Tumor-Penetrating Microparticles for Intraperitoneal Therapy of Ovarian Cancer

Abstract

Intraperitoneal chemotherapy prolongs survival of ovarian cancer patients, but its utility is limited by treatment-related complications and inadequate drug penetration in larger tumors. Previous intraperitoneal therapy used the paclitaxel/Cremophor EL (polyethoxylated castor oil) formulation designed for intravenous use. The present report describes the development of paclitaxel-loaded microparticles designed for intraperitoneal treatment (referred to as tumor-penetrating microparticles or TPM). Evaluation of TPM was performed using intraperitoneal metastatic, human ovarian SKOV3 xenograft tumor models in mice. TPM were retained in the peritoneal cavity and adhered to tumor surface. TPM consisted of two biocompatible and biodegradable polymeric components with different drug release rates; one component released the drug load rapidly to induce tumor priming, whereas the second component provided sustained drug release. Tumor priming, by expanding interstitial space, promoted transport and penetration of particulates in tumors. These combined features resulted in the following advantages over paclitaxel/Cremophor EL: greater tumor targeting (16-times higher and more sustained concentration in omental tumors), lower toxicity to intestinal crypts and less body weight loss, greater therapeutic efficacy (longer survival and higher cure rate), and greater convenience (less frequent dosing). TPM may overcome the toxicities and compliancerelated problems that have limited the utility of intraperitoneal therapy.

Multiscale Tumor Spatiokinetic Model for Intraperitoneal Therapy

“…The drug concentration-time profiles in the peritoneal fluid and plasma were obtained from our earlier study where nontumor-bearing mice were given an IP dose of paclitaxel (52,53). The C plasma,total -time profile was obtained by analyzing the drug concentrations in plasma at predetermined times.…”

Colloidal stability of nano-sized particles in the peritoneal fluid: Towards optimizing drug delivery systems for intraperitoneal therapy

“…In the past few years, different DDSs were evaluated for IP administration [21,22], Among them are targeted nanocarriers [23], nanoparticles for intraperitoneal gene delivery [24], micelles [25], microparticle [26,27] and hydrogels for sustained release in the peritoneal cavity [28][29][30].…”

Modelling drug transport during intraperitoneal chemotherapy

“…Three different equations for drug transport were written for each of the considered species: the transport of drug in the vascular component, transport of the unbound drug and the transport of the drug immobilized on the cells. Data used to describe the relation between bound and unbound drug was based on previous experimental studies of the same group [49,50]. The drug concentration boundary conditions imposed at the edge of the tumour and in the vascular component were also based on prior experiments by this group.…”