Pharmacological activity of a therapeutic agent is an outcome of two independent variables. Equilibrium constant can reflect how well an agent fits its target. Prerequisite for a successful therapeutic outcome from this molecular interaction is a sufficient amount of free drug molecules, i.e., thermodynamic activity, in the vicinity of the target site for a desired period of time. While the former constitutes the backbone of classical medicinal chemistry, my research program focuses exclusively on the drug delivery from the bench to the target site in vivo.

With rapidly advancing knowledge in cell/molecular biology and better understanding of pathogenesis of a disease state at the molecular level, contemporary and future medicine deals with various macromolecular agents of high therapeutic potential. It ranges from peptidomimetics, proteins, oligonucleotides, to genes. This trend has inevitably resulted in a great challenge in terms of in vivo, particularly in vivo cellular, delivery. My lab has been addressing some of the basic issues in contemporary molecular pharmaceutics that are essential in developing biotechnology-derived macromolecular therapeutics.

Cellular Delivery of Antisense/siRNA Oligonucleotides

Our curretn approach exploits so-called proton-sponge effect for the endosome-to-cytosol transfer and receptor-mediated endocytosis for cell-specific targeting.   At present, we are targeting hepatocyte vis asialoglycoprotein receptor using a synthetic ligand that carries three  copies of galactosamine. A weak base-containing polymer serves as the carrier backbone onto which oligonucleotide and the ligand are all chemically grafted. Pharmacokinetic consideration mandates pegylation.

Antibodies as a Carrier of CpG Oligonucleotides to Solid Tumors

Due to their prolonged t_1/2, naturally occurring antibodies (especially IgG isotype) are an ideal high-affinity low-capacity drug carrier for potent drugs that exhibit poor systemic pharmacokinetics. An example of such an agent is immunostimulatory oligonucleotides containing CpG motif. An important requirement in this approach is that the immune complex (IC) be in a 1:1 stoichio-metric ratio.   To this end, high-affinity monomeric (1:1) ICs between anti-dinitrophenyl (DNP) IgG and DNP-derivatized CpG-ODNs were formulated by modulating the valence, inter-epitope (DNP) linker length and flexibility of CpG-ODNs. Systemically-administered ICs are expected to preferentially accumulate in peritumoral areas due to the enhanced permeability and retention effect (EPR) exhibited by solid tumors.  Systemic administration of long-circulating ICs could result in a reduced therapeutic dose and dosing frequency. It could also allow for the treatment of occluded or metastasized tumors. Once at the tumor periphery, ICs are expected to be actively taken up by peritumoral dendritic cells and macrophages via FcR-mediated endocytosis.  In the endosome, IC dissociation is mediated by the acidic endosomal pH, effectively freeing CpG-ODN to bind its endosomal receptor, TLR9 and mount a powerful anti-tumor immune response.

Fatty acids bind albumin with an association constant comparable to that involved in antigen-antibody interactions. This high-affinity binding is a result of not only hydrophobic interaction between the binding pocket and inserting long alkyl chain but also electrostatic attraction between carboxylate anion and the positively charged periphery of the binding pocket. Our novel chemical conjugation efforts attempt to maintain and maximize these interactions. Interestingly both IgG and albumin are ligands of so-called Brambell receptor (also known as FcRn receptor) and hence share equally long circulatory t_1/2.  What is applicable to IgG discussed above is thus also applicable to albumin.