ARTIFICIAL POLYMERIC LIPOPROTEINS AS DRUG CARRIERS

Summary

Principal Investigator: GLEN KWON
Affiliation: University of Wisconsin
Country: USA
Abstract: The clinical role of many drugs currently used to fight opportunistic infections (OIs) and the impact of many potent drugs for OIs coming out of massive drug discovery programs have been hampered by poor watersolubility, high toxicity, and inadequate parenteral dosage forms despite encouraging results in preclinical and clinical testing. Current efforts to address these major bottlenecks in drug development fall in the realm of nanotechnology. In particular, polymeric micelles, nanoscopic supramolecular core-shell structures, have recently entered clinical trials for potent yet poorly water-soluble and toxic drugs, owing to safety, high drug loading, and improved pharmacokinetics. A unique aspect of polymeric micelles is the ability to adjust their chemical structures to fine-tune properties for drug delivery. Our results suggest that adjustments must be made with an individual drug or class of drugs in mind, and that easily made adjustments on poly(ethylene oxide)-block-poly(L-amino acid) (PEG-b-PLAA) micelles may enhance drug delivery. Our efforts focus on amphotericin B (AmB), the primary drug for opportunistic systemic fungal infections. These OIs are a major cause of morbidity among immunocompromised patients suffering from cancer or AIDS and organ transplant recipients. We believe that tailor-made PEG-b-PLAA micelles may increase the therapeutic index of AmB. Specifically, we hypothesize that beneficial changes in the pharmacokinetics of AmB, increased plasma halflife and reduced liver clearance, and changes in its self-aggregation state, owing to PEG-b-PLAA micelles may lower the drug's toxicity and increase its antifungal efficacy. In this context, we may adjust the structure of PEG-b-PLAA micelles to fine-tune the release kinetics of AmB and enhance its delivery. Specific Aims: (1) To study the pharmacokinetics (plasma profile, distribution in plasma, and tissue distribution) of AmB encapsulated by PEG-b-PLAA micelles in rodents. (2) To study the acute, renal and liver toxicity of AmB encapsulated in PEG-b-PLAA micelles in rodents. (3) To study the antifungal activity of AmB encapsulated in PEG-b-PLAA micelles in a neutropenic murine model of disseminated candidiasis. Comparisons will be made with a standard formulation of AmB and a liposomal AmB approved for refractory systemic fungal diseases. These proposed studies will provide insight into mechanisms behind the toxicity and antifungal activity of AmB and perhaps show that PEG-b-PLAA micelles increase the therapeutic index for the drug.
Funding Period: 1998-07-01 - 2007-04-05
more information: NIH RePORT

Top Publications

  1. ncbi Lipophilic prodrugs of Hsp90 inhibitor geldanamycin for nanoencapsulation in poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles
    M Laird Forrest
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, WI 53705 2222, USA
    J Control Release 116:139-49. 2006
  2. ncbi Biotin-triggered release of poly(ethylene glycol)-avidin from biotinylated polyethylenimine enhances in vitro gene expression
    May P Xiong
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, Wisconsin 53705 2222, USA
    Bioconjug Chem 18:746-53. 2007
  3. pmc Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(epsilon-caprolactone) micelles of rapamycin
    Jaime A Yáñez
    Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164, USA
    Cancer Chemother Pharmacol 61:133-44. 2008
  4. ncbi pH-responsive Multi-PEGylated dual cationic nanoparticles enable charge modulations for safe gene delivery
    May P Xiong
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705 2222, USA
    ChemMedChem 2:1321-7. 2007
  5. ncbi Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents
    Younsoo Bae
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, WI 53705 2222, USA
    J Control Release 122:324-30. 2007
  6. pmc Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors
    Ommoleila Molavi
    Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
    Int J Pharm 347:118-27. 2008
  7. ncbi Poly(aspartate-g-PEI800), a polyethylenimine analogue of low toxicity and high transfection efficiency for gene delivery
    May P Xiong
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705 2222, USA
    Biomaterials 28:4889-900. 2007
  8. pmc A cremophor-free formulation for tanespimycin (17-AAG) using PEO-b-PDLLA micelles: characterization and pharmacokinetics in rats
    May P Xiong
    Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047 3729, USA
    J Pharm Sci 98:1577-86. 2009
  9. doi Biodegradable PLGA based nanoparticles for sustained regional lymphatic drug delivery
    Deepa A Rao
    Department of Pharmaceutical Sciences, Drake University, Des Moines, Iowa 50265, USA
    J Pharm Sci 99:2018-31. 2010

Scientific Experts

  • Deepa A Rao
  • May P Xiong
  • Glen S Kwon
  • M Laird Forrest
  • Jaime A Yáñez
  • Neal M Davies
  • Younsoo Bae
  • Anni Zhao
  • Ommoleila Molavi
  • Abdullah Mahmud
  • Zengshuan Ma
  • Afsaneh Lavasanifar
  • John Samuel
  • Yusuke Ohgami
  • Aws Alshamsan
  • Raymond Lai
  • Shigeto Fukushima
  • Giangthy Ton
  • Angela L Karls
  • Nobuhiro Nishiyama
  • Kazunori Kataoka
  • Thomas A Diezi
  • Chee Youb Won
  • A Waseem Malick

Detail Information

Publications9

  1. ncbi Lipophilic prodrugs of Hsp90 inhibitor geldanamycin for nanoencapsulation in poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles
    M Laird Forrest
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, WI 53705 2222, USA
    J Control Release 116:139-49. 2006
    ..2 to 9.6 days. The free prodrugs hydrolyzed rapidly, t(1/2)<6 h, into the geldanamycin analogue 17-beta-hydroxyethylamino-17-demethoxygeldanamycin, which has high activity against MCF-7 breast cancer cells, IC(50) 240 nM...
  2. ncbi Biotin-triggered release of poly(ethylene glycol)-avidin from biotinylated polyethylenimine enhances in vitro gene expression
    May P Xiong
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, Wisconsin 53705 2222, USA
    Bioconjug Chem 18:746-53. 2007
    ....
  3. pmc Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(epsilon-caprolactone) micelles of rapamycin
    Jaime A Yáñez
    Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164, USA
    Cancer Chemother Pharmacol 61:133-44. 2008
    ....
  4. ncbi pH-responsive Multi-PEGylated dual cationic nanoparticles enable charge modulations for safe gene delivery
    May P Xiong
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705 2222, USA
    ChemMedChem 2:1321-7. 2007
    ..Our system supports an endosomal escape mechanism based on charge interactions rather than the proton-sponge effect, and may be an important step towards engineering new classes of intelligent nonviral vectors...
  5. ncbi Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents
    Younsoo Bae
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, WI 53705 2222, USA
    J Control Release 122:324-30. 2007
    ..These findings, therefore, bring an effective drug delivery methodology that might reduce the effective dose as well as toxicity in vivo compared to the conventional drug formulations...
  6. pmc Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors
    Ommoleila Molavi
    Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
    Int J Pharm 347:118-27. 2008
    ..The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B...
  7. ncbi Poly(aspartate-g-PEI800), a polyethylenimine analogue of low toxicity and high transfection efficiency for gene delivery
    May P Xiong
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705 2222, USA
    Biomaterials 28:4889-900. 2007
    ..Our study points to the need to optimize gene carriers to minimize toxicity, especially important for the safe delivery of therapeutic genes to explicit organs...
  8. pmc A cremophor-free formulation for tanespimycin (17-AAG) using PEO-b-PDLLA micelles: characterization and pharmacokinetics in rats
    May P Xiong
    Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047 3729, USA
    J Pharm Sci 98:1577-86. 2009
    ..Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH...
  9. doi Biodegradable PLGA based nanoparticles for sustained regional lymphatic drug delivery
    Deepa A Rao
    Department of Pharmaceutical Sciences, Drake University, Des Moines, Iowa 50265, USA
    J Pharm Sci 99:2018-31. 2010
    ..In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases...