Mucus penetrating nanoparticles for early stage cervical cancer

全身给药的药物通常以非常低的浓度到达宫颈阴道（CV）道。因此，用于影响CV道的疾病的药物疗法通常具有较差的功效和显著的不良全身副作用。在CV道中局部递送的药物（作为丸剂或凝胶）通常通过全身吸收结合粘液清除机制快速清除。因此，全身化疗是宫颈癌手术后或与放疗同时进行的最后或严格并行的选择;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递送的需求，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，适用于局部持续递送化疗药物（和其他药物）至CV道。虽然常规颗粒（CP）容易固定在粘液的最外“表面”层中，所述最外“表面”层迅速从CV道脱落，但我们发现用非粘膜粘附聚合物涂覆药物递送颗粒允许直径大至500 nm的颗粒快速穿透人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道快速消除，（ii）实现更均匀的分布，以及（iii）提供局部持续递送化疗剂，从而（iv）显著改善针对CV肿瘤的药物功效，同时（v）最小化全身毒性。我们将制备和评估装载有一线化疗药物的可生物降解MPP，并将其与除了没有粘膜惰性涂层之外在所有方面与MPP相同的颗粒进行测试。在目标1中，我们将制定MPP和细胞粘附MPP组成的可生物降解的聚合物，我们已经证明是能够持续提供广泛的生物活性分子。我们将对纳米颗粒进行全面的理化表征，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，我们将研究小鼠CV道中的保留和分布，并与CP相比，对MPP和细胞粘附MPP释放的药物进行仔细的药代动力学分析。在目标3中，我们将在肿瘤位于CV道的小鼠模型中评价载药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.