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.
Treatment options for patients with early stage cervical cancer, including surgery and radiation, are invasive, typically extremely painful, and are wrought with potential complications, including infertility in a significant fraction of cases. Systemic chemotherapy is not an option since early cervical tumors are not highly vascularized, so drug concentrations reaching the cervicovaginal (CV) tract are inadequate to affect tumor growth. This project seeks to develop a new biomaterial-based nanoparticle platform technology capable of providing local chemotherapeutic drug delivery in the CV tract, as a simple medical procedure alternative to surgery. A new technology, termed mucus-penetrating particles, is hypothesized to enable localized sustained drug delivery in the CV tract for long periods of time, which should greatly enhance drug efficacy.
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