Evidence for Delivery of Abraxane via a Denatured-Albumin Transport System.

Abraxane, an albumin-bound paclitaxel nanoparticle formulation, is superior to conventional paclitaxel preparations because it has better efficacy against unresectable pancreatic cancer. Previous reports suggest that this better efficacy of Abraxane than conventional paclitaxel preparation is probably due to its transport through Gp60, an albumin receptor on the surface of vascular endothelial cells. The increased tumor accumulation of Abraxane is also caused by the secreted protein acid and rich in cysteine in the tumor stroma. However, the uptake mechanism of Abraxane remains poorly understood. In this study, we demonstrated that the delivery of Abraxane occurred via different receptor pathways from that of endogenous albumin. Our results showed that the uptake of endogenous albumin was inhibited by a Gp60 pathway inhibitor in the process of endocytosis through endothelial cells or tumor cells. In contrast, the uptake of Abraxane-derived HSA was less affected by the Gp60 pathway inhibitor but significantly reduced by denatured albumin receptor inhibitors. In conclusion, these data indicate that Abraxane-derived HSA was taken up into endothelial cells or tumor cells by a mechanism different from normal endogenous albumin. These new data on distinct cellular transport pathways of denatured albumin via gp family proteins different from those of innate albumin shed light on the mechanisms of tumor delivery and antitumor activity of Abraxane and provide new scientific rationale for the development of a novel albumin drug delivery strategy via a denatured albumin receptor.

A novel preparative method for nanoparticle albumin-bound paclitaxel with high drug loading and its evaluation both in vitro and in vivo.

We developed a novel preparative method for nanoparticle albumin-bound (nab) paclitaxel with high drug loading, which was based on improved paclitaxel solubility in polyethylene glycol (PEG) and self-assembly of paclitaxel in PEG with albumin powders into nanoparticles. That is, paclitaxel and PEG were firstly dissolved in ethanol, which was subsequently evaporated under vacuum. The obtained liquid was then mixed with human serum albumin powders. Thereafter, the mixtures were added into phosphate-buffered saline and nab paclitaxel suspensions emerged after ultrasound. Nab paclitaxel was finally acquired after dialysis and freeze drying. The drug loading of about 15% (W/V) were realized in self-made nab paclitaxel, which was increased by approximately 50% compared to 10% (W/V) in Abraxane. Now this new preparative method has been authorized to obtain patent from China and Japan. The similar characteristics of self-made nab paclitaxel compared to Abraxane were observed in morphology, encapsulation efficiency, in vitro release, X-ray diffraction analysis, differential scanning calorimetry analysis, and circular dichroism spectra analysis. Consistent concentration-time curves in rats, biodistributions in mice, anti-tumor activities in mice, and histological transmutation in mice were also found between Abraxane and self-made nanoparticles. In a word, our novel preparative method for nab paclitaxel can significantly improve drug loading, obviously decrease product cost, and is considered to have potent practical value.

Formulation effects on paclitaxel transfer and uptake in the human placenta.

Diagnosis and treatment of breast cancer in pregnancy can result in morbidity and mortality for the mother and fetus. Many new paclitaxel nanoformulations commercially available worldwide for breast cancer treatment are being adopted due to favorable dosing regimens and side effect profiles, but their transplacental transport and resultant fetal exposure remain unknown. Here, we examine three formulations: Taxol (paclitaxel dissolved in Kolliphor EL and ethanol); Abraxane (albumin nanoparticle); and Genexol-PM (polymeric micelle). In the ex vivo dually perfused human placental cotyledon, placental accumulation of Genexol-PM is higher than Taxol, and both nanoformulations have lower maternal concentrations of paclitaxel over time. In vitro studies of these formulations and fluorescent nanoparticle analogs demonstrate that Genexol-PM allows paclitaxel to overcome P-glycoprotein efflux, but Abraxane behaves as a free drug formulation. We anticipate that these findings will impact future development of rational and safe treatment strategies for pregnancy-associated breast cancer and other diseases.

Reduction-Responsive and Multidrug Deliverable Albumin Nanoparticles: An Antitumor Drug to Abraxane against Human Pancreatic Tumor-Bearing Mice.

Many macromolecular antitumor drugs were developed based on the enhanced permeability and retention (EPR) effect, for example, albumin-bound paclitaxel nanoparticles (nab-PTX and Abraxane) and pegylated liposomal doxorubicin (Doxil). However, these EPR effect-based therapeutic systems are less effective in malignant tumors with low vascular permeability, such as pancreatic tumors. Because the EPR effect depends on nanoparticles' size, we first determined nanoparticles' size associated with a high tumor-targeting rate in a human pancreatic tumor xenograft model with low vascular permeability. Abraxane appears to behave as an albumin monomer (7 nm) in the blood circulation following intravenous injection. The in vitro and in vivo tumor-targeted delivery and antitumor activity of PTX-loaded albumin nanoparticles were significantly improved by optimizing the mean nanoparticle diameter to 30 nm. Furthermore, nitric oxide was added to 30 nm PTX-loaded albumin nanoparticles to examine the feasibility of albumin nanoparticles as a platform for multiple drug delivery. Their antitumor effect was evaluated in an orthotopic transplantation mouse model of a human pancreatic tumor. The nitric oxide PTX-loaded 30 nm albumin nanoparticle treatment on model mice achieved a significantly higher survival rate than Abraxane treatment. These findings suggest that 30 nm albumin nanoparticles have a high therapeutic effect as a useful platform for multiple drugs against human pancreatic tumors.

Albumin Nanoparticle of Paclitaxel (Abraxane) Decreases while Taxol Increases Breast Cancer Stem Cells in Treatment of Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a high rate of metastasis, which is associated with breast cancer stem-like cells (CSCs). Although Taxol (micelle formulation of paclitaxel) is the first line chemotherapy to treat TNBC, it increases CSCs in residual tumors. Abraxane, albumin nanoparticle of paclitaxel, showed lower plasma concentration compared to Taxol in both human and animal models, but it is not clear why Abraxane showed superior efficacy to Taxol in treatment of metastatic breast cancer in humans. In this study, we intend to investigate if Abraxane eliminates CSCs for its better efficacy. The results showed that Abraxane showed similar cytotoxicity in SUM149 cells in comparison with Taxol. Although Abraxane showed 3- to 5-fold lower blood drug concentration compared to Taxol, it achieved similar tumor drug concentration and 10-fold higher tumor/plasma ratio in SUM149 xenograft NOD/SCID mouse model. In addition, Abraxane and Taxol showed similar efficacy to shrink the tumor size in orthotopic breast cancer NOD/SCID mouse model. However, Abraxane decreased breast CSCs frequency by 3- to 9-fold, while Taxol increased breast CSCs frequency in an orthotopic breast cancer NOD/SCID mouse model. Furthermore, Abraxane increased 3- to 15-fold intracellular uptake in both ALDH+ CSCs and differentiated ALDH- cells in comparison with Taxol, which provides a mechanism for Abraxane's superior efficacy to eliminate CSCs in comparison with Taxol. Our data suggest albumin nanoparticle Abraxane may have a broad implication to enhance drug's efficacy by eliminating breast cancer stem cells for treatment of metastatic diseases.

Photothermal augment stromal disrupting effects for enhanced Abraxane synergy chemotherapy in pancreatic cancer PDX mode.

Cancer-associated fibroblasts (CAFs) are crucial for forming the desmoplastic stroma that is associated with chemoresistance in pancreatic ductal adenocarcinoma (PDAC). In the clinic, depleting dense stroma in PDAC tumor tissue is a promising chemotherapeutic strategy. In this study, we report that the local hyperthermia can reduce the number of CAFs in the PDAC PDX mouse mode, which further augments chemotherapeutic efficiency in the PDAC therapy. To achieve this goal, a photothermal-chemotherapeutic agent termed as Abraxane@MoSe2 as a vehicle-saving theranostic probe is prepared by simply mixing an FDA-approved Abraxane and hydrophobic MoSe2 nanosheets via electrostatic and hydrophobic interactions. After labeling with indocyanine green (ICG) dye on the Abraxane@MoSe2, a relatively high fluorescence signal (near infrared second (NIR II)) in PDX tumors can be obtained, which can be precisely imaging-guide local photothermal-chemotherapy upon the 808 nm laser irradiation in vivo. Importantly, the synergy therapeutic efficiency in PDAC is enhanced by the photothermal effect reduction of the number of CAFs, which is confirmed viaα-SMA and vimentin immunofluorescence analysis. This combined therapeutic strategy may provide a new sight for PDAC therapy.

Drug-binding albumins forming stabilized nanoparticles for efficient anticancer therapy.

Albumin is a serum transport protein, which has been utilized as a carrier for a variety of drugs to improve their delivery efficiency and to obtain favorable pharmacokinetic profiles. However, natural albumin possesses only a few high-affinity binding sites for a limited number of drugs. This results in deficiencies in drug-loading and serum stability, and consequently, in impaired therapeutic efficacy. Herein, BSA was modified with different isothiocyanate conjugates (BSA-ITCs), which self-assembled with paclitaxel (PTX) to produce BSA-ITCs/PTX nanoparticles. Among these BSA-ITCs, phenethyl isothiocyanate (PEITC)-modified BSA (BSA-PEITC35) conjugates effectively loaded PTX and formed highly stable BSA-PEITC35/PTX nanoparticles. Molecular modeling studies suggested that PEITC groups in BSA-PEITC35 can significantly lower the PTX binding free energy. BSA-PEITC35/PTX showed enhanced stability, prolonged blood circulation and increased tumor accumulation than unmodified BSA/PTX, and exerted more potent antitumor activity than both BSA/PTX and Abraxane in subcutaneous mouse tumor models after intravenous administration.

Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice.

PURPOSE: Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. METHODS: PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. RESULTS: A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. CONCLUSIONS: The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.

Efficacy of two-weekly nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy for breast cancer.

Aim: Compare the two-weekly regimens of nanoparticle albumin-bound paclitaxel (nab-P) with solvent-based paclitaxel (sb-P) as neoadjuvant chemotherapy for breast cancer. Materials & methods: Patients (n = 162) with operable early breast cancer received four cycles of dose-dense epirubicin and cyclophosphamide followed by four two-weekly cycles of nab-P (n = 83) or sb-P (n = 79), with trastuzumab when needed. Results: Across all the patients, the ypT0 ypN0 and ypT0/is ypN0 pathological complete response rates in the nab-P group were not superior to those in the sb-P group. However, pathological complete response rates for triple-negative breast cancer were significantly better with nab-P than with sb-P. Meanwhile, nab-P also induced more peripheral sensory neuropathy. Conclusion: The two-weekly nab-P regimen is a good neoadjuvant chemotherapy choice for triple-negative breast cancer.

Facile Deposition of Manganese Dioxide to Albumin-Bound Paclitaxel Nanoparticles for Modulation of Hypoxic Tumor Microenvironment To Improve Chemoradiation Therapy.

Tumor microenvironment with hypoxia and excess hydrogen peroxide (H2O2) tremendously limits the effect of chemoradiation therapy of colorectal cancer. For the first time, we developed a facile method to deposit manganese dioxide (MnO2) on the surface of albumin bound paclitaxel nanoparticles (ANPs-PTX) to obtain MnO2-functioned ANPs-PTX (MANPs-PTX). In the tumor microenvironment, MANPs-PTX could consume excess hydrogen peroxide (H2O2) to produce abundant oxygen for tumor oxygenation and improve chemoradiation therapy. Meanwhile, the released Mn2+ from MANPs-PTX had excellent T1 magnetic resonance imaging (MRI) performances for tumor detection. Notably, the obtained MANPs-PTX would be a promising theranostic agent and have potential clinical application prospects.

Neoadjuvant Therapy with Weekly Nanoparticle Albumin-Bound Paclitaxel for Luminal Early Breast Cancer Patients: Results from the NABRAX Study (GEICAM/2011-02), a Multicenter, Non-Randomized, Phase II Trial, with a Companion Biomarker Analysis.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) disease. MATERIALS AND METHODS: Women with ER+, HER2-, stage II-III BC were treated preoperatively with four cycles of weekly nab-Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. RESULTS: Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%-38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%-34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%-13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine-rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009-0.689; p = .0216). CONCLUSION: Despite failing to confirm an RCB III rate ≤16% in nab-Paclitaxel-treated patients, the RCB 0+I rate indicates a significant drug antitumor activity with low rates of grade 3-4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011-004476-10; ClinicalTrials.gov: NCT01565499). IMPLICATIONS FOR PRACTICE: The pathological response rate (residual cancer burden [RCB]; Symmans criteria) of nanoparticle albumin-bound paclitaxel administered as neoadjuvant treatment for early estrogen receptor-positive, human epidermal growth factor receptor 2-negative disease was evaluated. Whereas poor response (RCB III) was 24.7%, similar to that for docetaxel, good response (RCB 0+I) reached 23.0%, far superior to the 13% for docetaxel, while keeping toxicity low. Exploratory biomarker analysis suggests secreted protein, acidic, cysteine-rich overexpression in tumor cells as a potential predictor of complete response (RCB 0). Findings point to an encouraging single-agent neoadjuvant treatment with low toxicity, which warrants future research and development.

Gemcitabine enhances the transport of nanovector-albumin-bound paclitaxel in gemcitabine-resistant pancreatic ductal adenocarcinoma.

The mechanism for improved therapeutic efficacy of the combination therapy with nanoparticle albumin-bound paclitaxel (nAb-PTX) and gemcitabine (gem) for pancreatic ductal adenocarcinoma (PDAC) has been ascribed to enhanced gem transport by nAb-PTX. Here, we used an orthotopic mouse model of gem-resistant human PDAC in which increasing gem transport would not improve the efficacy, thus revealing the importance of nAb-PTX transport. We aimed to evaluate therapeutic outcomes and transport of nAb-PTX to PDAC as a result of (1) encapsulating nAb-PTX in multistage nanovectors (MSV); (2) effect of gem on caveolin-1 expression. Treatment with MSV/nAb-PTX + gem was highly efficient in prolonging animal survival in comparison to other therapeutic regimens. MSV/nAb-PTX + gem also caused a substantial increase in tumor PTX accumulation, significantly reduced tumor growth and tumor cell proliferation, and increased apoptosis. Moreover, gem enhanced caveolin-1 expression in vitro and in vivo, thereby improving transport of nAb-PTX to PDAC. This data was confirmed by analysis of PDACs from patients who received gem-based neo-adjuvant chemotherapy. In conclusion, we found that nAb-PTX treatment of gem-resistant PDAC can be enhanced by (1) gem through up-regulation of caveolin-1 and (2) MSV through increasing accumulation of nAb-PTX in the tumor.

Layer-by-layer assembly of hierarchical nanoarchitectures to enhance the systemic performance of nanoparticle albumin-bound paclitaxel.

Although protein-bound paclitaxel (PTX, Abraxane®) has been established as a standard PTX-based therapy against multiple cancers, its clinical success is limited by unfavorable pharmacokinetics, suboptimal biodistribution, and acute toxicities. In the present study, we aimed to apply the principles of a layer-by-layer (LbL) technique to improve the poor colloidal stability and pharmacokinetic pattern of nanoparticle albumin-bound paclitaxel (nab-PTX). LbL-based nab-PTX was successfully fabricated by the alternate deposition of polyarginine (pARG) and poly(ethylene glycol)-block-poly (L-aspartic acid) (PEG-b-PLD) onto an albumin conjugate. The presence of protective entanglement by polyamino acids prevented the dissociation of nab-PTX and improved its colloidal stability even at a 100-fold dilution. The combined effect of high nanoparticle internalization and controlled release of PTX from LbL-nab-PTX increased its cytotoxicity in MCF-7 and MDA-MB-231 breast cancer cells. LbL-nab-PTX consistently induced apoptosis in approximately 52% and 22% of MCF-7 and MDA-MB-231 cancer cells, respectively. LbL assembly of polypeptides effectively prevented exposure of PTX to the systemic environment and thereby inhibited drug-induced hemolysis. Most importantly, LbL assembly of polypeptides to nab-PTX effectively increased the blood circulation potential of PTX and improved therapeutic efficacy via a significantly higher area under the curve (AUC)0-∞. We report for the first time the application of LbL functional architectures for improving the systemic performance of nab-PTX with a view toward its clinical translation for cancer therapy.

Co-delivery of all-trans-retinoic acid enhances the anti-metastasis effect of albumin-bound paclitaxel nanoparticles.

Co-delivery of all-trans-retinoic acid and paclitaxel using albumin-bound nanoparticles demonstrated a significantly improved anti-metastatic effect to breast cancer both in vitro and in vivo. Notably, the co-delivery nanoparticles exhibited more pronounced therapeutic effects than the combination of two free drugs or two HSA loaded single drugs.

Paclitaxel-Loaded TPGS-b-PCL Nanoparticles: In Vitro Cytotoxicity and Cellular Uptake in MCF-7 and MDA-MB-231 Cells versus mPEG-b-PCL Nanoparticles and Abraxane®.

Nanomedicines have become an attractive platform for the development of novel drug delivery systems in cancer chemotherapy. Polymeric nanoparticles (NPs) represent one of the best well-investigated nanosized carriers for delivery of antineoplastic compounds. The "Pegylation strategy" of drug delivery systems has been used in order to improve carrier biodistribution, however, some nanosized systems with PEG on their surface have exhibited poorly-cellular drug internalization. In this context, the purpose of the present study was to compare in vitro performance of two paclitaxel (PTX)-loaded NPs systems based on two biocompatible copolymers of alpha tocopheryl polyethylene glycol 1000 succinate-block-poly(ε-caprolactone) (TPGS-b-PCL) and methoxyPEG- block-poly(ε-caprolactone) (mPEG-b-PCL) in terms of citotoxicity and PTX cellular uptake. Fur- thermore, TPGS-b-PCL NPs were also copared with the commercially available PTX nano-sized formulation Abraxane®. Both TPGS-b-PCL and mPEG-b-PCL derivates were synthesized by ring opening polymerization of ε-caprolactone employing microwaved radiation. NPs were obtained by a solvent evaporation technique where the PTX content was determined by reverse-phase HPLC. The resulting NPs had an average size between 200 and 300 nm with a narrow size distribution. Also both NPs systems showed a spherical shape. The in vitro PTX release profile from the NPs was characterized employing the dialysis membrane method where all drug-loaded formulations showed a sustained and slow release of PTX. Finally, in vitro assays demonstrated that PTX-loaded TPGS- b-PCL exhibited a significant higher antitumor activity than PTX-loaded mPEG-b-PCL NPs and Abraxane® against an estrogen-dependent (MCF-7) and an estrogen independent (MDA-MB-231) breast cancer cells lines. Furthermore TPGS-b-PCL NPs showed a significant increase on PTX cellular uptake, for both breast cell lines, in comparison with mPEG-b-PCL NPs and Abraxane®. Overall findings confirmed that NPs based on TPGS-b-PCL as biomaterial demonstrated a better in vitro performance than NPs with PEG, representing an attractive alternative for the development of novel nanosized carriers for anticancer therapy.

A toxic organic solvent-free technology for the preparation of PEGylated paclitaxel nanosuspension based on human serum albumin for effective cancer therapy.

Clinically, paclitaxel (PTX) is one of most commonly prescribed therapies against a wide range of solid neoplasms. Despite its success, the clinical applicability of PTX (Taxol) is severely hampered by systemic toxicities induced by Cremophor EL. While attempts to bypass the need for Cremophor EL have been developed through platforms such as Abraxane, nab relies heavily on the use of organic solvents, namely, chloroform. The toxicity introduced by residual chloroform poses a potential risk to patient health. To mitigate the toxicities of toxic organic solvent-based manufacture methods, we have designed a method for the formulation of PTX nanosuspensions (PTX-PEG [polyethylene glycol]-HSA [human serum albumin]) that eliminates the dependence on toxic organic solvents. Coined the solid-dispersion technology, this technique permits the dispersion of PTX into PEG skeleton without the use of organic solvents or Cremophor EL as a solubilizer. Once the PTX-PEG dispersion is complete, the dispersion can be formulated with HSA into nanosuspensions suitable for intravenous administration. Additionally, the incorporation of PEG permits the prolonged circulation through the steric stabilization effect. Finally, HSA-mediated targeting permits active receptor-mediated endocytosis for enhanced tumor uptake and reduced side effects. By eliminating the need for both Cremophor EL and organic solvents while simultaneously increasing antitumor efficacy, this method provides a superior alternative to currently accepted methods for PTX delivery.

Quantitative Proteomic Analysis of Cellular Resistance to the Nanoparticle Abraxane.

Abraxane, an FDA-approved albumin-bound nanoparticle (NP) form of paclitaxel (PTX) to treat breast cancer and nonsmall cell lung cancer (NSCLC), has been demonstrated to be more effective than the original Taxol, the single molecule form. We have established a cell line from NSCLC A549 cells to be resistant to Abraxane. To further understand the molecular mechanisms involved in the NP drug resistance, global protein expression profiles of Abraxane sensitive (A549) and resistant cells (A549/Abr), along with the treatment of Abraxane, have been obtained by a quantitative proteomic approach. The most significantly differentially expressed proteins are associated with lipid metabolism, cell cycle, cytoskeleton, apoptosis pathways and processes, suggesting several mechanisms are working synergistically in A549 Abraxane-resistant cells. Overexpression of proteins in the lipid metabolism processes, such as E3 ubiquitin-protein ligase RNF139 (RNF139) and Hydroxymethylglutaryl-CoA synthase (HMGCS1), have not been reported previously in the study of paclitaxel resistance, suggesting possibly different mechanism between nanoparticle and single molecular drug resistance. In particular, RNF139 is one of the most up-regulated proteins in A549 Abraxane-resistant cell line, but remains no change when the resistant cells were further treated with Abraxane and down-regulated in the sensitive cells after 4 h treatment of Abraxane. This study shows the use of a proteomic strategy to understand the unique response of drug resistant cells to a nanoparticle therapeutic.

Albumin-bound paclitaxel in solid tumors: clinical development and future directions.

Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.

Abraxane, the Nanoparticle Formulation of Paclitaxel Can Induce Drug Resistance by Up-Regulation of P-gp.

P-glycoprotein (P-gp) can actively pump paclitaxel (PTX) out of cells and induces drug resistance. Abraxane, a nanoparticle (NP) formulation of PTX, has multiple clinical advantages over the single molecule form. However, it is still unclear whether Abraxane overcomes the common small molecule drug resistance problem mediated by P-gp. Here we were able to establish an Abraxane-resistant cell line from the lung adenocarcinoma cell line A549. We compared the transcriptome of A549/Abr resistant cell line to that of its parental cell line using RNA-Seq technology. Several pathways were found to be up or down regulated. Specifically, the most significantly up-regulated gene was ABCB1, which translates into P-glycoprotein. We verified the overexpression of P-glycoprotein and confirmed its function by reversing the drug resistance with P-gp inhibitor Verapamil. The results suggest that efflux pathway plays an important role in the Abraxane-resistant cell line we established. However, the relevance of this P-gp mediated Abraxane resistance in tumors of lung cancer patients remains unknown.

Finding the Needle in the Haystack: Characterization of Trace Crystallinity in a Commercial Formulation of Paclitaxel Protein-Bound Particles by Raman Spectroscopy Enabled by Second Harmonic Generation Microscopy.

Second harmonic generation (SHG) microscopy was used to rapidly identify regions of interest for localized confocal Raman spectroscopy measurements in order to quantify crystallinity within lyophilized Abraxane powder (protein bound paclitaxel for injectable suspension). Water insoluble noncentrosymmetric crystalline particles ranging from ∼1 to 120 µm were identified by SHG, with wide variability in crystal size and frequency observed between several batches of Abraxane. By targeting the Raman analysis to these localized regions identified by SHG, the required measurement time was decreased over 2 orders of magnitude, from 8 h to 2 s. Experimental Raman spectra of SHG active domains in Abraxane were in good agreement with experimental spectra of pure crystalline paclitaxel. These collective results are consistent with up to 30% of the active ingredient being present as poorly soluble crystalline particulates in some batches of Abraxane.