Nab Technology
`
`A Drug Delivery Platform Utilising
`Endothelial gp60 Receptor-based
`Transport and' Tumour-derived SPARe
`for Targeting
`
`Neil Desai
`Vice President of Research and Development
`Abraxis BioScience, LLC, 11755 Wilshire Blvd, Suite 2000, Los Angeles, CA 90025, US
`Tel: + 1 310 883 1300, Fax: + 1 310 9988553
`Email: ndesaiêabraxisbio.com
`
`

`

`Reprinted from Drug Delivery Report Winter 2007/2008
`ISSN 1750-2322
`(Ç 2008, PharmaVentures Ltd
`
`Nab Technology:
`A Drug Delivery Platform Utilising
`Endothelial gp60 Receptor-based
`Transport and Tumour-derived SPARe
`for Targeting
`
`Neil Desai
`Abraxis BioScience, LLC
`
`ggg
`
`\l ~ ~~Q.. PharmaVentures
`
`Experts in deals and alliances
`
`PharmaVentures~ is a registered Trade Mark of PharmaVentures Ltd
`PharmaVentures Ltd, Florey House, Oxford Science Park, Oxford, OX4 4GP, UK
`Email: enquiries(gpharmaventures.com
`
`

`

`Nab Technology:
`
`A Drug Delivery
`Platform Utilising Endothelial' gp60
`Receptor-based Transport and Tumour-
`derived SPARe for Targeting
`
`Vice President of Research and Development
`Abraxis BioScience, LLC, 11755 Wilshire Blvd, Suite iooo, Los Angeles, CA 90025, US
`Tel: +1 310883 BOO, Fax: +1 3109988553, Email: ndesai~abraxisbio.com
`I Neil Desai
`Neil Desai is Vice President of Research and Development at Abraxis Bioscience, Inc. (ABI), in Los Angéles,
`CA. Dr Desai is an inventor of Abraxis' nanotechnology and nanoparticle-albumin bound (nab'") drug
`delivery platform and discovered its novel targeted biological pathway, He was primarily responsible for
`the development of the nanotechnology drug Abraxane~, which was approved by the FDA in January
`2005 as the first in a new class of nanotherapeutics for the treatment of metastatic breast cancer. Prior to
`joining ABI, Dr Desai was Senior Director of Biopolymer Research at VivoRx, Inc., where he developed novel
`encapsulation systems for living cells and was part of the team that performed the world's first successful
`encapsulated islet cell transplant in a diabetic patient. Dr Desai has more than 17 years' experience in the
`research and development of novel drug delivery systems and biocompatible polymers. He holds over 60
`issued US and foreign patents and has authored over 40 peer-reviewed publications. Dr Desai holds an MS
`and a PhD in Chemical Engineering from the University of Texas at Austin and a BS in Chemical Engineering
`from the University of Bombay.
`
`Introduction
`Despite intense research and recent advances in
`drug delivery, the effective and non-toxic delivery of
`hydrophobic therapeutic compounds remains a major
`,challenge for the pharmaceutical industry, The use of
`solvents and surfactants in formulations often impairs
`drug distribution and is associated with increased toxicity
`from these components. As an example, paclitaxel, a
`potent chemotherapeutic agent, is widely used against
`multiple tumour types. Due to its poor water solubility,
`the conventional paclitaxel formulation (Taxol~, made by
`Bristol-Myers Squibb Co.) contains a high concentration
`of Cremophor-EL ~ (polyethoxylated castor oil, made
`by BAS F), which is associated with significant toxicities
`including allergic, hypersensitivity and anaphylactic
`reactions that require premedication and prolonged
`peripheral neuropathy. In addition, paclitaxel is sequestered
`by Cremophor micelles, which prolongs the systemic
`exposure and increases drug toxicity. Several attempts have
`been made to create new, Cremophor-free formulations
`of paclitaxel, e.g. liposomal encapsulated paclitaxel (by
`rug paclitaxel polyglumex (Xyotax~, by
`
`NeoPharm), prod
`
`Cell Therapeutics), polymeric-micellar paclitaxel (Genexol-
`PM~ by Samyang and Nanoxel~ by Dabur Pharma),
`us
`paclitaxel vitamin E emulsion (Tocosol~, by Son
`Pharmaceuticals) and a polymer microsphere formulation
`of paclitaxel (Paclimer~, by Guilford Pharmaceuticals).
`None of these formulations has yet succeeded in obtaining
`approval from the US Food and Drugs Administration
`(FDA). The high risk in developing the novel paclitaxel
`
`Drug Delivery Report Winter 2007/2008
`
`formulations is highlighted by the failure of Xyotax in Phase
`III trials in non-small cell lung cancer (NSCLC) and also the
`most recent failure of Tocosol in its Phase III clinical trial for
`metastatic breast cancer (MBC).
`
`Abraxane: The First Prototype of Nab
`Technology
`Nanoparticle albumin-bound (nab'") technology is a
`patented novel nanotechnology-based drug delivery
`platform developed by Abraxis BioScience, which exploits
`the natural properties of 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 particle form of paclitaxel (see Abraxane package
`insert). Approved by the FDA in January 2005 for the
`treatment of breastcancer after a failure of combination
`chemotherapy for metastatic disease or a relapse within six
`months of adjuvant chemotherapy, Abraxane is recognised
`as the first nanotechnology-based drug' on the market.
`Abraxane consists of particles of paclitaxel in the
`nanometre-size range, stabilised with human albumin. The
`paclitaxel and albumin are not covalentlylinked 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 (Figure 1).
`
`, http://nano,cancer,gov/aboucailiancelq-and-a,asp
`
`

`

`T ,," ...
`SD-1S0 nm~ .,i4
`
`Mean size:
`
`._~--.\"
`,,~?d";¡\v...~
`
`.;\
`";'\
`, \~ ~.~o.'¿ ~ t,
`., .....~\~.,
`
`Concentration-dependent
`dissociation into individual
`drug.bound albumin
`
`.'
`,'-
`,\"-
`. ,;ecuies ~ ~
`, a+ *
`~8k~. 6i +
`4+
`
`Hydrophobic drugs,
`, e.g. paclitaxel, docetaxel,
`rapamycin etc.
`
`Figure 1 - Schematic of nanoparticles prepared by nab-
`technology
`
`CryoTE
`
`StandardE
`
`Figure 2 - Transmission electron micrographs of Abraxane
`(nab-paclitaxel) nanoparticles.
`
`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 (Figure 2). 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
`albumin
`size is virtually identical to that of endogenous
`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 tumour-derived SPARC protein (see below) to achieve
`enhanced drug targeting and penetration in tumours
`(Desai, Trieu, Yao et al. 2006).
`
`Nab Technology: Exploiting the
`Transport Properties of Albumin
`Albumin reversibly binds to and transports a wide range of
`molecules, including bilirubin, free fatty acids, hydrophobic
`vitamins, hormones, calcium and zinc, as well as many
`acidic and hydrophobic drugs. Human serum albumin
`constitutes approximately 60% of total plasma protein
`and is the most important drug carrier protein in plasma
`on account of its high abundance. Albumin can facilitate
`the diffusion of lipophilic drugs into the membrane lipid
`bilayer. In addition, various proliferating tumours are
`known to accumulate albumin and use it as a major energy
`and nitrogen source for de novo protein synthesis.
`The transcytosis of albumin across the endothelium of
`blood vessels is mediated by gp60 and caveolae. Gp60
`(albondin) is a 60-kDa glycoprotein localised on the
`endothelial cell surface that binds to native albumin with a
`high affinity in the nanomolar range (Schnitzer 1992). The
`
`binding of albumin to gp60 induces gp60 clustering and
`association with caveolar-scaffolding protein caveolin-1,
`which leads to the formation of vesicles called caveolae
`that carry both gp60-bound and fluid phase albumin or
`albumin-bound drugs in a process known as transcytosis
`from the apical to the basal membrane, where the vesicle
`contents are released into the sub-endothelial space.
`The importance of gp60 and caveolae in albumin-drug
`transcytosis has been demonstrated in several studies.
`Studies in our lab have demonstrated that nab-paclitaxel
`increased the endothelial binding of paclitaxel by 9.9
`fold (P -( 0.0001) and the transport of paclitaxel across
`microvessel endothelial cell monolayers by 4.2 fold (P -(
`0.0001), as compared to Cremophor-based paclitaxel
`(Desai, Trieu, Yao et at. 2006). In contrast, Taxol cannpt
`utilise and benefit from the gp60-mediated transcytosis,
`as the binding of paclitaxel to albumin and endothelial
`cells is inhibited by the presence of Cremophor even at
`low concentrations (Desai, Trieu, Yao et al. 2006). It is
`
`postulated that this inhibition of transcytosis occurs with
`
`other surfactants as welL.
`The accumulation of albumin and albumin-bound drugs
`in the tumour interstitium is further facilitated by SPARC
`
`(Secreted Protein, Acidic and Rich in Cysteine). SPARC, a
`secreted glycoprotein also referred to as osteonectin and
`BM 40, has been identified as an albumin-binding protein
`(Sage et al. 1984). We recently determined that the SPARC
`binding to albumin is saturable and specific and may play
`an important role in the increased tumour accumulation of
`albumin-bound drugs (Trieu et at. 2007). Over-expression
`of SPARC in multiple tumour types, including breast,
`prostate, oesophagus, gastric, colorectal, liver, lung,
`kidney, skin melanoma, bladder, head and neck, thyroid
`and brain tumours such as glioma, invasive meningioma,
`astrocytoma, etc., is associated with increased tumour
`invasion, metastasis and poor prognosis (Framson and Sage
`2004). We have previously shown that Abraxane achieved
`33% higher intratumour paclitaxel concentration when
`compared with an equal dose of Taxol in SPARC-positive
`MX-1 tumour xenografts (Desai, Trieu, Yao et al. 2006)
`(Figure 3). More importantly, our studies demonstrated that
`increased SPARC levels in tumours correlate with enhanced
`response to Abraxane. The SPARC over-expressing line PC31
`SP exhibited enhanced response to Abraxane compared
`
`~---- - ~
`
`1 min after I.V. mjectlon
`
`. nab-paditaxel containing 0.3% fluorescent marker.
`t Imaging under Hg.lamp with 50D-550 nm bandpass
`
`excitation.
`
`15 min after i.V.lnjection
`
`Figure 3 - Rapid uptake into tumours demonstrated by
`fluorescent labelled paclitaxel nanoparticles.
`
`Drug Delivery Report Winter 2007/2008
`
`

`

`with wild type PC3 xenograft (Trieu et al. 2007). In head
`and neck cancer patients there was correlation between
`high levels of SPARC expression and tumour response to
`Abraxane (Trieu et al. 2006).
`
`In summary, our research suggests that gp60 transport
`in tumour blood vessels and SPARC expression in tumours
`can enhance the transport and accumulation of albumin-
`bound paclitaxel in tumours, therefore improving its
`tumour targeting and efficacy. The transcytosis of
`albumin-bound paclitaxel across the endothelial barrier
`is facilitated by the binding to the gp60 receptor and
`caveolar transport. In the tumour interstitial space, albumin
`paclitaxel complexes bind to SPARC and are rapidly
`internalised in tumour cells via a non-lysosomal pathway
`(Figure 4).
`
`Clinical Results with Abraxane
`The advantages of nab technology can be directly
`translated into clinical benefits for Abraxane. In a Phase I
`trial, the lower toxicities of Abraxane allowed the
`administration of 70% higher dose than the approved
`dose of Taxol (300 mg/m2 vs 175 mg/m2, q3w) over a
`shorter infusion time (30 minutes vs 3 hours), without the
`need for corticosteroid premedication (Ibrahim et al. 2002).
`In a randomised Phase Iii study in patients with metastatic
`breast cancer (MBC), compared with Taxol at 175 mg/m2
`q3w, Abraxane administered at 260 mg/m2 q3w had
`statistically significantly higher response rates, longer time
`to tumour progression, and increased survival in the subset
`of patients receiving second-line or greater treatment. The
`incidence of grade 4 neutropenia and hypersensitivity
`reactions with Abraxane were significantly lower than in
`the Taxol group. Grade 3 neuropathy was higher for
`Abraxane due to higher dosage but was easily managed
`and improved quickly (Gradishar et al. 2005). These results
`were further supported by preliminary results from an
`open-label study of 210 Chinese patients with MBC, which
`suggested that Abraxane (260 mg/m2 IV over 30 minutes,
`q3w) provided higher response rates and longer time to
`
`tumour progression without increased toxicity compared to
`Taxol (175 mg/m2 IV over 3 hours, q3w) (Guan et al. 2007).
`In a randomised Phase ii clinical trial of first-line treatment
`of MBC in 300 patients, administration of Abraxane at 150
`mg/m2 weekly or 300 mg/m2 q3w resulted in longer
`progression-free survival compared to Taxotere (100 mg/m2
`q3w) while the 100 mg/m2 qw dose of Abraxane resulted
`in equivalent progression-free survival but a much
`improved toxicity profile compared to Taxotere (Gradishar
`et al. 2006). Preliminary clinical data with 40 patients with
`MBC showed that combination of Abraxane with
`bevacizumab (Avastin4i, by Genentech) was well tolerated
`and resulted in an overal,l response rate of 48.5% (Link et
`al. 2007). In addition, preliminary findings from Phase II
`studies of Abraxane in combination with gemcitabine pr
`capecitabine as first-line therapy for patients with MBC
`suggested that combination therapy was active in this
`patient population (Moreno-Aspitia and Perez 2005).
`Besides breast cancer, Abraxane is also being researched
`in a variety of other solid tumours. In one recent multi-
`centre Phase II study of patients with non-small cell
`lung cancer (NSCLC), Abraxane administered as a single
`agent at a dose of 260 mg/m2 q3w was found to be
`well tolerated and yielded a response rate of 16% and
`a disease control rate of 49% (Green et al. 2006), with
`median time to progression and median survival of 6 and
`11 months, respectively. Abraxane administered at 125
`mg/m2 q3/4w as first-line, single-agent therapy in elderly
`patients with NSCLC resulted in objective response and
`50%, respectively, with
`disease control rates of 30% and
`progression-free and overall survivals of 5 and 11 months,
`respectively (Rizvi et al. 2006). Other ongoing studies are
`exploring Abraxane in combination with platinum-based
`regimens, with and without bevacizumab, as first-line
`therapy in NSCLC (Reynolds et at. 2007). In a multi-centre
`Phase II study of patients with metastatic melanoma,
`preliminary data showed that Abraxane administered
`at 100 mg/m2 q3/4w (previously treated patients) or
`150 mg/m2 q3/4w (chemotherapy-naïve patients) was
`
`i
`
`,~
`
`gpGO receptor
`
`Red blood cell
`
`I Albumin-bou~d Drug I
`
`gp60 Receptor
`
`Caveolae
`
`SPARC
`
`,
`,
`,
`,
`
`Figure 4 - Mechanisms for the transport and accumulation of Abraxane in tumours.
`
`Drug Delivery Report Winter 2007/2008
`
`Albumin-drug
`Accumulation
`
`

`

`generally well tolerated except for incidence of peripheral
`neuropathy, with progression-free survival and overall
`survival of 3.5 and 12.9 months for the previously treated
`patients, and 4.5 and 9.6 months for the naïve patients,
`respectively. Preliminary data from an ongoing Phase II
`trial also highlighted the potential safety and efficacy for
`Abraxane as a single agent in platinum-sensitive patients
`with recurrent ovarian, peritoneal or fallopian tube cancer
`(Teneriello et al. 2007). Other preliminary data supported
`potential roles for Abraxane in carcinoma of the tongue
`and other head and neck cancers (Trieu et al. 2006).
`
`Nab Technology: A Platform for Next-
`generation Drugs
`
`With the validation of the nab-technology demonstrated
`by the success of Abraxane, Abraxis BioScience is
`developing other drugs based on the nab technology
`platform (Figure 5).
`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.
`ABI-009 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-01 0) is an albumin-bound form
`of the hydrophobic Hsp90 inhibitor 17-allylamino-17-
`
`Abraxaneofi~~i
`
`. ," ',~\
`",:..",uuo Kli: 11
`
`:.~::.._.- rh
`I, :~i;","""'.lllii
`lOOmg ~iir¡~
`~::, ~~ ,Ii'
`:=;;,.'"'i'= !
`ii"
`~.- ~.~~:;~jP
`ABI-007
`
`Figure 5 - Abraxane and other drugs in the nab-technology
`
`pipeline of Abraxis BioScience.
`
`demethoxygeldanamycin (17-AAG) with a mean size of
`110 nm. Hsp90 is an attractive therapeutic target as a
`chaperone for conformational maturation of oncogenic
`signalling proteins, including HER-2/ErbB2, Akt, Raf-1,
`Bcr-Abl and mutated p53 (Tao et al. 2005). ABI-O 1 0 clinical
`trials are planned for 2008.
`Nab-5404 (ABI-011), with a mean particle size of 90
`nm, is a nanoparticle albumin-bound form of a novel
`thiocolchicine dimer that possesses dual inhibition of
`tubulin polymerisation and topoisomerase i activities. In
`our studies, nab-5404 exhibits strong antiangiogenic and
`vascular targeting agent (VTA) activities. ABI-011 clinical
`trials are planned for 2008.
`Abraxis BioScience is also applying its nab~technology to
`indications outside of oncology. Because of its low tøxicity,
`Coroxane~, the albumin-bound particle form of paclitaxel
`used in cardiovascular applications, was well tolerate'd
`by systemic administration for the treatment of in-stent
`restenosis in coronary arteries (Margolis et al. 2007).
`Coroxane is being investigated in Phase ii studies for the
`treatment of coronary restenosis and peripheral restenosis
`and in Phase i studies for hemodialysis graft failure.
`Additionally, Abraxis BioScience is actively partnering
`with third parties to develop nab technology-based
`products for novel hydrophobic drugs.
`
`Summary
`Nab technology uses a proprietary manufacturing process
`to allow non-covalent association of hydrophobic drugs
`with albumin and the formation of nanoparticles that
`are readily water dispersible without any solvent and
`surfactant. Nab technology achieved improved and
`targeted drug delivery to tumours by exploiting the
`following natural properties of albumin:
`· It acts as a drug carrier to enhance the solubility of
`hydrophobic drugs.
`· It accumulates selectively and actively in tumours.
`· It actively transports across the endothelium of blood
`vessels via gp60 and caveolae-mediated transcytosis.
`· It increases retention in the tumour interstitium by
`association with the albumin-binding protein SPARe.
`· It facilitates the diffusion of lipophilic drug across cell
`membranes.
`Nab technology is a drug delivery system that turns the
`tumour nutrient albumin and cancer biology against the
`tumour itself by hijacking the biological pathways of
`albumin.
`Following the successful spin-off in November
`2007 from its generic drug business section APP
`Pharmaceuticals, Inc. (NASDAQ: APPX), the new Abraxis
`BioScience (NASDAQ:ABIl) is now a fully integrated
`biotechnology company dedicated to delivering progressive
`therapeutics and core technologies that offer patients
`and medical professionals saferand more effective
`treatments for cancer and other critical illnesses. The
`Abraxis portfolio includes the world's first and only
`protein-based nanoparticle chemotherapeutic compound
`
`Drug Delivery Report Winter 2007/2008
`
`

`

`(Abraxane). Abraxane is approved for marketing in the US,
`Canada and India. Abraxis BioScience is actively expanding
`the use of Abraxane to other world markets including
`Europe, Japan, China, Australia, Russia and South Korea.
`Numerous clinical trials are testing the use of Abraxane in
`primary, neoadjuvant and metastasis settings for cancer
`types including breast cancer, non-small cell lung cancer,
`ovarian cancer, melanoma, prostate cancer, head and
`neck cancer, and pancreatic cancer, and in combination
`with various agents including bevacizumab, trastazumab,
`lapatinib, sunitinib, epirubicin, cyclophosphamide,
`carboplatin, 5-fluorouracil, gemcitabine and rapamycin.
`The successful formulation of other hydrophobic drugs
`with nab technology demonstrates its broad application
`as a drug delivery platform. Nab technology-based
`chemotherapeutics could target multiple types of
`malignancies through exploitation of natural properties of
`albumin and tumour biology.
`
`References
`De, T., Trieu, v., Vim, Z., Cordia, J., Yang, A., Beals, B., Ci, S.,
`Louie, L. and Desai, N., 2007, 'Nanoparticle albumin-bound (nab)
`rapamycin as an anticancer agent', paper presented at American
`Association for Cancer Research (AACR) Annual Meeting, Los
`Angeles, CA, 14-18 ApriL.
`Desai, N., Trieu, v., Yang, A., De, T., Cordia, J., Vim, Z., Ci,
`S., Louie, L., Beals Grim, B., Azoulay, J., Soon-Shiong, P. and
`Hawkins, M., 2006, 'Enhanced efficacy and safety of nanoparticle
`albumin-bound nab-docetaxel versus taxotere', paper presented at
`American Association for Cancer Research (AACR), 96th Annual
`Meeting, Washington, DC, 1-5 ApriL.
`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, vol.
`12, no. 4, pp. 1317-24.
`Framson, P. E. and Sage, E. H., 2004, 'SPARC and tumor growth:
`Where the seed meets the soil?', Journal of Cellular Biochemistry,
`vol. 92, no. 4, pp. 679-90.
`
`Gradishar, w., Krasnojon, D., Cheporov, S., Makhson, A.,
`Manikhas, G. and Hawkins, M. J., 2006, 'A randomized phase 2
`trial of qw or q3w ABI-007 (ABX) vs. q3W solvent-based docetaxel
`(TXT) as first-line therapy in metastatic breast cancer (MBC)', paper
`presented at San Antonio Breast Cancer Symposium (SABCS)
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`N., Bhar, P., Hawkins, M. and O'Shaughnessy, J., 2005, 'Phase
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`polyethylated castor oil-based paclitaxel in women with breast
`cancer', Journal of Clinical Oncology, vol. 23, no. 31, pp. 7794-
`803.
`Green, M. R., Manikhas, G. M., Orlov, S., Afanasyev, B., Makhson,
`A. M., Bhar, P. and Hawkins, M. J., 2006, 'Long-term survival
`differences for bronchiolo-alveolar carcinoma patients with
`ipsilateral intrapulmonary metastasis at diagnosis', Annals of
`Oncology, vol. 17, no. 8, pp. 1263-8.
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`Huang, J., Yao, Z. and Hawkins, M. J., 2007, 'Randomized study
`comparing nab-paclitaxel with solvent-based paclitaxel in Chinese
`patients (pts) with metastatic breast cancer (MBC)', Journal of
`Clinical Oncology, American Society of Clinical Oncology (ASCO)
`Annual Meeting Proceedings Part I, vol. 25, no. 18S.
`
`Drug Delivery Report Winter 2007/2008
`
`first-in-human safety and dose-finding
`
`Ibrahim, N. K., Desai, N., Legha, S., Soon-Shiong, P., Theriault, R.
`L., Rivera, E., Esmaeli, B., Ring, S. E., Bedikian, A., Hortobagyi, G.
`N. and Ellerhorst, J. A., 2002, 'Phase i and pharmacokinetic study
`of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle
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`pp. 1038-44.
`Link, J. S., Waisman, J. R., Nguyen, B. and Jacobs, C. I., 2007,
`'Bevacizumab and albumin-bound paclitaxel treatment in
`metastatic breast cancer', Clinical Breast Cancer, vol. 7, no. 10, pp.
`779-83.
`Margolis, J., McDonald, J., Heuser, R., Klinke, P., Waksman, R.,
`Virmani, R., Desai, N. and Hilton, D., 2007, 'Systemic nanoparticle
`paclitaxel (nab-paclitaxel) for in-stent restenosis i (SNAPIST-I): a
`study', Clinical Cardiology,
`vol. 30, no. 4, pp. 165-70. .
`Moreno-Aspitia, A. and Perez, E. A., 2005, 'North Central Cancer
`Treatment Group N0531: Phase /I trial of weekly albumin-bound
`paclitaxel (ABI-007; AbraxaneTM) in combination with gemcitabine
`in patients with metastatic breast cancer', Clinical Breast Cahcer,
`vol. 6, no. 4,pp. 361-4.
`Reynolds, c., Barrera, D., Vu, D. Q., Jotte, R., Spira, A. I.,
`Weissman, C. H., Boehm, K. A., lIegbodu, D., Pritchard, S. and
`Asmar, L., 2007 , 'An open-label, phase /I trial of nanoparticle
`albumin bound paclitaxel (nab-paclitaxel), carboplatin, and
`bevacizumab in first-line patients with advanced non-squamous
`non-small cell lung cancer (NSCLC)', Journal of Clinical Oncology,
`American Society of Clinical Oncology (ASCO) Annual Meeting
`Proceedings Part i, vol. 25, no. 18S.
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