Tumor Vascular Permeability and Drug Delivery in a Preclinical Model of Brain Metastases of Breast Cancer

Introduction: Metastatic brain tumors are a common complication of most solid tumors. Brain metastases occur in 30-40% of metastatic breast cancer patients. One year survival after diagnosis of a brain metastasis is approximately 20%. The incidence of brain metastasis may be rising, particularly in the subset of patients with Her-2 amplified tumors. Little quantitative information exists on the BTB permeability in brain metastases. Further, most prior studies have used intracranial implantation models which do not capture many of the key steps in metastatic tumor implantation and development in CNS. In this dissertation we describe sensitive new fluorescent and phosphorescent imaging techniques to measure BTB permeability in brain metastases of breast cancer in mice. Further, this dissertation also shows the potential of a novel bioconjugate system for targeting metastatic lesions. Methods: Female mice were injected with either MDA-MB-231-Br-Her2 or 4T1Br5 (brain seeking metastatic lines) via left cardiac ventricle. Tumors developed over ~2-6 weeks, after which animals were injected with 14C-AIB and TX Red 3kDa. Tracer concentration in blood and brain were determined using fluorescent microscopy and autoradiography. Further, to target the metastatic lesions, a small molecular weight hyaluronic acid paclitaxel conjugate was explored as a mechanism to deliver drugs into metastasis cells. Results: A striking finding is the marked heterogeneity of BTB integrity among metastases. Based upon analysis of n>2000 metastases, statistically significant changes in BTB permeability were observed in ~90% of 231-BR-Her2 and ~96% of 4T1-BR5 brain metastases. No correlation was found between changes in the integrity of the BTB and metastasis size or tumor morphology. Further, the HA-paclitaxel bypassed tumor P-gp, accumulated at higher amounts than free paclitaxel, and showed similar cytotoxicity as that of paclitaxel. Conclusions: Tumor vascular permeability is heterogenous and is consistent with the limited and variable clinical efficacy of most chemotherapeutic drugs for brain metastases. Further, we propose that HA-paclitaxel may improve drug delivery to metastatic lesions.