Micelles for the solubilization of gossypol
Patent Number: US20120321715
Executive Summary:
General Description:
As cancer research progresses, it is increasingly evident that single drug formulations provide only limited treatment success. Patients would therefore benefit from the development of suitable combination therapies. One of the most important requirements of combination therapy is a simple and efficacious drug delivery system. Many currently used chemotherapeutics are poorly water soluble, which significantly complicates the process of partnering the chemotherapeutic with a suitable delivery system.
The invention provides micelle compositions that include an aqueous solvent system and drug-encapsulating micelles. The micelles can include a variety of polymers having an average molecular weight of about 1,000 to about 30,000. The polymers can be poloxamer polymers or PEG-b-PCL polymers. The polymers form micelles, encapsulating a drug within the micelle structure and increasing solubility and bioavailability of the chemotherapeutic agents that target more than one cancer cell growth mechanistic pathway.
Scientific Progress:
Radiosensitizing properties of the micelles carrying combination of three anti-cancer drugs has been recently reported (ref. 3, 6).
Future Directions:
Clinical trials
Strengths:
Patent Status:
Publications:
1: Tomoda K, Chiang HC, Kozak KR, Kwon GS. Injectable (-)-gossypol-loaded Pluronic P85 micelles for cancer chemoradiotherapy. Int J Radiat Biol. 2017 Apr;93(4):402-406. doi: 10.1080/09553002.2016.1257833. Epub 2016 Dec 9. PubMed PMID: 27827005; PubMed Central PMCID: PMC5379640.
2: Tam YT, Gao J, Kwon GS. Oligo(lactic acid)n-Paclitaxel Prodrugs for Poly(ethylene glycol)-block-poly(lactic acid) Micelles: Loading, Release, and Backbiting Conversion for Anticancer Activity. J Am Chem Soc. 2016 Jul 20;138(28):8674-7. doi: 10.1021/jacs.6b03995. Epub 2016 Jul 11. PubMed PMID:
27374999.
3: Tomoda K, Tam YT, Cho H, Buehler D, Kozak KR, Kwon GS. Triolimus: A Multi-Drug Loaded Polymeric Micelle Containing Paclitaxel, 17-AAG, and Rapamycin as a Novel Radiosensitizer. Macromol Biosci. 2017 Jan;17(1). doi: 10.1002/mabi.201600194. Epub 2016 Jul 1. PubMed PMID: 27365266; PubMed Central PMCID: PMC5320892.
4: Alvarez C, Shin DH, Kwon GS. Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B. Pharm Res. 2016 Sep;33(9):2098-106. doi: 10.1007/s11095-016-1948-7. Epub 2016 May 19. PubMed PMID: 27198671; PubMed Central PMCID: PMC4967395.
5: Cho H, Gao J, Kwon GS. PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels for drug delivery. J Control Release. 2016 Oct 28;240:191-201. doi: 10.1016/j.jconrel.2015.12.015. Epub 2015 Dec 15. PubMed PMID: 26699425; PubMed Central PMCID: PMC4909590.
6: Tomoda K, Chiang C, Kozak KR, Kwon GS. Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers. AAPS J. 2015 Nov;17(6):1369-75. doi: 10.1208/s12248-015-9809-6. Epub 2015 Aug 6. PubMed PMID: 26246329; PubMed Central PMCID: PMC4627454.
7: Cho H, Lai TC, Tomoda K, Kwon GS. Polymeric micelles for multi-drug delivery in cancer. AAPS PharmSciTech. 2015 Feb;16(1):10-20. doi: 10.1208/s12249-014-0251-3. Epub 2014 Dec 11. Review. PubMed PMID: 25501872; PubMed Central PMCID: PMC4309804.
8: Cho H, Cho CS, Indig GL, Lavasanifar A, Vakili MR, Kwon GS. Polymeric micelles for apoptosis-targeted optical imaging of cancer and intraoperative surgical guidance. PLoS One. 2014 Feb 26;9(2):e89968. doi: 10.1371/journal.pone.0089968. eCollection 2014. PubMed PMID: 24587157; PubMed Central PMCID: PMC3935963.
9: Cho H, Lai TC, Kwon GS. Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer. J Control Release. 2013 Feb 28;166(1):1-9. doi: 10.1016/j.jconrel.2012.12.005. Epub 2012 Dec 13. PubMed PMID: 23246471; PubMed Central PMCID: PMC3565042.
10: Hasenstein JR, Shin HC, Kasmerchak K, Buehler D, Kwon GS, Kozak KR. Antitumor activity of Triolimus: a novel multidrug-loaded micelle containing Paclitaxel, Rapamycin, and 17-AAG. Mol Cancer Ther. 2012 Oct;11(10):2233-42. doi: 10.1158/1535-7163.MCT-11-0987. Epub 2012 Aug 14. PubMed PMID: 22896668; PubMed Central PMCID: PMC3469732.
11: Shin HC, Cho H, Lai TC, Kozak KR, Kolesar JM, Kwon GS. Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin. J Control Release. 2012 Oct 10;163(1):93-9. doi: 10.1016/j.jconrel.2012.04.024. Epub 2012 Apr 23. PubMed PMID: 22549011; PubMed Central PMCID: PMC3422612.
12: Shin HC, Alani AW, Cho H, Bae Y, Kolesar JM, Kwon GS. A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs. Mol Pharm. 2011 Aug 1;8(4):1257-65. doi: 10.1021/mp2000549. Epub 2011 Jun 23. PubMed PMID: 21630670; PubMed Central PMCID: PMC4896148.
Inventor Bio: Glen Kwon
https://apps.pharmacy.wisc.edu/sopdir/glen_kwon/
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Granted
- Patent Link: https://patents.google.com/patent/US20120321715/
- Research Institute: University of Wisconsin
- Disease Focus: Cancer
- Basis of Invention: Many anti-cancer drugs and their combinations are poorly soluble in aqueous solutions. Poloxamer micelles increase their solubility in water
- How it works: Poloxamers form 15-150 nm micelles encapsulate the anti-cancer drugs. The drugs, in turn, stimulate formation of the micelles
- Lead Challenge Inventor: Glen S. Kwon
- Inventors: Glen S. Kwon, Ho-Chul Shin, Hyunah Cho
- Development Stage: Pre-clinical: in vivo data in mouse model of human ovarian cancer
- Novelty:
- Anti-cancer drug gossypol promotes formation of micelles by poloxamer to form micelles at room temperature
- The micelles are formed even at low concentrations of poloxamer
- Clinical Applications:
- Administration of high doses of gossypol
- Administration of combinations of gossypol, paclitaxel, and cyclopamine, their derivatives, or other anti-cancer drug combinations
General Description:
As cancer research progresses, it is increasingly evident that single drug formulations provide only limited treatment success. Patients would therefore benefit from the development of suitable combination therapies. One of the most important requirements of combination therapy is a simple and efficacious drug delivery system. Many currently used chemotherapeutics are poorly water soluble, which significantly complicates the process of partnering the chemotherapeutic with a suitable delivery system.
The invention provides micelle compositions that include an aqueous solvent system and drug-encapsulating micelles. The micelles can include a variety of polymers having an average molecular weight of about 1,000 to about 30,000. The polymers can be poloxamer polymers or PEG-b-PCL polymers. The polymers form micelles, encapsulating a drug within the micelle structure and increasing solubility and bioavailability of the chemotherapeutic agents that target more than one cancer cell growth mechanistic pathway.
Scientific Progress:
Radiosensitizing properties of the micelles carrying combination of three anti-cancer drugs has been recently reported (ref. 3, 6).
Future Directions:
Clinical trials
Strengths:
- Stability, biocompatibility, and low toxicity of the drug delivery agent
- Solid pre-clinical validation
Patent Status:
- Filing date 2012-05-04
- Publication date 2012-12-20
Publications:
1: Tomoda K, Chiang HC, Kozak KR, Kwon GS. Injectable (-)-gossypol-loaded Pluronic P85 micelles for cancer chemoradiotherapy. Int J Radiat Biol. 2017 Apr;93(4):402-406. doi: 10.1080/09553002.2016.1257833. Epub 2016 Dec 9. PubMed PMID: 27827005; PubMed Central PMCID: PMC5379640.
2: Tam YT, Gao J, Kwon GS. Oligo(lactic acid)n-Paclitaxel Prodrugs for Poly(ethylene glycol)-block-poly(lactic acid) Micelles: Loading, Release, and Backbiting Conversion for Anticancer Activity. J Am Chem Soc. 2016 Jul 20;138(28):8674-7. doi: 10.1021/jacs.6b03995. Epub 2016 Jul 11. PubMed PMID:
27374999.
3: Tomoda K, Tam YT, Cho H, Buehler D, Kozak KR, Kwon GS. Triolimus: A Multi-Drug Loaded Polymeric Micelle Containing Paclitaxel, 17-AAG, and Rapamycin as a Novel Radiosensitizer. Macromol Biosci. 2017 Jan;17(1). doi: 10.1002/mabi.201600194. Epub 2016 Jul 1. PubMed PMID: 27365266; PubMed Central PMCID: PMC5320892.
4: Alvarez C, Shin DH, Kwon GS. Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B. Pharm Res. 2016 Sep;33(9):2098-106. doi: 10.1007/s11095-016-1948-7. Epub 2016 May 19. PubMed PMID: 27198671; PubMed Central PMCID: PMC4967395.
5: Cho H, Gao J, Kwon GS. PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels for drug delivery. J Control Release. 2016 Oct 28;240:191-201. doi: 10.1016/j.jconrel.2015.12.015. Epub 2015 Dec 15. PubMed PMID: 26699425; PubMed Central PMCID: PMC4909590.
6: Tomoda K, Chiang C, Kozak KR, Kwon GS. Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers. AAPS J. 2015 Nov;17(6):1369-75. doi: 10.1208/s12248-015-9809-6. Epub 2015 Aug 6. PubMed PMID: 26246329; PubMed Central PMCID: PMC4627454.
7: Cho H, Lai TC, Tomoda K, Kwon GS. Polymeric micelles for multi-drug delivery in cancer. AAPS PharmSciTech. 2015 Feb;16(1):10-20. doi: 10.1208/s12249-014-0251-3. Epub 2014 Dec 11. Review. PubMed PMID: 25501872; PubMed Central PMCID: PMC4309804.
8: Cho H, Cho CS, Indig GL, Lavasanifar A, Vakili MR, Kwon GS. Polymeric micelles for apoptosis-targeted optical imaging of cancer and intraoperative surgical guidance. PLoS One. 2014 Feb 26;9(2):e89968. doi: 10.1371/journal.pone.0089968. eCollection 2014. PubMed PMID: 24587157; PubMed Central PMCID: PMC3935963.
9: Cho H, Lai TC, Kwon GS. Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer. J Control Release. 2013 Feb 28;166(1):1-9. doi: 10.1016/j.jconrel.2012.12.005. Epub 2012 Dec 13. PubMed PMID: 23246471; PubMed Central PMCID: PMC3565042.
10: Hasenstein JR, Shin HC, Kasmerchak K, Buehler D, Kwon GS, Kozak KR. Antitumor activity of Triolimus: a novel multidrug-loaded micelle containing Paclitaxel, Rapamycin, and 17-AAG. Mol Cancer Ther. 2012 Oct;11(10):2233-42. doi: 10.1158/1535-7163.MCT-11-0987. Epub 2012 Aug 14. PubMed PMID: 22896668; PubMed Central PMCID: PMC3469732.
11: Shin HC, Cho H, Lai TC, Kozak KR, Kolesar JM, Kwon GS. Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin. J Control Release. 2012 Oct 10;163(1):93-9. doi: 10.1016/j.jconrel.2012.04.024. Epub 2012 Apr 23. PubMed PMID: 22549011; PubMed Central PMCID: PMC3422612.
12: Shin HC, Alani AW, Cho H, Bae Y, Kolesar JM, Kwon GS. A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs. Mol Pharm. 2011 Aug 1;8(4):1257-65. doi: 10.1021/mp2000549. Epub 2011 Jun 23. PubMed PMID: 21630670; PubMed Central PMCID: PMC4896148.
Inventor Bio: Glen Kwon
https://apps.pharmacy.wisc.edu/sopdir/glen_kwon/