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BTM Nanocapsules for Formulationof Drugs and Vaccines and Imaging Agents
Carolina Seeds of InnovationNovember 4, 2010
Russell J. Mumper, Ph.D.Center for Nanotechnology in Drug Delivery
Division of Molecular PharmaceuticsUNC Eshelman School of Pharmacy
University of North Carolina at Chapel HillChapel Hill, North Carolina
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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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OilDrug (Rx)
Surfactant(s)
Oil
Surfactant(s) Water
Clear, Stable Oil-in-Water
Microemulsion“Nanotemplate”
at 50-65oC
+ Water
Cool to 25oC
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
Step 3Step 2Step 1
Add, Heat & Mix at 50-65oC
Nanoparticles or Nanocapsules
Nanotemplate Engineering
oil droplets
+_
Ni
OH
PEG-SH-NH2
-COOH
RXN
Y
Ligand
HO
RxPEG Rx
RxRx
Rx
Rx
Rx
Rx
Rx Rx
oil droplet nanotemplate
= surfactant
4
Vitamin E TPGS(d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate)
CH3 (CH2)17 (OCH2CH2)20OHBrij 78(Polyoxyethylene 20 stearyl ether)
E78 Nanoparticles vs. BTM Nanocapsules
Cetyl Alcohol (m.p. 49oC)
CH3 (CH2)14CH2OH
Miglyol® 812 Caprylic/Capric TriglycerideC8 (50-65%); C10 (30-45%)Oil Phase
Surfactants
+
Solid Lipid E78 Nanoparticles Oil-Filled BTM Nanocapsules
E78 NPs
BTM NPs
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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 ‘pegBTM 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
Dong et al. Eur. J. Pharm. Biopharm. (2009)
Lyophilized BTM NPs
15 s after rehydration
6Mice (n=6/group) were dosed i.v. with PX (4.5 mg/kg) on day 0, 7, 14, and 21
0
200
400
600
800
1000
1200
0 5 10 15 20 25 30
Day
Tum
or
siz
e (
mm
3 )
* * * * * * *
#
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)
In-Vivo Efficacy Study in Nude Mice Bearing P-gp+ Resistant Human Ovarian Tumors
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Retreatment of Mice
0
100
200
300
400
500
600
700
800
900
1000
0 3 6 9 12 15 18 21 24 27 30
0
200
400
600
800
1000
0 1 2 3 4 5 6 7 8 9 10 11
542
303
519
364 340
509559
420383**
***
*
Taxol-failed mice can be salvagedwith PX BTM NP treatment
Previously PX BTM NP treated mice respond to new course of PX
BTM NP treatment
Day Day
4.5 mg/kg
7.5 mg/kg
PX BTM dose
Tum
or
siz
e (
mm
3 )
Day 31 ofStudy #2
Day 49 ofStudy #2
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Enhancement of Tumor MRI Image with BTM-DTPA-Gd NPs
5 hr after i.v. injection in A549 s.c. xenograft tumors ~50-70 mm3
Compliments of Dr. Michael Jay in collaboration with SAICF at UNC-BRIC using 9.4T Micro-MRI
Control BTM-DTPA-Gd NPs
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J. Biomed. Nanotech. (2007) Pharmaceutical Research
(2007) Vaccine (2004, 2006)
HIV/AIDS (2009)
Nano-based Subunit HIV Vaccines
Dendritic Cell
Toll-like Receptor (TLR-9)
ReceptorMHC I
MHC II
DC targetingLigand
PEG
Tat (1-72)
Gag p24
Adjuvant (PRL)
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)
Tat & Gag antigens: conserved; critical; CTLs detected in LTNPs
NIH-NIAID R01 AI058842
NP benefits: Increased DC uptake/processing/
presentation Dose sparing Enhance MHC1 processing Enhance Th1-type responses Enhance (neutralizing) antibodies Co-delivery of antigen/adjuvant
DiOC18 NPs in DC
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Alum(1 µg)
Naive0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0P
41
sp
ec
ific
Ig
GO
.D.
at
45
0 n
m
1,000
2,000
5,000
10,000
E78-Ni(1 µg)
BTM-Ni (1 µg)
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 mg p41 His-tag p41 provided by Dr. Robert Seder, NIH-NIAID Vaccine Research Center
p41 Immunization; BTM-Ni vs. E78-Ni NPs
BTM-Ni(0.5 µg)
*
BTM-Ni(0.1 µg)
#
*
*
*#
#
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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 PharmaceuticsUNC Eshelman School of Pharmacy
University of North Carolina at Chapel HillChapel Hill, North Carolina
E-mail: [email protected]