ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast ffi ovary > prostate > colon. The LD 50 and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophorbased paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophorbased paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.Paclitaxel is a naturally occurring complex diterpenoid product extracted from the bark of the western yew, Taxus brevifolia (1). The unique mechanism of paclitaxel of stabilizing tubulin polymer and promoting microtubule assembly effectively inhibits mitosis, motility, and intracellular transport within cancerous cells and results in antineoplastic activity against a wide variety of malignancies (2 -4). Paclitaxel is widely used for the treatment of breast, lung, and advanced ovarian cancers (5).Because paclitaxel has very little aqueous solubility, Cremophor-based paclitaxel uses a Cremophor EL/ethanol vehicle. The amount of Cremophor EL necessary to deliver the requisite doses of paclitaxel is significantly higher than that given with any other marketed drug containing Cremophor EL, reaching plasma concentrations up to 0.4% and remaining >0.1% for 24 hours following a dose of 175 mg/m 2 (6). The Cremophor EL -containing paclitaxel formulation causes severe allergic, hypersensitivity, and anaph...

A B S T R A C T PurposeThe trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and MethodsPatients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. ResultsA total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2 , respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18 F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. ConclusionThe regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.

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Purpose: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophorethanol (Taxol). Experimental Design: ABI-007 andTaxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m 2 , 30 minutes; n = 14) or Taxol (175 mg/m 2 , 3 hours; n = 13), with cycles repeated every 3 weeks. Results:The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m 2 (P = 0.048) and 663.8 versus 433.4 L/m 2 (P = 0.040), respectively]. Conclusions: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated asTaxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.Paclitaxel, a naturally occurring hydrophobic diterpenoid product extracted from the bark of the western yew (Taxus brevifolia; ref. 1), exerts its anticancer effects by promotion of tubulin polymerization, stabilization of microtubules, blockade of cells at the G 2 -M interface, and induction of apoptosis (2, 3). Paclitaxel is used as standard therapy for ovarian, breast, and non -small cell lung cancer and has recognized antitumor activity in several other malignancies (4).Currently, paclitaxel is marketed commercially in a formulation that contains a solvent system of Cremophor and dehydrated ethanol USP (Taxol, Bristol-Myers Squibb Co., Princeton, NJ; ref. 4). However, the amount of Cremophor in paclitaxel per administration is relatively high and has been associated with serious toxicities, including severe, sometimes fatal, hypersensitivity reactions (5 -8). Consequently, patients who receive Taxol must be premedicated with steroids and antihistamines to reduce the risk of such reactions, and special non -di(2-ethylhexyl) phthalate tubing and in-line filters are required for i.v. administration (4). Therefore, the toxicologic and pharmacologic behavior of Cremophor in the context of chemotherapeutic treatment with paclitaxel is important.ABI-007 (Abraxane, American BioScience, Inc., Santa Monica, CA), a Cremophor-free, albumin-bound, nanoparticle paclitaxel (mean diameter, f130 nm), was developed to retain the therapeutic benefits of paclitaxel but eliminate the toxicities associated with Cremophor in the Taxo...

SPARC up-regulation is a poor prognostic factor in head and neck cancer. It was hypothesized that because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel (nab-paclitaxel). This hypothesis was tested by correlating the response to nab-paclitaxel and SPARC tumor expression in a retrospective analysis of a 60-patient clinical study of nab-paclitaxel as monotherapy against head and neck cancer. Sixteen tumor specimens were available for analysis. There were 11 responders (CR/PR) and 5 nonresponders (SD/PD) among the 16 nab-paclitaxel-treated patients (12/16 SPARC-positive, 75%). Response to nab-paclitaxel was higher for SPARC-positive patients (10/12, 83%) than SPARC-negative patients (1/4, 25%). The SPARC-negative patients exhibited significantly lower response than the overall response rate among all 60 patients (1/4, 25% vs 45/60, 75%). Although preliminary, data are supportive of the hypothesis that SPARC overexpression may correlate with response to nab-paclitaxel. If confirmed in larger studies, treatment with nab-paclitaxel may convert a poor prognosis SPARC-positive patient population into a group with better clinical outcomes.

Nanomedicine is the application of nanotechnology to the discipline of medicine: the use of nanoscale materials for the diagnosis, monitoring, control, prevention, and treatment of disease. Nanomedicine holds tremendous promise to revolutionize medicine across disciplines and specialties, but this promise has yet to be fully realized. Beyond the typical complications associated with drug development, the fundamentally different and novel physical and chemical properties of some nanomaterials compared to materials on a larger scale (i.e., their bulk counterparts) can create a unique set of opportunities as well as safety concerns, which have only begun to be explored. As the research community continues to investigate nanomedicines, their efficacy, and the associated safety issues, it is critical to work to close the scientific and regulatory gaps to assure that nanomedicine drives the next generation of biomedical innovation.