Recent advances in nanotechnology may offer a new hope for a significant improvement and success of cancer treatment, especially in preventing tumor growth and progression. This is particularly relevant to brain gliomas that have very poor prognosis, are largely incurable by current therapy, and therefore, need novel treatment modalities. Our research is dealing with a new nanoscale (20-30 nm) anti-tumor drug delivery system (Polycefin) based on naturally derived nanoplatform, poly(p-L-malic acid) (PMLA) fi-om a slime mold, Physarum polycephalum. This universal platform may be easily modified to include new moieties covalently attached to PMLA backbone, such as anti-cancer drugs inhibiting tumor cell targets. The current version of the delivery platform contains: biodegradable, non-toxic, and non-immunogenic PMLA;a drug releasing unit;Morpholino antisense oligonucleotide (AON) unit targeting two chains of angiogenic glioma-increased protein laminin 411;anti-transferrin receptor antibody for specific tissue targeting and endosomal uptake;biopolymer protector polyethylene glycol (PEG);a hydrophobic release unit for endosomal membrane disruption;and a fluorescent tracking dye. 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 because by conventional drugs. Preliminary data demonstrated drug delivery directly to the brain tumor site, inhibition of glioma molecular targets (laminin chains), and lack of visible toxicity in vivo. As a result, a 60% increase in survival of glioma bearing animals (p<0.01) with 10-fold tumor size reduction (p<0.01) was achieved. This I.V. systemic delivery system will be evaluated and developed in this proposal. The project will focus on the preclinical testing of basic nanoconjugate platform containing AON against our characterized glioma marker, laminin 411, a protein important for tumor vessel development. The ultimate goal is 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.
Our Aims i nclude (1) chemical optimization of Polycefin variants for the most efficient blocking of laminin 411 by varying the number of AON and targeting antibody molecules;(2) chemical, physical and pharmacokinetic characterization of the platform including studies of stability, in vivo half-life and tissue accumulation;(3) optimization of the number of injections and dosage for the most effective tumor treatment;and (4) GLP-compliant study of drug pharmacological properties (toxicity, distribution, metabolism and excretion).
This project is relevant to the NIH announcement RFA-CA-05-026 """"""""Cancer Nanotechnology Platform Partnerships"""""""" (UOl). Our multidisciplinary team created a new nanoscale (20-30 lun) anti-tumor drug delivery system based on poly(P-L-malic acid) (PMLA). This universal platform may IK easily modified to include new moieties covalently attached to PMLA backbone, such as anti-cancer drugs inhibiting tumor cell targets. This is particularly relevant to brain gliomas that have very poor prognosis, are largely incurable by current therapy, and therefore, need novel treatment modalities. The nanoplatform was developed to inhibit the synthesis of several tumor specific targets that play a significant role in tumor growth, invasion and metastasis, but previously could not be blocked by conventional drugs.
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