Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers
Nanoscale coordination polymer nanoparticles for the co-delivery of multiple therapeutic agents are described. The multiple therapeutic agents can include a combination of different chemotherapeutic agents, a combination of one or more chemotherapeutic agents and one or more nucleic acids, such as small interfering RNA (siRNA) or microRNA, a combination of one or more chemotherapeutic agents and a photosensitizer (i.e., for use in photodynamic therapy), or a plurality of different siRNAs. Pharmaceutical formulations including the nanoparticles, methods of using the nanoparticles to treat cancer, and methods of making the nanoparticles are also described.
1. A nanoscale particle for co-delivery of a plurality of therapeutic agents, wherein the plurality of therapeutic agents comprise at least one non-nucleic acid chemotherapeutic agent and at least one nucleic acid therapeutic agent, said nanoscale particle comprising:
a core comprising a metal bisphosphonate coordination polymer comprising a multivalent metal ion and a bisphosphonate, wherein the bisphosphonate is a prodrug of a platinum-based chemotherapeutic agent; and
wherein the core is coated with a lipid bilayer comprising (i) a cationic lipid, wherein at least one nucleic acid therapeutic agent is attached to the cationic lipid via electrostatic interactions; or (ii) a functionalized lipid, wherein said functionalized lipid is a thiol- or dithiol-functionalized lipid covalently bonded to at least one nucleic acid therapeutic agent.
2. The nanoscale particle of claim 1 , wherein the at least one nucleic acid therapeutic agent is a siRNA, a miRNA, or an AS ODN.
3. The nanoscale particle of claim 2 , wherein the at least one nucleic acid therapeutic agent is selected from the group consisting of survivin siRNA, ERCC-1 siRNA, P-glycoprotein siRNA (P-gp siRNA), Bcl-2 siRNA, or a mixture thereof.
4. The nanoscale particle of claim 1 , wherein the lipid bilayer further comprises: a passivating agent; a targeting agent; and/or an imaging agent.
5. The nanoscale particle of claim 1 , wherein the multivalent metal ion is selected from the group consisting of Ca 2+ , Mg 2+ , Mn 2+ , Zn 2+ , and combinations thereof.
6. The nanoscale particle of claim 1 , wherein the bisphosphonate is a cisplatin or oxaliplatin prodrug.
7. The nanoscale particle of claim 6 , wherein the bisphosphonate is an oxaliplatin prodrug.
8. The nanoscale particle of claim 6 , wherein the bisphosphonate is a cisplatin prodrug.
9. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising a nanoscale particle of claim 1 .
10. The method of claim 9 , wherein the cancer is selected from lung cancer, pancreatic cancer, ovarian cancer, breast cancer and colon cancer.
11. The method of claim 9 , wherein the cancer is ovarian cancer, optionally a cisplatin resistant ovarian cancer.
12. A method of preparing a nanoscale particle of claim 1 , the method comprising:
(a) contacting a microemulsion comprising a metal ion with a microemulsion comprising a bisphosphonate, optionally wherein the bisphosphonate is a cisplatin or oxaliplatin prodrug, thereby forming a metal bisphosphonate coordination polymer nanoparticle;
(b) dispersing the nanoparticle from (a) in a solution comprising a cationic lipid and/or a functionalized lipid to form a cationic lipid-coated and/or functionalized lipid coated nanoparticle; and
(c) contacting the lipid-coated nanoparticles with a solution comprising at least one nucleic acid therapeutic agent.
13. A pharmaceutical formulation comprising a nanoscale particle of claim 1 and a pharmaceutically acceptable carrier.