Transcript BTM NPs - Research at Carolina
BTM Nanocapsules for Formulation of Drugs and Vaccines and Imaging Agents
Russell J. Mumper, Ph.D.
Center for Nanotechnology in Drug Delivery Division of Molecular Pharmaceutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina Carolina Seeds of Innovation
November 4, 2010
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Nanotemplate Engineering
Focus Areas
Materials (Handbook of Pharmaceutical Excipients)
Engineering & Characterization
Cell Interaction / Uptake
Biofate & Biometabolism
Bio- and Hemocompatibility (toxicological aspects of NPs)
Cell and Tissue Targeting (therapeutics )
Therapeutic (and Imaging) Areas
– –
Addressing resistance in human cancer using nanotechnology
Subunit (protein) vaccines for HIV
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Nanotemplate Engineering
Enables manufacturing of stable NPs <200 nm using a reproducible and scalable process Manufacturing process is as few as 3-steps and is completed in one vessel Overcomes the limitations of commonly used methods to make sub-micron sized particles Oil Add, Heat & Mix at 50-65 o C Oil Drug (Rx) Surfactant(s) Step 1 Surfactant(s) + Water Step 2 Water Clear, Stable Oil-in-Water Microemulsion “Nanotemplate” at 50-65 o C Cool to 25 o C Step 3
oil droplet nanotemplate
HO Ligand PEG + Rx Rx Rx Rx Rx Rx Rx Rx Rx Rx
= surfactant
_ Ni RXN -SH -NH 2 -COOH PEG OH
oil droplets
Nanoparticles or Nanocapsules
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E78 Nanoparticles vs. BTM Nanocapsules
Oil Phase Solid Lipid E78 Nanoparticles Cetyl Alcohol (m.p. 49 o C)
CH 3 (CH 2 ) 14 CH 2 OH
Oil-Filled BTM Nanocapsules Miglyol ® 812 Caprylic/Capric Triglyceride C 8 (50-65%); C 10 (30-45%) E78 NPs + Surfactants Vitamin E TPGS (d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate) BTM NPs Brij 78 (Polyoxyethylene 20 stearyl ether)
CH 3 (CH 2 ) 17 (OCH 2 CH 2 ) 20 OH 4
A New Nanocapsule Formulation “BTM NPs”
First Generation BTM NPs identified by Sequential Simplex Optimization Composition: liquid tri-glyceride core with two surfactants Scalable, one vessel manufacturing process Lipid/drug ~ 20-30:1 w/w; [drug] up to 1.5 mg/ml Sustained-release of drug Can be pegylated to make ‘
peg
BTM NPs’ Easily sterile filtered Can be lyophilized with no cryoprotectant Very stable in suspension or lyophilized ‘Plug & Play’ platform based on oil properties Very well tolerated, repeated i.v. injection up to 750 mg/kg
Lyophilized BTM NPs
15 s after rehydration Dong et al.
Eur. J. Pharm. Biopharm. (
2009) 5
In-Vivo Efficacy Study in Nude Mice Bearing P-gp+ Resistant Human Ovarian Tumors
1200 1000 800 600 400 200 0 0 # 5 * 10 * * * 15
Day
20 * * 25 * 30 Saline Empty BTM NPs (4.5 mg/kg) Taxol (4.5 mg/kg) Taxol (20 mg/kg) Empty BTM NPs + Taxol (4.5 mg/kg) PX BTM NPs (4.5 mg/kg)
Mice (n=6/group) were dosed i.v. with PX (4.5 mg/kg) on day 0, 7, 14, and 21
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Retreatment of Mice
Taxol-failed mice can be salvaged with PX BTM NP treatment Previously PX BTM NP treated mice respond to new course of PX BTM NP treatment
1000 900 800 700 600 500 400 300 200 100 0 542 0 3 6 303 * * 519 364 * 340 * 9 12 15 18 21 24 27 30
Day 31 of Study #2
Day PX BTM dose
4.5 mg/kg 7.5 mg/kg 1000 800 600 400 509 200 0 0 1 2 3 4 5 6 7 8 9 10 11
Day 49 of Study #2
559 420 *
Day
383 * 7
Enhancement of Tumor MRI Image with BTM-DTPA-Gd NPs
Control BTM-DTPA-Gd NPs
5 hr after i.v. injection in A549 s.c. xenograft tumors ~50-70 mm 3 Compliments of Dr. Michael Jay in collaboration with SAICF at UNC-BRIC using 9.4T Micro-MRI 8
Nano-based Subunit HIV Vaccines
NIH-NIAID R01 AI058842 A DC-targeted nanoparticle with conserved proteins Tat (1-72) and Gag p24 to generate protective Th1, CTL, and neutralizing antibody responses that may be further enhanced by co-delivery of Adjuvants (PRLs) DiOC18 NPs in DC
Dendritic Cell
Toll-like Receptor (TLR-9) NP benefits:
Increased DC uptake/processing/ presentation Dose sparing Enhance MHC1 processing Enhance Th1-type responses Enhance (neutralizing) antibodies Co-delivery of antigen/adjuvant
Tat (1-72) MHC I Receptor
PEG
DC targeting Ligand Adjuvant (PRL)
J. Biomed. Nanotech.
(2007)
Pharmaceutical Research Vaccin
e (2004, 2006) (2007)
HIV/AIDS
(2009)
Gag p24 Tat & Gag antigens: conserved; critical; CTLs detected in LTNPs
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p41 Immunization; BTM-Ni vs. E78-Ni NPs
4.0
3.5
3.0
*
2.5
2.0
*
1.5
*
1.0
0.5
# # # 0.0
BTM-Ni (0.1 µg) BTM-Ni (0.5 µg) BTM-Ni (
1 µg
)
*
E78-Ni (
1 µg
) 1,000 2,000 5,000 10,000 Alum (
1 µg
) Naive
BALB/c mice (n=8/group) were dosed by s.c. injection on day 0 and 14; ELISA day 28 Doses: 0.1, 0.5, or 1
m
g p41 His-tag p41 provided by Dr. Robert Seder, NIH-NIAID Vaccine Research Center
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Concluding Remarks
“Nanoparticle Compositions Comprising Liquid Oil Cores” (PCT /US2009/060593 )
“Translational Nanotechnology” – all required elements
Nanotemplate Engineering
simple, one-vessel process, reproducible, scalable, cost-effective keys: 1) physical chemistry/pharmacy 2) excipient selection
Some ‘GRAS’ or USP/NF excipients may be ‘biological modifiers’
Nano-based Drug Delivery Systems
Improve drug solubility / bioavailability Address MDR in cancer to improve outcomes Can be used for imaging Co-delivery of antigens / adjuvants for improved vaccines
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Russell J. Mumper, Ph.D.
Center for Nanotechnology in Drug Delivery Division of Molecular Pharmaceutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina E-mail: [email protected]
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