Drug encapsulation into a nanoparticle improves its pharmacokinetics, decreases its toxicity and enables co-delivery of multiple drugs with contrast agents. Despite being widely explored, this approach has not been proven more efficacious in cancer eradication compared to free chemotherapy drugs, primarily due to low nanoparticle tumor uptake and heterogenous intratumoral distribution. To overcome these hurdles, multiple pre-treatment strategies that improve tumor permeability have been proposed, including chemically-induced vasodilation, radiation therapy, vascular-targeted photodynamic therapy (PDT), focused ultrasound, and local hyperthermia.<br/> <br/>Our lab has been exploring external means to enhance nanoparticle delivery to tumors via light, heat, and sound. First, we employed a low molecular weight (&lt;2 kDa) porphyrin photosensitizer targeting prostate-specific membrane antigen (Porphy-PSMA) in combination with sub-lethal PDT to enhance delivery of 100 nm liposomes, 20 nm lipoproteins and 15 nm gold nanoparticles, as demonstrated by fluorescence/photoacoustic imaging and ICP-MS, respectively. We found that the low molecular weight of Porphy-PSMA allows it to homogeneously distribute within the tumor, and its combination with PDT opens access to the deep layers of the tumor tissue for nanoparticle delivery. Secondly, we used lipid-based nanoparticles containing highly ordered porphyrin J-aggregates to locally administer photo-hyperthermia to tumors. The ordered porphyrins act as self-regulating photothermal agents, which allowed us to maintain the tumour temperature below therapeutic doses to efficiently enhance subsequent nanoparticle tumor accumulation. Finally, following our recent discovery of ultrasound-induced microbubble-to-nanoparticle conversion, we explored a strategy to harness this conversion as a tool to bypass the enhanced permeability and retention effect in order to directly deliver nanomedicines into tumors.<br/> <br/>Given the minimally invasive nature of these external triggers (light, heat, and sound), these new approaches could enhance both overall tumor accumulation and the intratumoral distribution of nanomedicines, which ultimately could lead to improvement in the therapeutic efficacy of FDA-approved nanoformulations.

Light, heat and sound to enhance nanoparticle delivery to the tumors

256th National Meeting (2018)

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