Nanobioconjugate Based on Polymalic Acid for Brain Tumor Treatment
Cedars-Sinai Medical Center
Principal Investigator: Julia Y. Ljubimova, M.D., Ph.D.
Recent advances in nanotechnology may offer new hope for significant improvement in the success of cancer treatment, especially in preventing tumor growth and progression. This application is particularly relevant to brain gliomas that have very poor prognosis, are largely incurable by current therapy, and therefore, need novel treatment modalities. The multidisciplinary team led by Dr. Ljubimova deals with a new nanoscale (20-30 nm) anti-tumor drug delivery system (Polycefin) based on a naturally derived nanoplatform, poly(β-L-malic acid) (PMLA). The principal limitations in the design of nanobioconjugates are biodegradability, toxicity, immunogenicity, and the ability to deliver drugs to the cytoplasm of the cancer cells. These challenges were addressed by creating a universal drug delivery platform based on poly(β-l-malic acid), or PMLA, a non-toxic, non-immunogenic polymer derived from the slime mold Physarum polycephalum.
Ljubimova and colleagues present a multifunctional nanobioconjugate that is capable of carrying antisense oligonucleotides (AONs) across the blood–brain barrier (BBB) and the blood–brain tumour barrier (BTB), targeting its payload to the tumor for receptor-mediated cellular uptake, endosomal escape and release into the cancer cell cytoplasm. Using this construct, the authors demonstrated dramatic inhibition of intracranial tumor growth in xenograft mouse models of human gliomas. This universal platform may be easily modified to include new moieties covalently attached to PMLA backbone, such as anticancer drugs inhibiting tumor cell targets. The nanoplatform was developed to inhibit the synthesis of complex proteins with systemic delivery. These proteins, such as trimeric laminins play a significant role in tumor growth, invasion, and metastasis, but previously could not be blocked by conventional drugs. This project will focus on the preclinical testing of a basic nanoconjugate platform containing antisense nucleotides against glioma marker, laminin 411, a protein important for tumor vessel development together with anti-VEGF, the vascular endothelial growth factor, which plays the role in tumor vessels formation. This project aims to select a lead vehicle-drug compound from several polymer-based conjugates by detailed chemical, chemical-physical, and preclinical evaluation, which would establish a solid rationale for clinical usage.
The goal of this project is to develop a nanoplatform based on polymalic acid that can cross the blood–brain barrier and the blood–brain tumor barrier to deliver anticancer drugs into the tumor cells directly. By systemic administration of this nanoplatform, anticancer drugs will inhibit the synthesis of several tumor specific targets, such as tumor vascular protein laminin 411 which plays a significant role in glioma growth, invasion, and metastasis.