Transcript nab technology : A nanotechnology platform for biologically interactive drug delivery and targeting

Nanoparticle albumin bound (nab)
technology :
A nanotechnology platform for biologically
interactive drug delivery and targeting
Neil P. Desai, PhD
Vice President, Research and Development
Abraxis BioScience, Inc
Nanoparticle Albumin-bound (nab)
platform technology
Albumin
Active drug in
nanoparticle
is in non-crystalline,
amorphous, readily
bioavailable state
Mean size =
50-150 nm
Hydrophobic drugs,
e.g.,Paclitaxel,
docetaxel, rapamycin
etc.
Concentration dependent
dissociation into
individual drug-bound
albumin molecules
cryo-TEM
Abraxane (nab-paclitaxel) is a solvent-free ‘nano’
version of Taxol (cremophor-based paclitaxel)
Taxol
Abraxane
Abraxane
received FDA
Approval
January, 2005
for metastatic
breast cancer
Contents:
100 mg paclitaxel
900 mg albumin
No Surfactants/Solvents
Contents:
Paclitaxel 6 mg/ml
Cremophor 537 mg/ml
Ethanol 396 mg/ml
Abraxane approved by FDA with about twice the
response rate of Taxol in metastatic breast cancer
Source: Abraxane Package Insert
A key aspect of nanoparticle stability of
nab-paclitaxel is size and zeta potential
Reproducible, narrow size
distribution by Laser Light Scattering
Negatively charged nanoparticles
resist agglomeration
25.0
Volume Percent
20.0
Mean Particle
Diameter ~ 130 nm
15.0
10.0
Negatively Charged Albumin
-
- - -
-
-
5.0
-
0.0
0
100 200 300 400 500 600 700 800 900 1000
-
- - - -
Particle Diameter (nm)
◆ nab nanoparticles are physically stable for several days in suspension
-
Nanoparticle Release of nab-paclitaxel in
simulated plasma measured by Laser Light Scattering
0 sec
30 sec
140
50 sec
70 sec
90 sec
Nanoparticle Size, nm
120
110 sec
Rapid
disintegration of
nanoparticle
100
130 sec
170 sec
190 sec
210 sec
80
Concentration
above which
nanoparticles
remain intact and
stable
60
Mean Cmax for
260mg/m2
40
250 sec
270 sec
290 sec
330 sec
350 sec
370 sec
390 sec
410 sec
430 sec
20
450 sec
470 sec
490 sec
0
0
10
20
30
40
50
60
70
80
90
Concn. (ug/mL)
Paclitaxel Concentration
in Plasma (ug/ml)
100
510 sec
530 sec
550 sec
570 sec
◆ From a nanoparticle size of ~ 130 nm, there is rapid dissociation upon dilution in
plasma into complexes in the 10 nm size range
Nab-platform utilizes endogenous albumin
pathways of endothelial transcytosis (gp60) and
intratumoral binding of SPARC
Tumor
endothelial cell
gp60 receptor
Albumin-Bound Drug
Red Blood cell
Gp60 Receptor
Albumin-drug
complex
TUMOR
BLOOD
VESSEL
gp60/Alb-drug complex
Caveolae
TUMOR
SPARC on Tumor
INTERSTITIUM cell surface
Alb-drug complex
transcytosed by gp60
Surface SPARC bound to
Alb-drug complex
SPARC
Internalized
SPARC/Alb-drug
complex
Tumor
cells
Albumin-Drug Accumulation
Rapid Tumor Accumulation of
nab-paclitaxel in tumor
Fluorescent nab-paclitaxel Nanoparticles* in
Syringe injected via tail vein
1 min after I.V. injection
Imaged Tumor
MOUSE TUMOR MODEL
Imaging under Hg-lamp with 500-550 nm
bandpass excitation; *nab-paclitaxel
containing 0.3% Fluorescent Marker
15 min after I.V. injection
◆ 33% higher tumor accumulation of paclitaxel over 24 hr confirmed with
radiolabelled nab-paclitaxel as compared to Taxol (p<0.0001)
ABI, data on file and Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24
Comparing ‘nano’ paclitaxel vs standard paclitaxel
◆ Close and extensive interaction with FDA over almost 10 years leading to
approval of Abraxane
◆ Extensive preclinical testing program comparing Abraxane and Taxol
–
–
–
–
–
–
–
–
Intravenous toxicology in multiple organ systems
Biodistribution
Metabolism
Excretion
Reproductive toxicology in males and females
Tumor efficacy studies
Mechanistic studies elucidating pathways of drug transport
Other studies…
◆ More than 1000 patients in carefully controlled clinical trials; more than 20000
patients treated since approval
◆ No new or unique toxicities seen with Abraxane that are different from
conventional paclitaxel (Taxol)
◆ We believe the FDA has adequate procedures in place to regulate
nanotechnology based drugs
Definitions of Nanotechnology adopted by FDA
◆ FDA has not established its own formal definition ..Our understanding is
that the FDA currently relies on the NNI definition.
◆ National Nanotechnology Initiative (NNI):
– Nanotechnology is the understanding and control of matter at dimensions of
roughly 1 to 100 nanometers, where unique phenomena enable novel
applications. …. At the nanoscale, the physical, chemical, and biological
properties of materials differ in fundamental and valuable ways from the
properties of individual atoms and molecules or bulk matter.
◆ NCI Cancer Nanotechnology Plan (July 2004):
– Nanotechnology refers to the interactions of cellular and molecular
components and engineered materials - typically clusters of atoms,
molecules, and molecular fragments - at the most elemental level of
biology. Such nanoscale objects - typically, though not exclusively, with
dimensions smaller than 100 nanometers - can be useful by themselves or
as part of larger devices containing multiple nanoscale objects.
Nanotechnology / drug-delivery literature review:
Is the 100 nm cutoff appropriate?
Search: Pubmed/Internet [keywords: nanoparticle AND size AND drug AND delivery]
◆ 446 abstracts found (1990 – 2006)
◆ 152 abstracts provided nanoparticle size information in
range of 1-1000 nm (96% from academia, only 4% from
industry)
◆ Majority, almost 80%, describe nanoparticles > 100 nm
% Distribution of publications with reference to nanoparticle size
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
118/152
(78%)
34/152
(22%)
<=100 nm
>100 nm
Meeting current definitions of Nanotechnology :
Other nab products in development
nab-rapamycin
nab-17AAG
nab-5404
Do these products, all produced by nab-technology, sharing similar physicohemical and
biological properties, meet the current NNI size definition ??
Size d istribution(s)
% in class
% in class
Size distribution(s)
nab-17AAG
nab-rapamycin
40
nab-5404
15
30
30
10
Volume (%)
20
Mean Particle
Diameter : 88 nm
< 100 nm
Yes
Mean Particle
Diameter : 113 nm
>100 nm
10
5
No
20
10
Mean Particle
Diameter ~ 89 nm
< 100 nm
Yes
0
200
400
Diameter (nm)
600
800
0
200
400
600
800
1000
200
400
Diameter (nm)
600
800
Recommendations for revising current
definitions of size range/function for
nanotechnology drug products
◆ Function:
– Must provide special characteristics – e.g., novel physical characteristics,
unique delivery, cellular penetration, receptor binding, targeting etc.
◆ Suggested size cutoff equivalent to pore size of sterile filter (220 nm) :
– 220 nm or 0.22 um is relevant size cutoff for sterile filtration to ensure that
injectable pharmaceutical nanotechnology products are sterile
– Below about 220 nm, we are outside the visible range of an optical
microscope and special techniques are required to characterize these
structures.
◆ Establish a committee to determine cut off size for nanotechnology
definition