Nano Construct for Brain Tumors (Glioblastoma)
Glioblastoma is aggressive cancer with a poor patient prognosis. The primary treatment for glioblastoma includes surgery, radiation therapy, and chemotherapy. The challenges in glioblastoma drug delivery treatment include the presence of the blood-brain barrier (BBB); unwanted damage to healthy brain cells caused by surgery, and the highly heterogeneous nature of the glioblastoma cells that are resistant to many therapeutic modalities. Therefore, the development of new, non-invasive, combinatorial treatment options constitutes an urgent medical need. Photodynamic therapy (PDT) is a promising therapeutic option that meets these requirements. PDT requires a light source to excite a photosensitizer (PS), which then reacts with molecular oxygen to generate reactive oxygen species. These reactive oxygen species then promote cell death via apoptosis, necrosis, or autophagy. However, the efficacy of PDT is limited by several factors: traditional photosensitizers used for PDT are organic molecules that have limited water solubility, leading to poor pharmacokinetic properties, and require excitation by UV or visible radiation, which have poor tissue penetration. This research proposal intends to use FDA-approved 5- aminolevulinic acid (5-ALA) as a prodrug to produce PpIX, a PS, for PDT treatment of glioblastoma. Since PpIX is produced endogenously and can selectively accumulate at the site of the tumor, this circumvents the challenges in targeted PS delivery. To address the second challenge, we propose to use lanthanide-doped upconversion nanoparticles (UCNPs). UCNPs have the unique capability to sequentially absorb 2 or more NIR photons and subsequently emit UV or visible photons, which can then excite PpIX to generate cell-damaging reactive oxygen species upon reaction with oxygen. Additionally, UCNPs can be designed for enhanced BBB permeability. Hence, we hypothesize that the use of NIR-excitable UCNPs with PDT can be used to treat deep-seated, highly malignant adult brain tumors and glioblastoma. Since PpIX is excited by light with wavelengths in the 600 nm (red) range, our UCNPs were engineered with manganese dopants to maximize emission intensities in this region. Results of our preliminary in vitro studies demonstrate that this UCNP-based phototherapeutic significantly inhibited the growth and colony formation, and induced apoptosis in glioblastoma cells. In this Phase I proposal, we plan to build on our UCNP-based PDT system with the following aims: Aim 1: Synthesize, characterize, and optimize UCNPs, and Aim 2: Evaluate the effect of UCNPs and NIR treatment on glioblastoma cells with and without chemo/radiation therapy. For Aim 2, we will further characterize functional and genomic studies. Successful development of these UCNPs will support future product development and evaluation of their therapeutic effect in preclinical small animal models (age and sex-matched mouse models) in Phase II. We anticipate that the successful development and evaluation of our nano-construct will ultimately provide a novel treatment option for glioblastoma and present an exciting opportunity to improve the treatment of this devastating disease.
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