ARTIFICIAL POLYMERIC LIPOPROTEINS AS DRUG CARRIERS

Summary

Principal Investigator: GLEN KWON
Affiliation: University of Wisconsin
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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 Amphotericin B/sterol co-loaded PEG-phospholipid micelles: effects of sterols on aggregation state and hemolytic activity of amphotericin B
    Thomas A Diezi
    University of Wisconsin, Madison, Wisconsin, USA
    Pharm Res 29:1737-44. 2012
  2. pmc In vivo cancer imaging by poly(ethylene glycol)-b-poly(ɛ-caprolactone) micelles containing a near-infrared probe
    Hyunah Cho
    Department of Pharmaceutical Science, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA
    Nanomedicine 8:228-36. 2012
  3. doi Pharmacokinetics and nephrotoxicity of amphotericin B-incorporated poly(ethylene glycol)-block-poly(N-hexyl stearate l-aspartamide) micelles
    Thomas A Diezi
    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin Madison, Madison, Wisconsin 53705 2222, USA
    J Pharm Sci 100:2064-70. 2011
  4. pmc Pluronic-based cationic block copolymer for forming pDNA polyplexes with enhanced cellular uptake and improved transfection efficiency
    Tsz Chung Lai
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, Madison, WI 53705 2222, USA
    Biomaterials 32:4594-603. 2011
  5. doi Mixed pH-sensitive polymeric micelles for combination drug delivery
    Younsoo Bae
    Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536 0596, USA
    Pharm Res 27:2421-32. 2010
  6. pmc The virucidal EB peptide protects host cells from herpes simplex virus type 1 infection in the presence of serum albumin and aggregates proteins in a detergent-like manner
    Hermann Bultmann
    Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA
    Antimicrob Agents Chemother 54:4275-89. 2010
  7. pmc Enhanced stability of PEG-block-poly(N-hexyl stearate l-aspartamide) micelles in the presence of serum proteins
    Thomas A Diezi
    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, Wisconsin 53705 2222, USA
    Mol Pharm 7:1355-60. 2010
  8. pmc pH-sensitive multi-PEGylated block copolymer as a bioresponsive pDNA delivery vector
    Tsz Chung Lai
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, Wisconsin 53705 2222, USA
    Pharm Res 27:2260-73. 2010
  9. pmc Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs
    Ho Chul Shin
    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
    J Control Release 140:294-300. 2009
  10. 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

  • Younsoo Bae
  • Deepa A Rao
  • Glen S Kwon
  • May P Xiong
  • Thomas A Diezi
  • M Laird Forrest
  • Tsz Chung Lai
  • Neal M Davies
  • Ho Chul Shin
  • Kazunori Kataoka
  • Jaime A Yáñez
  • Hyunah Cho
  • Hermann Bultmann
  • Ommoleila Molavi
  • Anni Zhao
  • Guilherme L Indig
  • Jamey Weichert
  • GLEN KWON
  • Jody K Takemoto
  • Curtis R Brandt
  • Gary Girdaukas
  • Takayuki Yoshida
  • Nicole C Rockich
  • Adam W G Alani
  • Raymond Lai
  • Zengshuan Ma
  • Afsaneh Lavasanifar
  • Abdullah Mahmud
  • Yusuke Ohgami
  • John Samuel
  • Aws Alshamsan
  • Nobuhiro Nishiyama
  • Giangthy Ton
  • Shigeto Fukushima
  • Angela L Karls
  • A Waseem Malick
  • Chee Youb Won

Detail Information

Publications18

  1. ncbi Amphotericin B/sterol co-loaded PEG-phospholipid micelles: effects of sterols on aggregation state and hemolytic activity of amphotericin B
    Thomas A Diezi
    University of Wisconsin, Madison, Wisconsin, USA
    Pharm Res 29:1737-44. 2012
    ..To elucidate the effect of sterols on the aggregation of amphotericin B (AmB) in PEG-phospholipid micelles and its consequences on the hemolytic activity of AmB...
  2. pmc In vivo cancer imaging by poly(ethylene glycol)-b-poly(ɛ-caprolactone) micelles containing a near-infrared probe
    Hyunah Cho
    Department of Pharmaceutical Science, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA
    Nanomedicine 8:228-36. 2012
    ..These results suggest that PEG-b-PCL micelles with DiR are a promising nanosized imaging agent that will provide a basis for enhanced surgical guidance via NIR visualization of tumors...
  3. doi Pharmacokinetics and nephrotoxicity of amphotericin B-incorporated poly(ethylene glycol)-block-poly(N-hexyl stearate l-aspartamide) micelles
    Thomas A Diezi
    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin Madison, Madison, Wisconsin 53705 2222, USA
    J Pharm Sci 100:2064-70. 2011
    ..In summary, PEG-b-PHSA micelles reduced the nephrotoxicity of AmB, the dose-limiting toxicity of this important antifungal agent...
  4. pmc Pluronic-based cationic block copolymer for forming pDNA polyplexes with enhanced cellular uptake and improved transfection efficiency
    Tsz Chung Lai
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, Madison, WI 53705 2222, USA
    Biomaterials 32:4594-603. 2011
    ..The improvement of gene delivering ability was shown to be correlated with the enhanced cellular internalization of the P85-based polyplexes...
  5. doi Mixed pH-sensitive polymeric micelles for combination drug delivery
    Younsoo Bae
    Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536 0596, USA
    Pharm Res 27:2421-32. 2010
    ..To prepare mixed polymeric micelles that can carry two different drugs, doxorubicin (DOX) and 17-hydroxyethylamino-17-demethoxygeldanamycin (GDM-OH), for combination cancer chemotherapy...
  6. pmc The virucidal EB peptide protects host cells from herpes simplex virus type 1 infection in the presence of serum albumin and aggregates proteins in a detergent-like manner
    Hermann Bultmann
    Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA
    Antimicrob Agents Chemother 54:4275-89. 2010
    ..EB resembles natural antimicrobial peptides, such as melittin, but when acting in a nonspecific detergent-like manner, it primarily seems to target proteins...
  7. pmc Enhanced stability of PEG-block-poly(N-hexyl stearate l-aspartamide) micelles in the presence of serum proteins
    Thomas A Diezi
    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, Wisconsin 53705 2222, USA
    Mol Pharm 7:1355-60. 2010
    ..PEG-b-PHSA micelles are remarkably stable in the presence of serum proteins and a more stable alternative for poorly water-soluble drugs, which have been solubilized by PEG-DSPE micelles...
  8. pmc pH-sensitive multi-PEGylated block copolymer as a bioresponsive pDNA delivery vector
    Tsz Chung Lai
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin Madison, 777 Highland Avenue, Madison, Wisconsin 53705 2222, USA
    Pharm Res 27:2260-73. 2010
    ..The first block, p[Asp(Hyd)], was used for multi-PEG conjugations, and the second block, p[Asp(DET)], was used for DNA condensation and endosomal escape...
  9. pmc Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs
    Ho Chul Shin
    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
    J Control Release 140:294-300. 2009
    ..In vitro, t(1/2) values for 2- and 3-drug combination PEG-b-PLA micelles spanned 1-5 h. PEG-b-PLA micelles offer a promising alternative for combination drug therapy without formulation related side effects...
  10. 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...
  11. 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...
  12. 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...
  13. 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...
  14. 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...
  15. 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...
  16. 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
    ....
  17. 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
    ....
  18. 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...