Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases.

There is a huge demand for pro-/anti-angiogenic nanomedicines to treat conditions such as ischemic strokes, brain tumors, and neurodegenerative diseases such as Alzheimer's and Parkinson's. Nanomedicines are therapeutic particles in the size range of 10-1000 nm, where the drug is encapsulated into nano-capsules or adsorbed onto nano-scaffolds. They have good blood-brain barrier permeability, stability and shelf life, and able to rapidly target different sites in the brain. However, the relationship between the nanomedicines' physical and chemical properties and its ability to travel across the brain remains incompletely understood. The main challenge is the lack of a reliable drug testing model for brain angiogenesis. Recently, microfluidic platforms (known as "lab-on-a-chip" or LOCs) have been developed to mimic the brain micro-vasculature related events, such as vasculogenesis, angiogenesis, inflammation, etc. The LOCs are able to closely replicate the dynamic conditions of the human brain and could be reliable platforms for drug screening applications. There are still many technical difficulties in establishing uniform and reproducible conditions, mainly due to the extreme complexity of the human brain. In this paper, we review the prospective of LOCs in the development of nanomedicines for brain angiogenesis-related conditions.

Chemotherapeutic and antiangiogenic drugs beyond tumor progression in colon cancer: Evaluation of the effects of switched schedules and related pharmacodynamics.

The aim of the study was to evaluate the effects and the related pharmacological mechanisms of switched schedules of antiangiogenic and chemotherapeutic drugs beyond progression after a first-line treatment in a colorectal cancer preclinical model. In vivo studies were performed in nude mice subcutaneously transplanted with colon cancer cells. The treatments included drug combinations with a switch between chemotherapeutic (i.e., irinotecan and 5-fluorouracil) and/or antiangiogenic drugs (i.e., anti-VEGF antibodies and sunitinib) at the time of tumor progression. Proliferation assays were also achieved in vitro on different colon cancer cell lines exposed to SN-38 and sunitinib alone or in combination. ABCG2 gene expression was performed with real-time PCR and SN-38 intracellular concentrations were measured. The switch in the combined treatments, at the time of tumor progression, of the chemotherapeutic (from irinotecan to 5-fluoruracil), or the antiangiogenic drug (from anti-VEGF antibodies to sunitinib) or of both drugs induced a new response. Immunohistochemistry of stromal PDGF-C, PlGF, SD1-α, Tie-2, and VEGFR-2 showed statistical differences between tumors at the time of relapse and after the switched therapy. Moreover, the combination of SN-38 and sunitinib caused synergism on colon cancer cells, with significant inhibition of the ABCG2 gene expression and an increase of SN-38 intracellular concentrations. Our observations may be of clinical relevance, suggesting the switch of single chemotherapeutic or antiangiogenic drugs beyond progression of the disease to obtain a new tumor response due to a modulation of angiogenic factors and a direct effect on tumor cells with a possible variation of intracellular drug concentrations.