Methods, compositions and systems for local delivery of drugs
Implantable medical device eluting drug locally and in a prolonged fashion are provided.
1. A method of treating a solid tumor in a subject, the method comprising the step of implanting an implant within said solid tumor or into a tumor bed thereof, wherein said implant is a solid matrix that has a volume between 0.1-1000 mm 3 , and said solid matrix comprises:
A. a biocompatible polymeric matrix, comprising a polymer selected from the group consisting of poly(glycolide-co-lactide) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), and polycaprolactone (PCL); and
B. an RNAi (RNA interference) agent that targets an oncogene or a tumor-promoting factor within said tumor, wherein said RNAi agent is incorporated within said biocompatible polymeric matrix and treats said tumor,
wherein the amount of said RNAi agent is at least 1:20 weight/weight of the amount of said polymer in said biocompatible polymeric matrix.
2. The method according to claim 1 , wherein said implant further comprises mannitol.
3. The method according to claim 1 , wherein said RNAi agent is selected from the group consisting of a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a Dicer-substrate siRNA (DsiRNA), a locked nucleic acid (LNA), a microRNA, and a non-coding RNA.
4. The method according to claim 1 , wherein said oncogene is a mutated K-ras gene.
5. The method according to claim 4 , wherein said mutated K-ras gene is K-ras G12D.
6. The method according to claim 1 , wherein said RNAi agent is conjugated to a substance selected from the group consisting of cholesterol, palmitate, α-tocopherol (Vitamin E), a protein transduction domain, a membrane-penetrating peptide, a multi-component polymer system, and a lipophilic moiety.
7. The method according to claim 1 , wherein said RNAi agent is complexed with a substance selected from the group consisting of a cationic peptide, spermin, phosphatidylethanolamine (cephalin), L-α-cephalin, DOTAP, DOPE, polyethyleneimine (PEI), a derivative of PEI, a polyamine, a cationic polymer, a lipid, a non-cationic polymer, and a natural polymer.
8. The method according to claim 1 , wherein said implant is configured to be implantable using a needle and cylindrically shaped having a diameter between 17 gauge and 19 gauge.
9. The method according to claim 1 , wherein the amount of said RNAi agent in said implant is at least 4 μg.
10. The method according to claim 1 , wherein said implant further comprises polymeric fibers encapsulating said RNAi agent.
11. The method according to claim 1 , wherein said biocompatible polymeric matrix comprises nanoparticles.
12. The method according to claim 1 , wherein said implant further comprises a polymeric envelope.
13. A method of treating a solid tumor in a subject, the method comprising the step of implanting an implant within said solid tumor or into a tumor bed thereof, wherein said implant is a solid matrix that has a volume between 0.1-1000 mm 3 , and said solid matrix comprises:
A. a biocompatible polymeric matrix comprising poly(glycolide-co-lactide) (PLGA) and mannitol; and
B. an RNAi (RNA interference) agent that targets an oncogene or a tumor-promoting factor within said tumor, wherein said RNAi agent is incorporated within said biocompatible polymeric matrix;
wherein the amount of said RNAi agent is at least 1:20 weight/weight of the amount of said PLGA in said biocompatible polymeric matrix,
and wherein said implant, when implanted into a subject's body tissue, treats said tumor and has an effective release period comprising 10 weeks.
14. The method according to claim 13 , wherein said PLGA has a ratio of polylactic acid (PLA) and polyglycolic acid (PGA) of greater than 75:25.