Poly(beta malic acid) with pendant Leu-Leu-Leu tripeptide for effective cytoplasmic drug delivery
The invention relates to the use of Polycefin-LLL nanoconjugate as a means of cytoplasmic delivery of drugs. In one embodiment, the present invention provides a drug delivery molecule, comprising a polymerized carboxylic acid molecular scaffold covalently linked to L-leucylleucylleucine. In another embodiment, the Polycefin-LLL includes drug antisense morpholino oligos, targeting antibodies, and a pH-sensitive endosome escape unit. In addition, the drug could be siRNA, microRNA, and aptamer.
1. A method of decreasing the volume of a tumor in an individual, comprising:
providing a composition including a drug delivery system configured to destabilize an endosome membrane, wherein the drug delivery system comprises a polymerized polymalic acid molecular scaffold having a plurality of pendant carboxyl groups and one or more biologically active molecular modules, wherein the one or more biologically active molecular modules includes L-leucylleucylleucine and an anticancer agent, each of the one or more biologically active molecular modules is covalently linked to a pendant carboxyl group of the polymerized polymalic acid molecular scaffold; and
administering the composition to the individual.
2. The method of claim 1 , wherein the anticancer agent comprises a nucleic acid-based therapeutic.
3. The method of claim 1 , wherein the tumor is a glioma.
4. The method of claim 2 , wherein the nucleic acid-based therapeutic inhibits protein synthesis of laminin-411.
5. The method of claim 4 , wherein the nucleic acid-based therapeutic comprises a Laminin α4 antisense polynucleotide and/or β1 antisense polynucleotide.
6. The method of claim 5 , wherein the Laminin α4 antisense polynucleotide comprises the 5′ to 3′ polynucleotide sequence described as SEQ. ID. NO.: 1.
7. The method of claim 5 , wherein the Laminin β1 antisense polynucleotide comprises the 5′ to 3′ polynucleotide sequence described as SEQ. ID. NO.: 2.
8. The method of claim 5 , wherein the one or more biologically active molecular modules further comprises a targeting antibody.
9. The method of claim 1 , wherein the step of providing the composition includes synthesizing the drug delivery system, comprising providing a quantity of a L-leucylleucylleucine; providing a quantity of a polymalic acid; and conjugating the L-leucylleucylleucine with the polymalic acid.
10. The method of claim 9 , wherein the polymalic acid comprises PMLA.
11. The method of claim 9 , wherein L-leucylleucylleucine is conjugated with the polymalic acid by an amide bond.
12. The method of claim 8 , wherein the step of administering comprises delivering the composition to the individual at a concentration of up to 1 mg/mL.
13. The method of claim 1 , wherein the composition is administered systemically.
14. The method of claim 1 , wherein the composition is administered near the tumor.
15. The method of claim 1 , wherein the composition is administered by an intra-tumoral injection.
16. The method of claim 1 , wherein the composition is administered by an implantable device from which the composition elutes.
17. The method of claim 1 , wherein the composition is administered subcutaneously, intraperitoneally and/or intravenously.