Abstract 5142: Molecular intersection of a 3-in-1 nanomedicine targeting microtubules, ERK tyrosine kinases with profound nuclear modulations, and quantum imaging for hepatocellular carcinoma therapy
Authors: Poojari Radhika J. , Srivastava Rohit , Panda Dulal 
Published: July 2017

Hepatocellular carcinoma is the fifth malignant form of cancer worldwide with poor survival rates. Despite advances in clinical diagnosis, surgery and chemotherapy till date systemic treatment of solid tumour like hepatocellular carcinoma has not been effective in most cases and its clinical therapy is a major challenge. Hence, it is important to search for innovative therapeutic modalities. Nanomedicines that can target both microtubules and kinases may provide new avenues to treat hepatocellular carcinoma. Small molecule inhibitors like docetaxel and sorafenib represent one of them. Clinical trials have revealed unacceptable toxicities such as neutropenia, severe hypersensitivity, anaphylactic reaction, hypertension, dermatological toxicities and hand-foot skin reaction, etc with these drugs in cancer patients. Other major drawbacks are insolubility, poor bioavailability, short half-life and non-specificity. To mitigate these issues, we developed a next generation highly compact nanocarrier system, the 3-in-1 nanomedicine platform with in-depth understanding of the intracellular machinery responsible for its uptake and the molecular mechanisms for regulating the delivery efficacy. Development of a 3-in-1 nanomedicine (100-200 nm) comprised of microtubule inhibitor docetaxel, tyrosine kinase inhibitor sorafenib and an imaging probe quantum dots encapsulated in a biocompatible polymer PLA against human hepatocellular carcinoma cells. Monotherapy strategies in cancer treatment fail due to several complex issues like narrow therapeutic window, non-specificity, administration of higher, repetitive doses, adverse clinical toxicities and resistance mechanisms of drugs. The advantages of 3-in-1 nanomedicine strategy are delineated. The real-time imaging of quantum dots in hepatocellular carcinoma cells showed accelerated internalization. The 3-in-1 nanomedicine exhibited potent inhibition in hepatocellular carcinoma cell proliferation, clonogenicity, induced strong G2/M phase block and apoptosis induction in comparison to single drug monotherapy. The 3-in-1 nanomedicine strongly promoted the microtubule bundling via increased polymer tubulin expression level, augmented multinucleation, aberrant mitosis, and significantly inhibited downstream protein tyrosine kinase, ERK1/2 activation in hepatocellular carcinoma cells in comparison to single drug monotherapy. These findings provide a significant insight into the intrinsic molecular interplays of 3-in-1 nanomedicine in hepatocellular carcinoma cells. The 3-in-1 nanomedicine integrates several avenues in a single nanoscale-platform for dual-drug delivery, and high sensitivity quantum dots imaging as well as diagnostics for hepatocellular carcinoma therapy, holding high translational research potentials in the near future.

Citation Format: Radhika J. Poojari, Rohit Srivastava, Dulal Panda. Molecular intersection of a 3-in-1 nanomedicine targeting microtubules, ERK tyrosine kinases with profound nuclear modulations, and quantum imaging for hepatocellular carcinoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5142. doi:10.1158/1538-7445.AM2017-5142