Protein and peptide-based molecular nanomaterials for biomedical applications.
1. Micro- and nano-particulate drug delivery technologies for topical, regional and systemic applications: Our efforts in the drug delivery arena focus on two drug delivery technologies, one veteran and one novel, that are inventions of our group. These technologies each yield, micro and nano sized particles that are composed of biomaterials with particular emphasis on naturally occurring adhesion macromolecules as integral components for drug delivery and targeting. The two technologies we developed have the potential to resolve limitations of the other carriers. The veteran technology is named Bioadhesive Liposomes (BAL). These are drug-encapsulating liposomes that have been surface-modified by covalent binding of target-recognition agents such as hyaluronan, collagen, EGF or gelatin to their surface. Developed originally for local (topical and regional) drug therapies, recent studies have shown that nano (unilamellar) hyaluronan-liposomes are also suitable for therapies that require systemic administration. The novel technology (currently in the process of patenting), while also belonging to the particulate class of drug carriers, is an entirely new conceptual approach; it is different from liposomes and other lipid-based particles, as well as from nanospheres and microspheres, be they from biological or synthetic materials. It has a wide scope of therapeutic applications, and is suitable for both local and systemic applications. These novel carriers are, furthermore, non toxic. In all cases tested, and for both carrier technologies, the therapeutic outcomes with carrier-mediated therapy are significantly increased as compared to free drugs.
Current projects with the novel technology include:Structural characterization, in particular size, shape, surface properties and mapping of internal domains.
- Formulation studies of large and small drugs, hydrophilic and hydrophobic.
- In vitro and in vivo studies in tumor chemotherapy, focusing on syngeneic and on nude mouse tumor models.
- Gene transfection (in vitro and in vivo) and
- Drug delivery for the treatment of neurodegenerative diseases, especially exploring (in vivo) BBB bypass approaches.
2. Novel chemosensitizers for overturning multidrug resistance (MDR) to tumor chemotherapy; Chemotherapy frequently fails cancer patients due to inherent or acquired multidrug resistance (MDR). In the dominant mechanism, intracellular levels of cytotoxic drugs are reduced below their lethal thresholds due to active extrusion of the cytotoxic drug(s) from the tumor cell, operated by ATP-dependent pumps such as P-glycoprotein (Pgp), Multidrug Resistance-associated Protein (MRP), Lung Resistance-related Protein (LRP) and others. Reducing, or better yet, abolishing the extrusion, by pump inhibition, is a main approach to overturning MDR. The search for effective inhibitors (also named chemosensitizers, MDR modulators, MDR reversal agents) is now into the third generation. Chemical derivatization of 1st-generation molecules and combinatorial chemistry lead to 2nd and 3rd generation chemosensitizers. These were more potent and less toxic than 1st-generation compounds, yet many were still prone to adverse effects, to unfavorable changes in plasma pharmacokinetics (PK) of the anticancer drugs, and to poor solubility. Few are currently in early clinical trials.
Current projects in the lab include:
- Extension of the in vivo studies with the identified molecule, to include a wide repertoire of anticancer drugs and tumor types.
- Exploration of additional approved drugs from the same family of the identified one, for their potential in MDR reversal.
- Studies on the mechanism(s) by which this new class of chemosensitizers modulates MDR.
- Investigation of potential benefits from combinations of carrier-mediated chemotherapy and chemosensitizers.
For a more detailed research description.