Cedars-Sinai Medical Center, USA
The author has received his PhD in Germany 1967 in Chemistry and his venialegendi 1974 in Biochemistry. After ground breaking research in enzymology and pharmacology, he joined 2008 the emerging Nanodrug Research Center at Cedars-Sinai Medical Center, Los Angeles, California, and introduced polymalic acid as a biodegradable and versatile platform for drug delivery.Project supported by Martz Translational Breast Cancer Research Discovery Fund.
Biodegradable polymers such as polylacticor polyglycolic acidwhen conjugated withpolyethylene glycolfind wide applicationsas material for nanoparticles due totheir selfassociationin aqueous milieu. Self assembly restricts these polymers to spending their surfacefor intermolecular contacts and allows only one or a few covalentattachments on the interface to bulk solvent.In contrast, biopolymers composed of units with pendant functional groups can usemultiple attachmentsto obtainhighly reactive nanobrushes. Such aparticularly useful biopolymer is poly(β-L-malic acid), which can be obtained in high purity frombiological sources. Among these covalently attached functional groups are antibodies, antisense oligonucleotides and/or chemotherapeutic prodrugs, membrane destabilizing peptides, protecting polyethylene glycol, gadolinium MRI contrast agent and fluorophores for imaging. While being biodegradable and nontoxic, these nano conjugates have demonstrated high efficacy in the treatment of brain and breast cancer and proven as powerful MRI contrast agents for the diagnosis of primary and metastatic brain tumors in preclinical animal models. Because antibodies obscure the nanobrush character, we replace them by affinity peptides. These polymalic acid-based nanobrushes are expected to have, among other advantages, reduced manufacturing costs, increased loading capacity,increased shelf stability, superior penetration efficacy into deep tumor tissue,reduced immunogenicity. We have succeeded in the design of such nanobrushes using public referenced receptor-specific affinity peptides. The brake through was finding appropriate linkers for optimal geometric arrangements. Emerging resultsobtained by in vivo imaging demonstrated excellent tumor specificityidentifyinghuman HER2-positive breast cancer orsolid brain tumor.
Speaker PPTsDownload PPT