# Presentation: 349346

## Neil P. Desai, PhD
Vice President, Research and Development
Abraxis BioScience, Inc

- 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

- Nanoparticle Albumin-bound (*nab*) platform technology

**Hydrophobic drugs, e.g.,Paclitaxel, docetaxel, rapamycin etc.**

**Albumin**

**Mean size = 50-150 nm**

**cryo-TEM**

**Concentration dependent dissociation into individual drug-bound albumin molecules**

**Active drug in nanoparticle **
**is in non-crystalline, **_**amorphous**_**, **_**readily**_** **_**bioavailable**_**  state**

## Abraxane (nab-paclitaxel) is a solvent-free ‘nano’ version of Taxol (cremophor-based paclitaxel)

- Abraxane (*nab*-paclitaxel) is a solvent-free ‘nano’ version of Taxol (cremophor-based paclitaxel)

**Contents:**
- Paclitaxel 6 mg/ml
**Cremophor 537 mg/ml**
**Ethanol 396 mg/ml**

**Contents:**
- 100 mg paclitaxel
- 900 mg albumin
**No Surfactants/Solvents**

**Abraxane received  FDA **
**Approval **
**January, 2005**
**for metastatic  breast cancer**

**Notes:**
This slide clearly delineates the differences between the two paclitaxel formulations.  While Abraxane contains only paclitaxel and albumin, Taxol contains almost 100 mg of Cremophor for every 1 mg of paclitaxel, plus a strong shot of ethanol.  

## Abraxane approved by FDA with about twice the response rate of Taxol in metastatic breast cancer

**Source:  Abraxane Package Insert**

**Notes:**
Since it was the primary study endpoint, the statistically significantly higher reconciled, target-lesion response rate is the one that is included in the Abraxane Package Insert.

## A key aspect of nanoparticle stability of nab-paclitaxel is size and zeta potential 

*nab* nanoparticles are physically stable for several days in suspension

**Mean Particle Diameter ~ 130 nm**

**Reproducible, narrow size distribution by Laser Light Scattering**

**Negatively charged nanoparticles resist agglomeration**

## Nanoparticle Release of nab-paclitaxel in simulated plasma measured by Laser Light Scattering

- 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

***Albumin-Drug Accumulation***

***Albumin-Bound Drug***

## Rapid Tumor Accumulation of nab-paclitaxel in tumor

**1 min after I.V. injection**

**15 min after I.V. injection**

- Fluorescent *nab*-paclitaxel Nanoparticles* in Syringe injected via tail vein

- MOUSE TUMOR MODEL

**Imaged Tumor**

- Imaging under Hg-lamp with 500-550 nm bandpass excitation; **nab*-paclitaxel containing 0.3% Fluorescent Marker

- ABI, data on file and Desai N, et al. *Clin Cancer Res* 2006;12(4), 1317-24

- 33% higher tumor accumulation of paclitaxel over 24 hr confirmed with radiolabelled *nab*-paclitaxel as compared to Taxol (p<0.0001)

## 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

## Meeting current definitions of Nanotechnology :  

- Meeting current definitions of Nanotechnology :
- Other *nab* products in development

*nab*-rapamycin

**Mean Particle Diameter : 88 nm**
**   ****< 100 nm**

***nab*****-rapamycin**

*nab*-17AAG

**Mean Particle Diameter : 113 nm**
**      ****>100 nm**

***nab*****-17AAG**

*nab*-5404

**Mean Particle Diameter ~ 89 nm**
**        ****< 100 nm**

***nab*****-5404**

- Do these products, all produced by *nab*-technology, sharing similar physicohemical  and biological properties, meet the current NNI size definition ??

**Yes**

**No**

**Yes**

## 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