Abraxane: The First Prototype of Nab Tecnology Nanoparticle albumin-bound technology is a patented novel nanotechnology-based drug delivery platform

developed by Abraxis Bioscience, which exploits the natural properties to albumin to achieve a safe, solvent free, efficient and targeted drug delivery. Abraxane is the first successful example of nab technology-based drug delivery, and consists of paclitaxel protein-bound particles for injectable suspension (albumin bound). Abraxane or nab-paclitaxel, is a cremophor-free, albumin-bound 130-nm particles of paclitaxel. Abraxane is recognized as the first nanotechnology-based drug on the market. Abraxane consists of particles of paclitaxel in the nanometer-size range, stabilized with human albumin. The paclitaxel and albumin are not covalently linked but rather associated through hydrophobic interactions. The particles of paclitaxel are in a non-crystalline, amorphous, readily bioavailable state, allowing for rapid drug release from the particles following intravenous administration. Upon reconstitution with a 0.9% sodium chloride injection to a concentration of 5 mglmL, the paclitaxel particles are stable with an average size of 130 nm. In vitro and in vivo drug dissolution studies have shown that, once injected into circulation, paclitaxel nanoparticles quickly dissolve into smaller albumin-paclitaxel complexes whose size is virtually identical to that of endogenous albumin molecules in blood. Thus, the albumin-paclitaxel complexes are fully capable of utilising the natural albumin pathways, including gp60 and caveolae-mediated transcytosis and increased intratumoral accumulation, through association with tumourderived SPARC protein to achieve enhanced drug targeting and penetration in tumours (Desai, Trieu, Yao et al. Desai, N., Trieu, v., Yao, Z., Louie, L., Ci, S., Yang, A., Tao, c., De, T., Beals, B., Dykes, D., Noker, P., Yao, R., Labao, E., Hawkins, M. and Soon-Shiong, P., 2006, 'Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel', Clinical Cancer Research, 2006,vol. 12, no. 4, pp. 1317-24.). Pharmacokinetics and pharmacodynamics of Nab-paclitaxel Nab-paclitaxel is prepared by high-pressure homogeneization of paclitaxel in the presence of serum albumin, resulting in a nanoparticle colloidal suspensin.(Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8:1038104).These particles have an average size of approximately 130 to 150 nm, approximately one-hundredth the size of a single red blood cell, and do not have the risk of capillary blockage concentration. Sparreboon et al (Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H. Cremophor EL-mediated alteration of paclitaxel distri- bution in human blood: clinical pharmacokinetic implications. Cancer Res. 1999;59(7):14541457).studied in a comparative preclinical and clinical study the pharmacokinetics of nab-paclitaxel and cremophor EL paclitaxel. Using a dose of 260 mg/m2 and 175 mg/m2of nab-paclitaxel and CrEL paclitaxel, the half-life was 21.6 hours and 20.5 hour, respectively, while the aras under curve (AUC) were similar despite the difference dose. Nab-paclitaxel had significantly higher plasma clearance and volume distribution. Disappearance from the blood is bi-phasic.The different

pharmacokinetics of nab-paclitaxel reflects the entrapment absence of Cr-EL-paclitaxel in micelles, which are the principal carriers of paclitaxel in the systemic circulation. When Nab-paclitaxel circulates, the particles are taken up through the endotelial wall, which is facilated not only through leaky vessels but also through albumin, or an albumin receptor.Preclinical work has demonstrated that there is preferential uptake of nab-paclitaxel in the tumor issue as opposed to paclitaxel. The albodin receptors transport albumin-bound drugs is exactly same way as does normal albumin (Schnitzer JE, Oh P. Antibodies to SPARC inhibit albumin binding to SPARC, gp60, and microvascular endothelium. Am J Physiol. 1992;263(6 Pt 2):H1872H1879)Albumin-bound macromolecules can leave the circulation through the leaky tumor microvasculature and accumulate in the interstitium because of the enhanced permeation and retention effects that are characteristics of neoplasia. In addition, albumin is actively transported across micro-vessel endotelial cells via unique receptormeditated transport mechanism using gp-60 receptor. When gp-60(crucial protein found on endotelial plasma membrane involved in mediating the flux of albumin across the endotelial barrier) is activated, it interacts with caveolin-1 protein, leading to the formationof vesicles (caveolae) which then transport their cargo, albumin loaded with cytotoxic agent, across the endotelial cells and into the tumor interstitium where is trapped. Nab-paclitaxel can achieved enhanced intratumoral concentrations. The nab-paclitaxel formulations provides several advantages over the classical formulation of paclitaxel:premedication is not required because the formulation does not include CrEL, the intravenous infusion time of nab-paclitaxel is shorter tan CrEL-paclitaxel (30 minutes versus 3 hours), the set of infusion equipment does not require a particular type of plastic structure, and the volumen for the reconstitution of nab-paclitaxel is reduced because it can be recontituted in normal saline at concentration (Green MR, Manikhas GM, Orlov S, Afanasyev B, Makhson AM, Bhar P, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-lung cancer. Ann Oncol. 2006;17(8):1263 1268). Desai et al (OJO CITADA YA ANTES. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell trans- port of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12(4):13171324).reported an increased activity in terms of efficacy and reduced toxicity of nab-paclitaxel in five animal models. They described the plasma pharmacokinetics and tumor tissue/red blood cell partitioning of radiolabeled paclitaxel from nab-paclitaxel and paclitaxel in athymic mice implanted with a human breast tumor cell line. Nab- paclitaxel partitioned rapidly into red blood cells after parenteral administration, and showed an enhanced biodistribution and prolonged half-life. The concentration of nab-paclitaxel in the tumor cells was 33% higher than standard paclitaxel. Derivatives of paclitaxel In recent years, extensive research has been done to find a way to mitigate the side effects of paclitaxel, by altering its administration. DHA-paclitaxel, PG-paclitaxel, and tumor-activated Taxol prodrugs are undergoing continued testing, and are actually on the way to being introduced into widespread clinical use.

Protarga has linked paclitaxel to docosahexaenoic acid (DHA), a fatty acid easily taken up by tumor cells; the DHA-paclitaxel appears not to be cytotoxic until the bond with DHA is cleaved within the cell.[ Whelan, Jo "Targeted taxane therapy for cancer". Drug Discovery Today (2002). 7 (2): 902. doi:10.1016/S1359-6446(01)02149-3. PMID 11790612. The advantage of DHA-paclitaxel over paclitaxel is DHA-paclitaxels ability to carry much higher concentrations of paclitaxel to the cells, which are maintained for longer periods in the tumor cells, thus increasing their action. With increased activity, DHA-paclitaxel, also known as Taxoprexin, may have a more successful response in cancer patients than paclitaxel, and it may be able to treat more types of cancer than paclitaxel has been able to treat. Cell Therapeutics has formulated PG-paclitaxel, which is paclitaxel bonded to a polyglutamate polymer; tumor cells are significantly more porous to polyglutamate polymers than normal cells, due to the leaky endothelial membranes of tumor cells. PG-paclitaxel has been introduced into clinical use, and has proven to initiate very mild side effects and to effectively treat many patients who were not responsive to the action of Taxol. The PG-paclitaxel may be a very promising anticancer drug, as it is much more selective than paclitaxel for which cells it targets.[cita anterior de Whelan] ImmunoGen has been introducing tumor-activated prodrug (TAP) technology in recent years, and is now working to apply this technology to paclitaxel. Tumor-activated Taxol prodrugs are designed for accurate targeting, by the action of a monoclonal antibody which is very specific to certain cells. Tumor-activated Taxol prodrugs research is progressing, and in mice, the taxane-based TAP completely eradicated human tumour xenografts at non-toxic doses.[cita anterio whelan] ANG1005 is made up of one molecule of a peptide called angiopep-2 joined with three molecules of paclitaxel. It is in phase I clinical trials for some types of cancer. Abraxis BioScience is developing other drugs based on the nab technology platform .Nabdocetaxel (ABI-008, albumin-based nanoparticles of docetaxel), with a mean size of 130 nm, is the 'nab' version of the active drug in TaxotereQ (made by sanofi- aventis), which utilises polysorbate 80/ethanol as a surfactant/solvent to solubilise docetaxel. In preclinical studies, nab-docetaxel exhibited superior antitumour efficacy and decreased toxicity compared to Taxotere in the HCT-116 colon and PC-3 prostate tumour xenografts Nab Technology: A Platform for Next- generation Drug With the validation of the nab-technology demonstratedby the success of Abraxane, Abraxis BioScience is developing other drugs based on the nab technology platform). Nab-docetaxel (ABI-008, albumin-based nanoparticles of docetaxel), with a mean size of 130 nm, is the 'nab' version of the active drug in TaxotereQ (made by sanofi- aventis), which utilises polysorbate 80/ethanol as a surfactant/solvent to solubilise docetaxel. In preclinical studies, nab-docetaxel exhibited superior antitumour efficacy and decreased toxicity compared to Taxotere in the HCT-116 colon and PC-3 prostate tumour xenografts (Desai, Trieu, Yang et al. 2006). ABI-008 is currently in Phase I clinical trials. Nab-rapamycin (ABI-009), with a mean particle size of 90 nm, is a nab-based injectable form of rapamycin. The

mammalian target of rapamycin, mTOR, is a key regulator of cell proliferation and an important target in tumour therapy. The development of rapamycin as an anti-cancer agent has been hampered by poor solubility, low oral bioavailability, and dose-limiting intestinal toxicity. Nab- rapamycin was well tolerated in preclinical studies with no significant toxicity and no hypercholesterolemia and hypertriglyceridemia, a known side-effect of rapamycin. ABI009 was highly effective against MX-1 (breast) HCT- 116 (colon) and HT29 (colon) tumour xenografts (De et at. 2007) and is currently in Phase i clinical trials. Nab-17 AAG (ABI-010) is an albumin-bound form of the hydrophobic Hsp90 inhibitor 17-allylam demethoxygeldanamycin (17-AAG) with a mean size of 110 nm. for novel hydrophobic drugs.