较，进行仔细的药代动力学分析。在目标3中，我们将评估载药MPP和细胞黏附MPP与CP和未包裹的药物在小鼠模型中的体内疗效。

Drugs administered systemically typically reach the cervicovaginal (CV) tract in very low concentrations. As a result, drug therapies for diseases that affect the CV tract typically suffer from poor efficacy and significant adverse systemic side effects. Drugs delivered locally in the CV tract (as a bolus or in gels) are typically cleared rapidly by systemic absorption combined with mucus clearance mechanisms. Thus, systemic chemotherapy is the last or strictly concurrent option for cervical cancer, after surgery or together with radiotherapy; local chemotherapy is not currently an option for patients. To address the need for localized and sustained drug delivery for cervical cancer therapy, we have developed mucus-penetrating particles (MPP), a polymer-based nanoparticle technology suitable for sustained delivery of chemotherapeutics (and other drugs) locally to the CV tract. While conventional particles (CP) are easily immobilized in the outermost “surface” layers of mucus that are shed rapidly out of the CV tract, we discovered that coating drug delivery particles with non-mucoadhesive polymers allows particles as large as 500 nm in diameter to rapidly penetrate human CV mucus barriers. By penetrating the rapidly shed surface mucus layer, we hypothesize that MPP will: (i) avoid rapid elimination from the CV tract, (ii) achieve more uniform distribution, and (iii) provide sustained delivery of chemotherapeutics locally and, thereby, (iv) significantly improve drug efficacy against CV tumors while (v) minimizing systemic toxicity. We will prepare and evaluate biodegradable MPP loaded with frontline chemotherapeutic drugs, and test them against particles that are in all ways identical to the MPP, except without muco-inert coatings. In Aim 1, we will formulate MPP and cell-adhesive MPP composed of biodegradable polymers that we have shown are capable of sustained delivery of a wide range of bioactive molecules. We will perform thorough physicochemical characterization of the nanoparticles, including drug loading, release kinetics and nanoparticle diffusion speeds in fresh, undiluted human CV mucus. In Aim 2, we will investigate retention and distribution in the CV tract of mice, and perform careful pharmacokinetic analysis of drugs released from MPP and cell-adhesive MPP as compared to CP. In Aim 3, we will evaluate the in vivo efficacy of drug-loaded MPP and cell-adhesive MPP compared to CP and unencapsulated drug in a mouse model where tumor is localized in the CV tract.