Granted Patent
B2
US 12,195,531 · App. 16/568,702 · Granted Jan 14, 2025
Cellular delivery of DNA intercalating agents
Inventors:
Robert C. Getts (Collegeville, PA); James Kadushin (Gilbertsville, PA); Mindy George-Weinstein (Wynnewood, PA); Jacquelyn Gerhart (Wynnewood, PA); Emanuela Dylgjeri (Hatfield, PA); Kelly Rhodes (Hatfield, PA)
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Abstract
Compositions and methods for targeted delivery of active agents to cells are provided. The compositions comprise a wholly or partially double-stranded synthetic DNA carrier, and an active agent intercalated in double-stranded portions of the DNA carrier. The DNA carrier may also be linked to a targeting agent. The compositions are useful for delivering an active agent into a targeted cell type, for example a cytotoxic agent.
Claims (37)
1. A method of delivering an active agent to a cell comprising contacting the cell with a pharmaceutical composition, the pharmaceutical composition comprising:
i) a DNA dendrimer comprising an active agent,
wherein the DNA dendrimer comprises a plurality of DNA monomers comprising a double-stranded region and four single-stranded arms,
wherein each DNA monomer comprises a first oligonucleotide molecule and a second oligonucleotide molecule,
wherein the first oligonucleotide molecule comprises a central portion and two terminal portions,
wherein the second oligonucleotide molecule comprises a central portion and two terminal portions,
wherein the central portion of the first oligonucleotide molecule and the central portion of the second oligonucleotide molecule are complementary to form the double-stranded region and the four single-stranded arms; and
ii) a targeting agent linked to a capture sequence complement, wherein the targeting agent is selected from the group consisting of:
a) an antibody or peptide that binds to the transferrin receptor, and
b) an antibody or peptide that binds to G8 antigen; and
wherein the capture sequence complement is complementary to one or more capture sequences ligated to one or more of the DNA dendrimer single stranded arms.
2. The method of claim 1 , wherein the targeting agent is an antibody or peptide that binds to G8 antigen, and the pharmaceutical composition is administered for prevention of posterior capsular opacification or for reducing the incidence of posterior capsular opacification.
3. The method of claim 2 , wherein the targeting agent is a monoclonal antibody that binds to G8 antigen and the active agent is doxorubicin.
4. The method of claim 1 , wherein the targeting agent is an antibody or peptide that binds to the transferrin receptor, and the pharmaceutical composition is administered for depletion of pancreatic tumor cells.
5. The method of claim 4 , wherein the targeting agent is a peptide that binds to the transferrin receptor and the active agent is doxorubicin.
6. The method of claim 1 , wherein the composition comprising the DNA dendrimer, comprising an active agent and the targeting agent linked to the DNA dendrimer through a capture sequence complement is internalized by the cells in a subject and the active agent is released into the cell, thereby delivering the active agent to the cell.
7. The method of claim 6 , wherein the active agent is intercalated in the double-stranded region of the DNA monomer.
8. The method of claim 1 , wherein the contacting the cell comprises administering the composition to a patient.
9. The method of claim 1 , wherein the active agent is intercalated in the double-stranded region of the DNA monomers.
10. The method of claim 9 , wherein the active agent is intercalated in the double-stranded region of the DNA monomers through hydrogen bonding.
11. The method of claim 1 , wherein the active agent is selected from the group consisting of chemotherapeutics, anti-infective agents, antimalarial agents, antiviral agents, and antifungal agents.
12. The method of claim 1 , wherein the active agent is berberine, an acridine, daunomycin, doxorubicin, daunorubicin, dactinomycin, cisplatin, carboplatin, or thalidomide.
13. The method of claim 1 , wherein 10-15% of the DNA dendrimer single-stranded arms are ligated to a capture sequence of the one or more capture sequences.
14. The method of claim 1 , wherein 2-5 targeting agents are attached per DNA dendrimer.
15. A method of delivering an active agent to a cell comprising contacting the cell with a pharmaceutical composition, the pharmaceutical composition consisting essentially of:
i) a DNA dendrimer comprising an active agent,
wherein the DNA dendrimer comprises a plurality of DNA monomers comprising a double-stranded region and four single-stranded arms,
wherein each DNA monomer comprises a first oligonucleotide molecule and a second oligonucleotide molecule,
wherein the first oligonucleotide molecule comprises a central portion and two terminal portions,
wherein the second oligonucleotide molecule comprises a central portion and two terminal portions,
wherein the central portion of the first oligonucleotide molecule and the central portion of the second oligonucleotide molecule are complementary to form the double-stranded region and the four single-stranded arms; and
ii) a targeting agent linked to a capture sequence complement, wherein the targeting agent is selected from the group consisting of:
a) an antibody or peptide that binds to the transferrin receptor, and
b) an antibody or peptide that binds to G8 antigen; and
wherein the capture sequence complement is complementary to one or more capture sequences ligated to one or more of the DNA dendrimer single stranded arms.
16. The method of claim 15 , wherein 10-15% of the DNA dendrimer single-stranded arms are ligated to a capture sequence of the one or more capture sequences.
17. The method of claim 15 , wherein 2-5 targeting agents are attached per DNA dendrimer.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 29, 2021
From: GENISPHERE, LLC
To: CODE BIOTHERAPEUTICS, INC.
Reel/Frame 057023/0151 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 28, 2021
From: GETTS, ROBERT C.; KADUSHIN, JAMES; DYLGJERI, EMANUELA; RHODES, KELLY
To: GENISPHERE, LLC
Reel/Frame 057001/0175 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 28, 2021
From: GEORGE-WEINSTEIN, MINDY; GERHART, JACQUELYN
To: LANKENAU INSTITUTE OF MEDICAL RESEARCH
Reel/Frame 057003/0265 →
Continuity (4)
Division
14778716
Provisional Application
61803863
· Mar 21, 2013
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