|
 |
One of the founders of Acornex has successfully designed and prepared novel molecular carrier vectors whose structures consist of a scaffold (inositol, carbohydrate for example) and an appropriate number (5-9) of the guanidine residues linked to the scaffold via a highly flexible and variable chain length of Ω-amino carboxylic acid. In addition, the carrier design has the necessary attachment
arms (X and Y) for targeting and/or
|
|
lipophilicity-modulating group as shown in the Scheme. This molecular design has the following desirable features: 1) Molecular size and weight are minimal, since the scaffolds chosen have the highest functionality density among all organic compounds. 2) The scaffolds are naturally occurring with reasonably well understood physicochemical and biological properties. 3) The scaffold molecules,
namely carbohydrates are economical starting material without discernible toxicity. 4) A diverse linker design can modulate the lipophilicity and geometric flexcibility, as well as the ease of the hydrolytic dissolution.
It has been demonstrated that many of these molecular carrier vectors could efficiently cross several types of mammalian cell membrane (Cos-7, Raw264.7 and HeLa) and blood-brain barrier(BBB) in mice, either alone or when conjugated to a drug cargo (for example, quinolone antibacterials, doxorubicin and taxol anticancers, nucleoside reverse transcriptase inhibitor antivirals, e. g. AZT). The carrier vector alone did not show discernable cell toxicity, but when conjugated to doxorubicin, they showed
much enhanced cell killing effect at micromolar concentrations. In addition, the carrier-taxol conjugates showed much enhanced aqueous solubility, for example. Certain modified carriers were also found to enhance the transfection efficiency in the luciferase gene delivery with NIH/3T3 cells as a simple carrier/DNA complex or preferably in the form of lipid vesicles (MEND), and the degree of enhancement was equal to or better than those observed with Lipofectin. In another application, the proprietary carrier
vectors displayed excellent properties as condensing agent of siRNA for inhibiting the luciferase gene expression in HeLa cells. Yet another type of carriers were found to show a high targeting affinity for mitochondria, and thus these carriers are expected to have a major contribution in studying and developing therapeutic agents for various mitochondrial diseases.
Design features of novel molecular carriers
|
Hence, the proprietary delivery technology based on these novel carrier vectors may be used to dramatically improve the bioavailability of many types of drug molecules: small molecules, peptides, proteins and nucleotides and genes. The technology will be applicable to approved drugs with demonstrated clinical values but with limited indication spectrums, as well as drug candidates with promising in vitro activities but low solubility or cellular uptake. Preliminary experiments also suggest that these carrier vectors will be effective in delivering cargo molecules in the manner of non-conjugate complex.
In the initial phase of developmental work, Acornex will be demonstrating that 1) the carrier-doxorubicin and carrier-taxol (taxotere) can indeed be used to cause remission of the brain cancer (glioblastoma) and to increase the survival rate in the mouse model, 2) the carrier-AZT conjugate can be used to treat the HIV-induced encephalopathy, 3) delivery of the nucleotides (gene, antisense, siRNA) could be optimized by using our carriers either as surface-modifying agent or condensing agent, 4) BBB-permeable inositol derivatives could be used as therapeutic/prophylactic agents for Alzheimer’s disease, and 5) BBB-permeable trehalose derivatives could be employed as a therapeutic/ prophylactic agents for Huntington's disease. Furthermore, we plan to develop carrier vectors with highly selective targeting properties for certain intracellular organelles and tissue types. We will also develop practical experimental protocols to enhance non-conjugative delivery of drug molecules for gene therapy and skin related diseases.
|
