Nano drug carriers offer the potential for enhanced tumor drug accumulation. However, poor intra-tumoral penetration is a key limitation of these systems. Our recent studies show that lung and other solid tumors are characterized by extensive deposition of fibrin in the extracellular matrix (ECM). We hypothesize that modifying the tumor microenvironment using a fibrinolytic agent such as tissue plasminogen activator (tPA) will significantly improve nanomedicine penetration into otherwise inaccessible regions of the tumor and improve their therapeutic efficacy. In our studies utilizing a mouse model of human non-small cell lung carcinoma (NSCLC), co-administration of a fibrinolytic significantly improved the anticancer efficacy of nanoparticle-encapsulated paclitaxel. Co-treatment with tPA led to decompression of blood vessels and improved tumor perfusion. Further, treatment with tPA resulted in greater intratumoral penetration of a model nanocarrier (Doxil), leading to enhanced availability of the drug in the tumor core. Fibrinolytics such as tPA are already approved for other indications. Fibrinolytic cotherapy is therefore a rapidly translatable strategy for improving therapeutic effectiveness of anticancer nanomedicine.

Therapeutic modification of the tumor microenvironment to overcome intratumoral transport barriers for nanomedicine

256th National Meeting (2018)

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