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1.  Peptide ligand and PEG-mediated long-circulating liposome targeted to FGFR overexpressing tumor in vivo 
Background and methods
Paclitaxel, a widely used antitumor agent, has limited clinical application due to its hydrophobicity and systemic toxicity. To achieve sustained and targeted delivery of paclitaxel to tumor sites, liposomes composed of egg phosphatidylcholine, cholesterol, and distearolyphosphatidyl ethanolamine-N-poly(ethylene glycol) (PEG2000) were prepared by a lipid film method. In addition, the liposomes also contained truncated fibroblast growth factor fragment-PEG-cholesterol as a ligand targeting the tumor marker fibroblast growth factor receptor. Physicochemical characteristics, such as particle size, zeta potential, entrapment efficiency, and release profiles were investigated. Pharmacokinetics and biodistribution were evaluated in C57BL/6 J mice bearing B16 melanoma after intravenous injection of paclitaxel formulated in Cremophor EL (free paclitaxel), conventional liposomes (CL-PTX), or in targeted PEGylated liposomes (TL-PTX).
Compared with CL-PTX and free paclitaxel, TL-PTX prolonged the half-life of paclitaxel by 2.01-fold and 3.40-fold, respectively, in plasma and improved the AUC0→t values of paclitaxel by 1.56-fold and 2.31-fold, respectively, in blood. Biodistribution studies showed high accumulation of TL-PTX in tumor tissue and organs containing the mononuclear phagocyte system (liver and spleen), but a considerable decrease in other organs (heart, lung, and kidney) compared with CL-PTX and free paclitaxel.
The truncated fibroblast growth factor fragment-conjugated PEGylated liposome has promising potential as a long-circulating and tumor-targeting carrier system.
PMCID: PMC3423151  PMID: 22923988
paclitaxel; truncated fibroblast growth factor fragment; poly(ethylene glycol); liposomes; targeted drug delivery
2.  Preparation, Pharmacokinetics, Biodistribution, Antitumor Efficacy and Safety of Lx2-32c-Containing Liposome 
PLoS ONE  2014;9(12):e114688.
Lx2-32c is a novel taxane that has been demonstrated to have robust antitumor activity against different types of tumors including several paclitaxel-resistant neoplasms. Since the delivery vehicles for taxane, which include cremophor EL, are all associated with severe toxic effects, liposome-based Lx2-32c has been developed. In the present study, the pharmacokinetics, biodistribution, antitumor efficacy and safety characteristics of liposome-based Lx2-32c were explored and compared with those of cremophor-based Lx2-32c. The results showed that liposome-based Lx2-32c displayed similar antitumor effects to cremophor-based Lx2-32c, but with significantly lower bone marrow toxicity and cardiotoxicity, especially with regard to the low ratio of hypersensitivity reaction. In comparing these two delivery modalities, targeting was superior using the Lx2-32c liposome formulation; it achieved significantly higher uptake in tumor than in bone marrow and heart. Our data thus suggested that the Lx2-32c liposome was a novel alternative formulation with comparable antitumor efficacy and a superior safety profiles to cremophor-based Lx2-32c, which might be related to the improved pharmacokinetic and biodistribution characteristics. In conclusion, the Lx2-32c liposome could be a promising alternative formulation for further development.
PMCID: PMC4266495  PMID: 25506928
3.  Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery 
Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)0–∞ (20.343 ± 9.119 μg · h · mL−1 vs 5.196 ± 1.426 μg · h · mL−1), greater clearance (2.050 ± 0.616 L · kg−1 · h−1 vs 0.556 ± 0.190 L · kg−1 · h−1), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC0–∞ in liver, lung, and spleen (all P < 0.01), but not in heart or kidney.
PMCID: PMC3141875  PMID: 21796250
high-pressure homogenization; tissue distribution; surfactant
4.  A Liposomal Formulation Able to Incorporate a High Content of Paclitaxel and Exert Promising Anticancer Effect 
Journal of Drug Delivery  2010;2011:629234.
A liposome formulation for paclitaxel was developed in this study. The liposomes, composed of naturally unsaturated and hydrogenated phosphatidylcholines, with significant phase transition temperature difference, were prepared and characterized. The liposomes exhibited a high content of paclitaxel, which was incorporated within the segregated microdomains coexisting on phospholipid bilayer of liposomes. As much as 15% paclitaxel to phospholipid molar ratio were attained without precipitates observed during preparation. In addition, the liposomes remained stable in liquid form at 4°C for at least 6 months. The special composition of liposomal membrane which could reduce paclitaxel aggregation could account for such a capacity and stability. The cytotoxicity of prepared paclitaxel liposomes on the colon cancer C-26 cell culture was comparable to Taxol. Acute toxicity test revealed that LD50 for intravenous bolus injection in mice exceeded by 40 mg/kg. In antitumor efficacy study, the prepared liposomal paclitaxel demonstrated the increase in the efficacy against human cancer in animal model. Taken together, the novel formulated liposomes can incorporate high content of paclitaxel, remaining stable for long-term storage. These animal data also demonstrate that the liposomal paclitaxel is promising for further clinical use.
PMCID: PMC3065869  PMID: 21490755
5.  Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy 
Paclitaxel is an anticancer agent effective for the treatment of breast, ovarian, lung, and head and neck cancer. Because of water insolubility, paclitaxel is formulated with the micelle-forming vehicle Cremophor EL to enhance drug solubility. However, the addition of Cremophor EL results in hypersensitivity reactions, neurotoxicity, and altered pharmacokinetics of paclitaxel. To circumvent these unfavorable effects resulting from the addition of Cremophor EL, efforts have been made to develop new delivery systems for paclitaxel administration. For example, ABI-007 is a Cremophor-free, albumin-stabilized, nanoparticle paclitaxel formulation that was found to have significantly less toxicity than Cremophor-containing paclitaxel in mice. Pharmacokinetic studies indicate that in contrast to Cremophor-containing paclitaxel, ABI-007 displays linear pharmacokinetics over the clinically relevant dose range of 135–300 mg/m2. In a phase III study conducted in patients with metastatic breast cancer, patients treated with ABI-007 achieved a significantly higher objective response rate and time to progression than those treated with Cremophor-containing paclitaxel. Together these findings suggest that nanoparticle albumin-bound paclitaxel may enable clinicians to administer paclitaxel at higher doses with less toxicity than is seen with Cremophor-containing paclitaxel. The role of this novel paclitaxel formulation in combination therapy with other antineoplastic agents needs to be determined.
PMCID: PMC1661618  PMID: 18360550
paclitaxel; nanoparticle; albumin-bound paclitaxel; pharmacokinetics
6.  Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients 
To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism.
Twenty-seven female patients with metastatic breast cancer received epirubicin 90 mg m−2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m−2. Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined.
An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration-time curve (AUC) of epirubicinol (+0.5 µmol l−1 h [95% CI for the difference: 0.29, 0.71],+0.66 µmol l−1 h [95% CI for the difference: 0.47, 0.85] and +0.82 µmol l−1 h [95% CI for the difference: 0.53, 1.11] at paclitaxel doses of 175, 200 and 225 mg m−2, respectively), compared with epirubicin followed by paclitaxel 30 h later (0.61±0.1 µmol l−1 h). A significant increase in epirubicin AUC (+0.74 µmol l−1 h [95% CI for the difference: 0.14, 1.34] and +1.09 µmol l−1 h [95% CI for the difference: 0.44, 1.74]) and decrease in drug clearance (CLTB) (−25.35 l h−1 m−2[95% CI for the difference: −50.18, −0.52] and −35.9 l h−1 m−2[95% CI for the difference −63,4,−8,36]) occurred in combination with paclitaxel 200 and 225 mg m−2 with respect to the AUC (3.16±0.6 µmol l−1 h) and CLTB (74.4±28.4 l h−1 m−2) of epirubicin followed by paclitaxel 30 h later. An Emax relationship was observed between neutropaenia and the time over which paclitaxel plasma concentrations were equal to or greater than 0.1 µmol l−1 (tC0.1). The tC0.1 value predicted to yield a 50% decrease in neutrophil count was 7.7 h. Finally, Cremophor EL markedly inhibited the metabolism of epirubicin to epirubicinol in whole blood.
Paclitaxel/Cremophor EL affects the disposition of epirubicinol and epirubicin. Furthermore, the slope factor of the Emax relationship between neutropenia and tC0.1 of paclitaxel suggests that the drugs might also interact at the pharmacodynamic level.
PMCID: PMC1874362  PMID: 11994057
drug interaction; epirubicin; metabolism; paclitaxel; pharmacodynamics; pharmacokinetics
7.  Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer 
A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.
The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.
The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.
Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.
PMCID: PMC3352867  PMID: 22605931
telodendrimer; nanomicelle; paclitaxel; microSPECT/CT; imaging guided drug delivery
8.  SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice 
Gut  2013;63(6):974-983.
Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA).
nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, KrasG12D;p53flox/−;p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response.
nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents.
PMCID: PMC4033275  PMID: 24067278
Pancreatic Cancer
9.  VIP-targeted Cytotoxic Nanomedicine for Breast Cancer 
Cancer chemotherapy is hampered by serious toxicity to healthy tissues. Conceivably, encapsulation of cytotoxic drugs in actively-targeted, biocompatible nanocarriers could overcome this problem. Accordingly, we used sterically stabilized mixed micelles (SSMM) composed of biocompatible and biodegradable phospholipids to solubilize paclitaxel (P), a hydrophobic model cytotoxic drug, and deliver it to breast cancer in rats. To achieve active targeting, the surface of SSMM was grafted with a ligand, human vasoactive intestinal peptide (VIP) that selectively interacts with its cognate receptors overexpressed on breast cancer cells. We found that even in vitro cytotoxicity of P-SSMM-VIP was 2-fold higher that that of free paclitaxel (p<0.05). Given the unique attributes of P-SSMM and P-SSMM-VIP, most notable small hydrodynamic diameter (~15nm) and stealth properties, biodistribution of paclitaxel was significantly altered. Accumulation of paclitaxel in breast tumor was highest for P-SSMM-VIP, followed by P-SSMM and Cremophor based paclitaxel (PTX). Importantly, bone marrow accumulation of paclitaxel encapsulated in both SSMM-VIP and SSMM was significantly less than that of PTX. Administration of clinically-relevant dose of paclitaxel (5mg/kg) as P-SSMM-VIP and P-SSMM eradicated carcinogen-induced orthotopic breast cancer in rats, whereas PTX decreased tumor size by only 45%. In addition, a 5-fold lower dose (1mg/kg) of paclitaxel in actively targeted P-SSMM-VIP was associated with ~80% reduction in tumor size while the response to PTX and P-SSMM was significantly less. Hypotension was not observed when VIP was grafted onto SSMM. Based on our findings, we propose further development of effective and safe VIP-grafted phospholipid micelle nanomedicines of anti-cancer drugs for targeted treatment of solid tumors in humans.
PMCID: PMC3546828  PMID: 23336096
phospholipid mixed micelles; targeted drug delivery; human vasoactive intestinal peptide; breast cancer; paclitaxel; MNU-induced breast cancer
10.  The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients 
British Journal of Cancer  2001;85(10):1472-1477.
The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m−2 dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m−2, for the other three 15 ml m−2. Prior to paclitaxel administration patients received 15 mg kg−1 oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C max) and area under the concentration–time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m−2, paclitaxel C max and AUC values were 0.10 ± 0.06 μM and 1.29 ± 0.99 μM h−1, respectively, whereas these values were 0.31 ± 0.06 μM and 2.61 ± 1.54 μM h−1, respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m−2, paclitaxel excretion in faeces was 38.8 ± 13.0% of the administered dose, whereas this value was 18.3 ±15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel © 2001 Cancer Research Campaign
PMCID: PMC2363961  PMID: 11720431
paclitaxel; oral administration; Cremophor EL
11.  Paclitaxel Nano-Delivery Systems: A Comprehensive Review 
Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles.
PMCID: PMC3806207  PMID: 24163786
Nanoparticles; Poly(lactic-co-glycolic acid); Nanocapsules; Drug-polymer conjugates; Multi-drug resistance; Solid lipid nanoparticles
12.  Assessing the effectiveness and safety of liposomal paclitaxel in combination with cisplatin as first-line chemotherapy for patients with advanced NSCLC with regional lymph-node metastasis: study protocol for a randomized controlled trial (PLC-GC trial) 
Trials  2013;14:45.
Lung cancer is still the leading cause of cancer-related mortality worldwide. Around 80 to 85% of lung cancers are non-small cell lung cancer (NSCLC). Regional lymphatic metastasis is a frequent occurrence in NSCLC, and the extent of lymphatic dissemination significantly determines the prognosis of patients with NSCLC. Hence, identification of alternative treatments for these patients should be considered a priority. Liposomal paclitaxel is a new formulation composed of paclitaxel and liposomes, with favorable pharmacokinetic properties. In particular, it produces dramatically higher drug concentrations in the lymph nodes than occurs with the current formulations of paclitaxel, thus we believe that patients with NSCLC with regional lymphatic metastasis may benefit from this new drug. Cisplatin-based doublet chemotherapy is recommended as the first-line treatment for patients with advanced NSCLC. We have designed a trial to assess whether first-line chemotherapy using liposomal paclitaxel combined with cisplatin (LP regimen) is superior to gemcitabine combined with cisplatin (GP regimen) in efficacy (both short-term and long-term efficacy) and safety (adverse events; AEs).
This is a prospective, open-label, controlled randomized clinical trial (RCT) to assess the therapeutic effects and safety of liposomal paclitaxel. The study aims to enroll 126 patients, who will be randomly allocated to one of the two treatment groups (LP and GP), with 63 patients in each group. Patients will receive four to six cycles of the assigned chemotherapy, and primary outcome will be assessed every two cycles. Patients will be recommended for surgery if the tumor becomes resectable. All participants will be followed up for at least 12 months. The objective response rate (ORR), changes in regional lymphatic metastasis (including number and size) and TNM (tumor, node, metastasis) staging will be the primary outcome measures. Progression-free survival, objective survival, median survival time, 1-year survival rate, toxicity, and time to disease progression will be the secondary outcome measures.
A systematic search has indicated that this proposed study will be the first RCT to evaluate whether liposomal paclitaxel plus cisplatin will have beneficial effects, compared with gemcitabine plus cisplatin, on enhancing ORR, changing TNM staging, improving long-term survival, and reducing the frequency of AEs for patients with NSCLC with regional lymphatic metastasis.
Trial registration Identifier: ChiCTR-TRC-12602105
PMCID: PMC3599280  PMID: 23413951
Liposomal paclitaxel; Cisplatin; Gemcitabine; Regional lymph node metastasis; Trials
13.  Update on taxane development: new analogs and new formulations 
The taxanes (paclitaxel and docetaxel) represent an important class of antineoplastic agents that interfere with microtubule function leading to altered mitosis and cellular death. Paclitaxel (Taxol®) was originally extracted from a yew tree (Taxus spp., Taxaceae) a small slow-growing evergreen, coniferous tree. Due to the initial scarcity of paclitaxel, docetaxel (Taxotere®) a semisynthetic analog of paclitaxel produced from the needles of European yew tree, Taxus baccata was developed. Docetaxel differs from paclitaxel in two positions in its chemical structure and this small alteration makes it more water soluble. Today, paclitaxel and docetaxel are widely prescribed antineoplastic agents for a broad range of malignancies including lung cancer, breast cancer, prostate cancer, Kaposi’s sarcoma, squamous cell carcinoma of the head and neck, gastric cancer, esophageal cancer, bladder cancer, and other carcinomas. Although very active clinically, paclitaxel and docetaxel have several clinical problems including poor drug solubility, serious dose-limiting toxicities such as myelosuppression, peripheral sensory neuropathy, allergic reactions, and eventual development of drug resistance. A number of these side effects have been associated with the solvents used for dilution of these antineoplastic agents: Cremophor EL for paclitaxel and polysorbate 80 for docetaxel. In addition, reports have linked these solvents to the alterations in paclitaxel and docetaxel pharmacokinetic profiles. In this review, we provide preclinical and clinical data on several novel taxanes formulations and analogs which are currently US Food and Drug Administration (FDA)-approved or in clinical development in various solid tumor malignancies. Of the new taxanes nab-paclitaxel and cabazitaxel have enjoyed clinical success and are FDA-approved; while many of the other compounds described in this review are unlikely to be further developed for clinical use in daily practice. Furthermore, the successful clinical emergence of novel nontaxane microtubule-targeting chemotherapy agents such as epothilones and eribulin is liable to further restrict the development of novel taxanes.
PMCID: PMC3523563  PMID: 23251087
taxane(s); novel taxanes; taxane analogs; new taxane formulations; new antimicrotubule agents
14.  A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979) 
To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl.
The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg m−2 or 225 mg m−2) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1.
The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor EL™ impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 µg l−1 h to 19115 µg l−1 h following paclitaxel 175 mg m−2) when zosuquidar Cmax was greater than 350 µg l−1. This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 µg l−1). A standard dose of 175 mg m−2 of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition.
This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax > 350 µg l−1) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials.
PMCID: PMC1884334  PMID: 12848775
paclitaxel; P-glycoprotein modulator; population pharmacokinetics; Zosuquidar 3HCl
15.  Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial 
Annals of Oncology  2010;21(11):2227-2232.
Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival.
Patients and methods: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel (arm A) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned.
Results: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively.
Conclusions: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms.
PMCID: PMC2962260  PMID: 20439345
liposomal cisplatin; NSCLC
16.  Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats 
The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome.
The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111.
High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome.
A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the 111In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation.
PMCID: PMC3282608  PMID: 22359447
Indium-111; vinorelbine; liposome; pharmacokinetics; radiochemotherapy
17.  Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer 
OncoTargets and therapy  2009;2:179-188.
Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL® (CrEL) and Tween 80® respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane®), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.
PMCID: PMC2886338  PMID: 20616905
breast cancer; nab-paclitaxel; chemotherapy
18.  A Pharmacodynamic Study of the P-glycoprotein Antagonist CBT-1® in Combination With Paclitaxel in Solid Tumors 
The Oncologist  2012;17(4):512.
This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin.
CBT-1® was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. 99mTc-sestamibi imaging was performed on the same schedule. The area under the concentration–time curve from 0–3 hours (AUC0–3) was determined for 99mTc-sestamibi.
Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%–100% lower (p < .0001) with CBT-1®. Among 10 patients who completed imaging, the 99mTc-sestamibi AUC0–3 for liver (normalized to the AUC0–3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1® administration. Lung uptake was not changed.
CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1® to evaluate its ability to modulate drug uptake in tumor tissue.
Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1−/−; p53−/− mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of “targeted therapies,” trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.
PMCID: PMC3336838  PMID: 22416063
19.  Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel 
Abraxane (ABI-007) is a 130 nm albumin-bound (nab™) particle formulation of paclitaxel, devoid of any additional excipients. We hypothesized that this change in formulation alters the systemic disposition of paclitaxel compared with conventional solvent-based formulations (sb-paclitaxel, Taxol®), and leads to improved tolerability of the drug.
Patients and Methods:
Patients with malignant solid tumors were randomized to receive the recommended single agent dose of nab-paclitaxel (260 mg/m2 as a 30 minute infusion) or sb-paclitaxel (175 mg/m2 as a 3 hour infusion). Following cycle 1, patients crossed over to the alternate treatment. Pharmacokinetic studies were carried out for the first cycle of sb-paclitaxel and the first two cycles of nab-paclitaxel.
Seventeen patients were treated, with 14 receiving at least one cycle each of nab-paclitaxel and sb-paclitaxel. No change in nab-paclitaxel pharmacokinetics was found between the first and second cycles (P =0.95), suggesting limited intrasubject variability. Total drug exposure was comparable between the two formulations (P= 0.55) despite the dose difference. However, exposure to unbound paclitaxel was significantly higher following nab-paclitaxel administration, due to the increased free fraction (0.063 ± 0.021 vs 0.024 ± 0.009, P <0.001).
This study demonstrates that paclitaxel disposition is subject to considerable variability depending on the formulation used. Since systemic exposure to unbound paclitaxel is likely a driving force behind tumoral uptake, these findings explain, at least in part, previous observations that the administration of nab-paclitaxel is associated with augmented antitumor efficacy as compared with solvent-based paclitaxel.
PMCID: PMC2661025  PMID: 18594000
20.  Design and characterization of anionic PEGylated liposomal formulation loaded with paclitax for ovarian cancer 
Journal of Pharmacy & Bioallied Sciences  2012;4(Suppl 1):S17-S18.
Despite its strong antitumor activity, paclitaxel (Taxol®) has limited clinical applications due to its low aqueous solubility and hypersensitivity caused by cremophor EL and ethanol which is the vehicle used in the current commercial product. In an attempt to develop a pharmaceutically acceptable formulation that could replace Taxol®, we have prepared PEGylated liposomes containing paclitaxel to improve its solubility and physicochemical stability. Its percent drug entrapment (PDE), mean particle size, zeta potential and in vitro release profile were determined. The optimized PEGylated liposomes provided high percent entrapment efficiency (64.29%) and mean particle size of 228.6 nm. The electroflocculation method showed 5 mol% of DSPE-mPEG2000 was required to obtain maximum stability for PEGylated liposome. In vitro release data showed its long circulating characteristic. Paclitaxel loaded PEGylated liposomes can be considered a promising long circulating paclitaxel delivery with absence of side effects related to Taxol®.
PMCID: PMC3467822  PMID: 23066189
Antitumor activity; electroflocculation; in vitro release; thin film hydration
Pharmaceutical research  2007;24(9):1691-1701.
The rationale for intraperitoneal (IP) chemotherapy is to expose peritoneal tumors to high drug concentrations. While multiple phase III trials have established the significant survival advantage by adding IP therapy to intravenous therapy in optimally debulked ovarian cancer patients, the use of IP chemotherapy is limited by the complications associated with indwelling catheters and by the local chemotherapy-related toxicity. The present study evaluated the effects of drug carrier on the disposition and efficacy of IP paclitaxel, for identifying strategies for further development of IP treatment.
Experimental Design
Three paclitaxel formulations, i.e., Cremophor formulation, Cremophor-free paclitaxel-loaded gelatin nanoparticles and polymeric microparticles, were evaluated for peritoneal targeting advantage and antitumor activity in mice. Whole body autoradiography and scanning electron microscopy were used to visualize the spatial drug distribution in tissues. A kinetic model, depicting the multiple processes involved in the peritoneal-to-plasma transfer of paclitaxel and its carriers, was established to determine the mechanisms by which drug carrier alters the peritoneal targeting advantage.
Autoradiographic results indicated that IP injection yielded much higher paclitaxel concentrations in intestinal tissues compared to intravenous injection. Compared to the Cremophor and nanoparticle formulations, the microparticles showed slower drug clearance from the peritoneal cavity, slower absorption into the systemic circulation, longer residence time in the peritoneal cavity, 5- to 22-times greater peritoneal targeting advantage and ∼2-times longer increase in survival time (p<0.01 for all parameters).
Our results indicate the important roles of drug carrier in determining the peritoneal targeting advantage and antitumor activity of IP treatment.
PMCID: PMC2774739  PMID: 17447121
paclitaxel; intraperitoneal therapy; carrier; microparticles
22.  Design and development of multivesicular liposomal depot delivery system for controlled systemic delivery of acyclovir sodium 
AAPS PharmSciTech  2005;6(1):E35-E41.
The aim of the present study was to design a depot delivery system of acyclovir sodium using multivesicular liposomes (MVLs) to overcome the limitations of conventional therapies and to investigate its in vivo effectiveness for sustained delivery. MVLs of acyclovir were prepared by the reverse phase evaporation method. The loading efficiency of the MVLs (45%–82%) was found to be 3 to 6 times higher than conventional multilamellar vesicles (MLVs). The in vitro release of acyclovir from MVL formulations was found to be in a sustained manner and only 70% of drug was released in 96 hours, whereas conventional MLVs released 80% of drug in 16 hours. Following intradermal administration to Wistar rats, the MVL formulations showed effective plasma concentration for 48 hours compared with MLVs and free drug solution (12–16 hours). Cmax values of MVL formulations were significantly less (8.6–11.4 μg/mL) than MLV and free drug solution (12.5 μg/mL). The AUC0–48 of the MVL formulations was 1.5- and 3-fold higher compared with conventional liposomes and free drug solution, respectively. Overall, formulations containing phosphatidyl glycerol as negatively charged lipid showed better results. The MVL delivery system as an intradermal depot offers the advantage of a very high loading and controlled release of acyclovir for an extended period of time. The increase in AUC and decrease in Cmax reflects that the MVL formulations could reduce the toxic complications and limitations of conventional IV and oral therapies.
PMCID: PMC2750409  PMID: 16353961
multivesicular liposomes; acyclovir sodium; herpes simplex virus; sustained delivery; intradermal depot systems
23.  Improved pharmacokinetics and reduced toxicity of brucine after encapsulation into stealth liposomes: role of phosphatidylcholine 
Brucine was encapsulated into stealth liposomes using the ammonium sulfate gradient method to improve therapeutic index.
Materials and methods:
Four brucine stealth liposomal formulations were prepared, which were made from different phosphatidylcholines (PCs) with different phase transition temperatures (Tm). The PCs used were soy phosphatidylcholine (SPC), dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoyl phosphatidylcholine (DSPC). The stabilities, pharmacokinetics, and toxicities of these liposomal formulations were evaluated and compared.
Size, zeta potential, and entrapment efficiency of brucine-loaded stealth liposomes (BSL) were not influenced by PC composition. In vitro release studies revealed that drug release rate increased with decreased Tm of PCs, especially with the presence of rat plasma. After intravenous administration, the area under the curve (AUC) values of BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC in plasma were 7.71, 9.24, 53.83, and 56.83-fold as large as that of free brucine, respectively. The LD50 values of brucine solution, BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC following intravenous injection were 13.17, 37.30, 37.69, 51.18, and 52.86 mg/kg, respectively. It was found in calcein retention experiments that the order of calcein retention in rat plasma was SPC < DPPC << HSPC < DSPC stealth liposomes.
PC composition could exert significant influence on the stabilities, pharmacokinetics, and toxicities of brucine-loaded stealth liposomes. DSPC or HSPC with Tm above 50°C should be used to prepare the stealth liposomal formulation for the intravenous delivery of brucine. However, it was found in the present paper that the pharmacokinetics and toxicity of BSL were not influenced by the PC composition when the Tm of the PC was in the range of −20°C to 41°C.
PMCID: PMC3418081  PMID: 22904620
brucine; stealth liposomes; phosphatidylcholine; pharmacokinetics; toxicity
24.  Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients 
Anti-cancer drugs  2008;19(3):275-281.
The formulation excipient Cremophor EL (CrEL) is known to limit absorption of oral paclitaxel given together with cyclosporin A (CsA). We hypothesized that the use of oral Genetaxyl, a paclitaxel formulation containing only 20% CrEL would have an improved oral bioavailability. Cohorts of 6 patients were treated with oral Genetaxyl at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received intravenous (i.v.) Genetaxyl (175 mg/m2, 3-hour infusion). Three additional patients received one dose of generic i.v. paclitaxel (Genaxol, containing 50% CrEL; 175 mg/m2, 3-hour infusion). The median area under the plasma concentration-time curve (AUC) and peak concentration of total paclitaxel following i.v. Genetaxyl were lower than those for i.v. Genaxol, as a result of significantly increased clearance (P = 0.017), and the AUC ratio for unbound to total paclitaxel for i.v. Genetaxyl was about 2 times higher than that for i.v. Genaxol (P = 0.0077). After oral administration of Genetaxyl at doses of 60, 120, and 180 mg/m2, the median total paclitaxel AUCs were 1.29, 1.60, and 1.85 µg×h/mL, respectively, suggesting a less than proportional increase in systemic exposure with increasing doses. The corresponding median values for the apparent bioavailability of oral Genetaxyl were similar when calculated either based on data for total paclitaxel (30.1%) or unbound paclitaxel (30.6%) when compared to i.v. Genetaxyl.
PMCID: PMC2718426  PMID: 18510173
Oral paclitaxel; Pharmacokinetics; Cyclosporin A; Formulation; Cremophor
25.  Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings 
Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood–brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo.
The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice.
The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC50 of the CLA-PTX microemulsion was 1.61 ± 0.83 μM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol® had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD50 of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg.
CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.
PMCID: PMC3529648  PMID: 23269869
CLA-PTX; microemulsion; pharmacokinetics; brain tumor; antitumor efficacy; safety

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