Assessment of polymeric mucin-drug interactions.

Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in polymeric mucins, a major structural component of mucus, potentially acting as important physiological regulators of mucosal drug absorption, there are no reports that have systematically evaluated the interaction between mucins and drugs. In this study, we assessed the potential interaction between human polymeric mucins (MUC2, MUC5B, and MUC5AC) and various drugs with different chemical profiles by simple centrifugal method and fluorescence analysis. We found that paclitaxel, rifampicin, and theophylline likely induce the aggregation of MUC5B and/or MUC2. In addition, we showed that the binding affinity of drugs for polymeric mucins varied, not only between individual drugs but also among mucin subtypes. Furthermore, we demonstrated that deletion of MUC5AC and MUC5B in A549 cells increased the cytotoxic effects of cyclosporin A and paclitaxel, likely due to loss of mucin-drug interaction. In conclusion, our results indicate the necessity to determine the binding of drugs to mucins and their potential impact on the mucin network property.

Single-cell impedance cytometry of anticancer drug-treated tumor cells exhibiting mitotic arrest state to apoptosis using low-cost silver-PDMS microelectrodes.

Chemotherapeutic drugs such as paclitaxel and vinblastine interact with microtubules and thus induce complex cell states of mitosis arrest at the G2/M phase followed by apoptosis dependent on drug exposure time and concentration. Microfluidic impedance cytometry (MIC), as a label-free and high-throughput technology for single-cell analysis, has been applied for viability assay of cancer cells post drug exposure at fixed time and dosage, yet verification of this technique for varied tumor cell states after anticancer drug treatment remains a challenge. Here we present a novel MIC device and for the first time perform impedance cytometry on carcinoma cells exhibiting progressive states of G2/M arrest followed by apoptosis related to drug concentration and exposure time, after treatments with paclitaxel and vinblastine, respectively. Our results from impedance cytometry reveal increased amplitude and negative phase shift at low frequency as well as higher opacity for HeLa cells under G2/M mitotic arrest compared to untreated cells. The cells under apoptosis, on the other hand, exhibit opposite changes in these electrical parameters. Therefore, the impedance features differentiate the HeLa cells under progressive states post anticancer drug treatment. We also demonstrate that vinblastine poses a more potent drug effect than paclitaxel especially at low concentrations. Our device is fabricated using a unique sacrificial layer-free soft lithography process as compared to the existing MIC device, which gives rise to readily aligned parallel microelectrodes made of silver-PDMS embedded in PDMS channel sidewalls with one molding step. Our results uncover the potential of the MIC device, with a fairly simple and low-cost fabrication process, for cellular state screening in anticancer drug therapy.

Preclinical Assessment of ADAM9-Responsive Mesoporous Silica Nanoparticles for the Treatment of Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) remains largely refractory to chemotherapeutic treatment regimens and, consequently, has the worst survival rate of all cancers. The low efficacy of current treatments results largely from toxicity-dependent dose limitations and premature cessation of therapy. Recently, targeted delivery approaches that may reduce off-target toxicities have been developed. In this paper, we present a preclinical evaluation of a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSNs) functionalized with a protease linker that is specifically cleaved by PDAC cells. Our previous work demonstrated that ADAM9 is a PDAC-enriched protease and that paclitaxel-loaded ADAM9-responsive MSNs effectively kill PDAC cells in vitro. Here, we show that paclitaxel-loaded ADAM9-MSNs result in off-target cytotoxicity in clinically relevant models, which spurred the development of optimized ADAM9-responsive MSNs (OPT-MSNs). We found that these OPT-MSNs still efficiently kill PDAC cells but, as opposed to free paclitaxel, do not induce death in neuronal or bone marrow cells. In line with these in vitro data, paclitaxel-loaded OPT-MSNs showed reduced organ damage and leukopenia in a preclinical PDAC xenograft model. However, no antitumor response was observed upon OPT-MSN administration in vivo. The poor in vivo antitumor activity of OPT-MSNs despite efficient antitumor effects in vitro highlights that although MSN-based tumor-targeting strategies may hold therapeutic potential, clinical translation does not seem as straightforward as anticipated.

Assessment of superiority of HSP70-targeting aptamer-functionalized drug-nanocarrier over non-targeted commercially available counterpart in HCC therapy: in vitro and in vivo investigations and molecular modeling.

AIMS: This research aims to compare the therapeutic potential of target-specific phosphorothioate backbone-modified aptamer L5 (TLS9a)-functionalized paclitaxel (PTX)-loaded nanocarrier (PTX-NPL5) that we formulated with that of non-targeted commercial formulation, protein albumin-bound nanoparticles of PTX, Abraxane® (CF) against hepatocellular carcinoma (HCC) through a myriad of preclinical investigations. MAIN METHODS: A variety of in vitro and in vivo assays have been executed to compare the therapeutic effects of the formulations under investigation, including the investigation of the degree of apoptosis induction and its mechanism, cell cycle analysis, the level of ROS production, and redox status, the morphological and histological characteristics of malignant livers, and in vivo imaging. The formulations were also compared concerning pharmacokinetic behaviors. Finally, in silico molecular docking has been performed to predict the possible interactions between aptamer and target(s). KEY FINDINGS: PTX-NPL5 exhibited therapeutic superiority over CF in terms of inducing apoptosis, cell cycle arrest, endorsing oxidative stress to neoplastic cells, and reducing hepatic cancerous lesions. Unlike CF, PTX-NPL5 did not exhibit any significant toxicity in healthy hepatocytes, proving enough impetus regarding the distinctive superiority of PTX-NPL5 over CF. The pharmacokinetic analysis further supported superior penetration and retention of PTX-NPL5 in neoplastic hepatocytes compared to CF. A molecular modeling study proposed possible interaction between aptamer L5 and heat shock protein 70 (HSP70). SIGNIFICANCE: The target-specificity of PTX-NPL5 towards neoplastic hepatocytes, probably achieved through HSP70 recognition, enhanced its therapeutic efficacy over CF, which may facilitate its real clinical deployment against HCC in the near future.

Technology Invention and Mechanism Analysis of Rapid Rooting of Taxus × media Rehder Branches Induced by Agrobacterium rhizogenes.

Taxus, a vital source of the anticancer drug paclitaxel, grapples with a pronounced supply-demand gap. Current efforts to alleviate the paclitaxel shortage involve expanding Taxus cultivation through cutting propagation. However, traditional cutting propagation of Taxus is difficult to root and time-consuming. Obtaining the roots with high paclitaxel content will cause tree death and resource destruction, which is not conducive to the development of the Taxus industry. To address this, establishing rapid and efficient stem rooting systems emerges as a key solution for Taxus propagation, facilitating direct and continuous root utilization. In this study, Agrobacterium rhizogenes were induced in the 1-3-year-old branches of Taxus × media Rehder, which has the highest paclitaxel content. The research delves into the rooting efficiency induced by different A. rhizogenes strains, with MSU440 and C58 exhibiting superior effects. Transcriptome and metabolome analyses revealed A. rhizogenes' impact on hormone signal transduction, amino acid metabolism, zeatin synthesis, and secondary metabolite synthesis pathways in roots. LC-MS-targeted quantitative detection showed no significant difference in paclitaxel and baccatin III content between naturally formed and induced roots. These findings underpin the theoretical framework for T. media rapid propagation, contributing to the sustainable advancement of the Taxus industry.

Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells.

Breast carcinoma (BC) is the most commonly diagnosed type of cancer in women in the world. Although the advances in the treatment of BC patients are significant, numerous side effects, severe toxicity towards normal cells as well as the multidrug resistance (MDR) phenomenon restrict the effectiveness of the therapies used. Therefore, new active compounds which decrease the MDR, extend disease-free survival, thereby ameliorating the effectiveness of the current treatment regimens, are greatly needed. Histone deacetylase inhibitors (HDIs), including sirtuin inhibitors (SIRTi), are the epigenetic antitumor agents which induce a cytotoxic effect in different types of cancer cells, including BC cells. Currently, combined forms of therapy with two or even more chemotherapeutics are promising antineoplastic tools to obtain a better response to therapy and limit adverse effects. Thus, on the one hand, much more effective chemotherapeutics, e.g., sirtuin inhibitors (SIRTi), are in demand; on the other hand, combinations of accepted cytostatics are trialed. Thus, the aim of our research was to examine the combination effects of a renowned cytotoxic drug paclitaxel (PAX) and SIRT2 inhibitor AGK2 on the proliferation and viability of the T47D, MCF7, MDA-MB-231, MDA-MB-468, BT-549 and HCC1937 BC cells. Moreover, cell cycle arrest and apoptosis induction were explored. The type of pharmacological interactions between AGK2 and PAX in different molecular subtypes of BC cells was assessed using the advanced isobolographic method. Our findings demonstrated that the tested active agents singly inhibited viability and proliferation of BC cells as well as induced cell cycle arrest and apoptosis in the cell-dependent context. Additionally, AGK2 increased the antitumor effect of PAX in most BC cell lines. We observed that, depending on the BC cell lines, the combinations of tested drugs showed synergistic, additive or antagonistic pharmacological interaction. In conclusion, our studies demonstrated that the consolidated therapy with the use of AGK2 and PAX can be considered as a potential therapeutic regimen in the personalized cure of BC patients in the future.

Paclitaxel-Induced Epidermal Alterations: An In Vitro Preclinical Assessment in Primary Keratinocytes and in a 3D Epidermis Model.

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent approved for the treatment of ovarian, non-small cell lung, head, neck, and breast cancers. Despite its beneficial effects on cancer and widespread use, paclitaxel also damages healthy tissues, including the skin. However, the mechanisms that drive these skin adverse events are not clearly understood. In the present study, we demonstrated, by using both primary epidermal keratinocytes (NHEK) and a 3D epidermis model, that paclitaxel impairs different cellular processes: paclitaxel increased the release of IL-1α, IL-6, and IL-8 inflammatory cytokines, produced reactive oxygen species (ROS) release and apoptosis, and reduced the endothelial tube formation in the dermal microvascular endothelial cells (HDMEC). Some of the mechanisms driving these adverse skin events in vitro are mediated by the activation of toll-like receptor 4 (TLR-4), which phosphorylate transcription of nuclear factor kappa B (NF-κb). This is the first study analyzing paclitaxel effects on healthy human epidermal cells with an epidermis 3D model, and will help in understanding paclitaxel's effects on the skin.

Experimental and computational assessment of the synergistic pharmacodynamic drug-drug interactions of a triple combination therapy in refractory HER2-positive breast cancer cells.

The development of innate and/or acquired resistance to human epidermal growth factor receptor type-2 (HER2)-targeted therapy in HER2-positive breast cancer (HER2 + BC) is a major clinical challenge that needs to be addressed. One of the main mechanisms of resistance includes aberrant activation of the HER2 and phosphatidylinositol 3-kinase/AKT8 virus oncogene cellular homolog/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways. In the present work, we propose to use a triple combination therapy to combat this resistance phenomenon. Our strategy involves evaluation of two targeted small molecule agents, everolimus and dasatinib, with complementary inhibitory circuitries in the PI3K/Akt/mTOR pathway, along with a standard cytotoxic agent, paclitaxel. Everolimus inhibits mTOR, while dasatinib inhibits Src, which is a protein upstream of Akt. An over-activation of these two proteins has been implicated in approximately 50% of HER2 + BC cases. Hence, we hypothesize that their simultaneous inhibition may lead to enhanced cell-growth inhibition. Moreover, the potent apoptotic effects of paclitaxel may help augment the overall cytotoxicity of the proposed triple combination in HER2 + BC cells. To this end, we investigated experimentally and assessed computationally the in vitro pharmacodynamic drug-drug interactions of the various dual and triple combinations to assess their subsequent combinatorial effects (synergistic/additive/antagonistic) in a HER2-therapy resistant BC cell line, JIMT-1. Our proposed triple combination therapy demonstrated synergism in JIMT-1 cells, thus corroborating our hypothesis. This effort may form the basis for further investigation of the triple combination therapy in vivo at a mechanistic level in HER2-therapy resistant BC cells.

Assessment of modelling strategies for drug response prediction in cell lines and xenografts.

Data from several large high-throughput drug response screens have become available to the scientific community recently. Although many efforts have been made to use this information to predict drug sensitivity, our ability to accurately predict drug response based on genetic data remains limited. In order to systematically examine how different aspects of modelling affect the resulting prediction accuracy, we built a range of models for seven drugs (erlotinib, pacliatxel, lapatinib, PLX4720, sorafenib, nutlin-3 and nilotinib) using data from the largest available cell line and xenograft drug sensitivity screens. We found that the drug response metric, the choice of the molecular data type and the number of training samples have a substantial impact on prediction accuracy. We also compared the tasks of drug response prediction with tissue type prediction and found that, unlike for drug response, tissue type can be predicted with high accuracy. Furthermore, we assessed our ability to predict drug response in four xenograft cohorts (treated either with erlotinib, gemcitabine or paclitaxel) using models trained on cell line data. We could predict response in an erlotinib-treated cohort with a moderate accuracy (correlation ≈ 0.5), but were unable to correctly predict responses in cohorts treated with gemcitabine or paclitaxel.

The Market Reacts Quickly: Changes in Paclitaxel Vascular Device Purchasing Within the Ascension Healthcare System.

BACKGROUND: A meta-analysis of trials in endovascular therapy suggested an increased mortality associated with treatment exposure to paclitaxel. Multiple publications and corrections of prior data were performed, and the United States Food and Drug Administration has issued multiple advisories regarding paclitaxel use. We analyzed how this controversy impacted device purchasing and related utilization patterns in the period immediately following publication of the meta-analysis. METHODS AND RESULTS: Ascension Healthcare System purchase data over a 14-month period were synthesized across centers for both paclitaxel and non-paclitaxel devices. A fixed-effects regression model and a binary regression model with facility-level controls were used to compare purchasing patterns before and after the meta-analysis. Purchase volumes of each paclitaxel device fell. Pooled purchase volumes of all paclitaxel devices decreased from a 14-month peak of 631 devices in October 2018 to a 14-month nadir of 359 devices in February 2019. An F-test comparing the pooled-month specific fixed effects for the months before vs after the publication of the meta-analysis has an F-statistic of 11.64, suggesting that average purchasing levels in the two periods are statistically different (P<.001). Utilization of non-paclitaxel devices did not decline. CONCLUSIONS: Purchase volumes of paclitaxel devices decreased immediately during the months following publication of the related meta-analysis. Total Ascension-wide paclitaxel device purchase volume in February 2019 demonstrated a 43.1% reduction from peak monthly purchase volume during the assessed period and a 32.5% reduction compared with November 2019, the last month preceding publication of the meta-analysis.

Liquisolid system of paclitaxel using modified polysaccharides: In vitro cytotoxicity, apoptosis study, cell cycle analysis, in vitro mitochondrial membrane potential assessment, and pharmacokinetics.

The research was aimed to develop a liquisolid formulation of paclitaxel using novel, highly porous liquisolid carriers (modified polysaccharides) to enhance bioavailability of orally administered paclitaxel. Modified polysaccharides namely co-grinded treated guar gum (C-TGG), co-grinded treated tamarind kernel powder (C-TTKP) and co-grinded treated locust bean gum (C-TLBG) were developed by sequentially subjecting the corresponding polysaccharides to wetting, drying and co-grinding with mannitol (1:1). A total of 12 liquisolid systems of paclitaxel (LSP-1 to LSP-12) were formulated using non-volatile solvent (polysorbate 80/Solutol HS 15®), carrier material (C-TGG/C-TTKP/C-TLBG), and Aerosil® 200 as coating material, and evaluated for pre-compression parameters. The liquisolid systems were directly compressed to produce liquisolid tablets (LTP-1 to LTP-12) and assessed for post compression parameters, cytotoxic/cellular analysis and pharmacokinetics. The modified polysaccharides exhibited narrow symmetrical particle size distribution, high liquid absorption potential, diminutive swelling index, favorable in vitro biodegradability and compression amenability. Among the directly compressed liquisolid tabs, LTP-10 exhibited highest CDR of 98.70 ±â€¯2.68% and permeability of 61.59%. The IC50 of <20 mmol/L indicated remarkable cytotoxic potential on human gastro-enteric tumor cancerous cell lines (NCI-N87). Additionally, LTP-10 exhibited significantly high values for cell death 37.92 and 54.17% (P < 0.01) in early and late apoptosis and mitochondrial membrane potential regain (33%) in comparison to paclitaxel (P < 0.05) and 5-fluorouracil (P < 0.01). Pharmacokinetics revealed Cmax of 536.48 ±â€¯4.63 µg/L at 1.64 ±â€¯0.44 h for LTP-10 indicating enhancement in bioavailability (5.43 fold) of paclitaxel on oral administration.

α-Tocopherol Succinate-Anchored PEGylated Poly(amidoamine) Dendrimer for the Delivery of Paclitaxel: Assessment of in Vitro and in Vivo Therapeutic Efficacy.

This study involves development of a dendrimer-based nanoconstruct by conjugating α-tocopheryl succinate (α-TOS) and polyethylene glycol (PEG) on a poly(amidoamine) dendrimer (G4 PAMAM) to improve intracellular delivery of a poorly water-soluble chemotherapeutic drug, paclitaxel (PTX). The conjugates were characterized by NMR, and PTX-loaded nanocarriers (G4-TOS-PEG-PTX) were evaluated for hydrodynamic diameter, polydispersity index (PDI), zeta potential, percentage encapsulation efficiency (%EE), and percentage drug loading (%DL). A hemolysis study was performed, which indicated that the synthesized dendrimer conjugates were not toxic to red blood cells; hence, they were biocompatible. A cellular uptake study in (B16F10 and MDA MB231) monolayer cells and 3D spheroids showed that α-TOS conjugation improved the time dependent uptake of nanosized dendrimer conjugates. The cell viability assay revealed that G4-TOS-PEG-PTX enhanced the cytotoxicity of PTX as compared to free PTX and PTX-loaded G4-PEG (G4-PEG-PTX) at tested concentrations. Correspondingly, the α-TOS-anchored dendrimer induced more apoptosis as compared to free PTX and G4-PEG-PTX. Moreover, the fluorescently labeled G4-TOS-PEG penetrated deeper into MDA MB231 3D spheroids as visualized by confocal microscopy. G4-TOS-PEG-PTX showed significant growth inhibition in 3D spheroids as compared to free PTX and G4-PEG-PTX. Further, the in vivo efficacy study using B16F10 xenografted C57Bl6/J mice indicated that the G4-TOS-PEG localized in tumor sections. G4-TOS-PEG-PTX reduced the tumor growth significantly compared to free PTX and G4-PEG-PTX. G4-TOS-PEG-PTX had more apoptotic potential in tumor sections as analyzed by TUNEL assay. Hence, the newly developed dendrimer conjugate, G4-TOS-PEG, has the potential to target loaded drug to the tumor, and G4-TOS-PEG-PTX has the potential to be utilized successfully in cancer treatment.

Cost-Effectiveness of Niraparib and Olaparib as Maintenance Therapy for Patients with Platinum-Sensitive Recurrent Ovarian Cancer.

BACKGROUND: The recent approval of olaparib and niraparib as maintenance therapy can significantly affect the management of ovarian cancer. Clinical benefits, however, come with trade-offs in adverse events and costs. OBJECTIVE: To evaluate the cost-effectiveness of new ovarian cancer poly-ADP ribose polymerase (PARP) inhibitor therapies, olaparib and niraparib, as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer. METHODS: A decision tree model was constructed to evaluate the costs and effectiveness of olaparib and niraparib compared with placebo from a U.S. health care sector perspective. Costs included drug costs and costs of disease monitoring and management of adverse events throughout the treatment course. Costs were estimated from RED BOOK, Medicare reimbursement rates, and the literature and reported in 2017 U.S. dollars. Clinical effectiveness was measured in progression-free survival (PFS) life-years based on clinical trial results (NCT00753545, NCT01874353, and NCT01847274). The incremental cost-effectiveness ratio (ICER) was computed by dividing the incremental cost by the incremental effectiveness. RESULTS: At base case, niraparib was the more effective treatment option with slightly higher PFS, followed by olaparib. The ICERs for niraparib and olaparib compared with common baseline placebo were $235K and $287K per PFS life-year, respectively, with olaparib extended-dominated by niraparib. Both drugs were associated with lower ICERs in patients with a gBRCA mutation than in patients without a gBRCA mutation. One-way sensitivity analysis suggested that drug prices and PFS could affect ICERs significantly, but the ICERs remained above $100K per PFS life-year within the plausible ranges of all parameters. Probabilistic sensitivity analysis suggested that niraparib was associated with higher net benefits compared with placebo only when willingness-to-pay (WTP) values were above $210K per PFS life-year thresholds. CONCLUSIONS: PARP inhibitors niraparib and olaparib will extend PFS in platinum-sensitive recurrent ovarian cancer patients but are also associated with high drug acquisition costs. The base case ICERs were around or above $250K per PFS life-year in this model. No formal cost-effectiveness WTP threshold for health technology assessment exists in the United States. At a reference WTP of $100K per PFS life-year, the PARP inhibitors may not be cost-effective options. DISCLOSURES: This study was unfunded. The authors have nothing to disclose.

Assessment of novel core-shell Fe3O4@poly l­DOPA nanoparticles for targeted Taxol® delivery to breast tumor in a mouse model.

Drug delivery systems using nanoparticles can deliver to tumor cells without affecting normal cells. In this study, a novel well dispersed magnetic nano drug was synthesized. Thus, a selective drug delivery system was designed for potential cancer treatment. A new nanocomposite, poly 3,4­dihydroxy­l­phenylalanine/Fe3O4 (l­DOPA/Fe3O4), was synthesized and used for targeted Taxol® delivery to breast tumor in inbreed Balb/c mice model with or without magnetic field. Fe and Taxol® concentrations were measured by flame atomic absorption spectrometry and high-performance liquid chromatography, respectively. Antitumor effectiveness was investigated in terms of tumor growth features. In the presence of magnetic field, Taxol® was significantly deposited in tumor tissue in Taxol-nanocomposite-treated group. In addition, the Taxol®-nanocomposite-treated group with magnetic field showed higher antitumor efficacy than the commercial Taxol and Taxol-nanocomposite without magnetic field. The magnetic nanocomposite is promising for targeted Taxol® delivery to breast tumor in a mouse model yielding high performance.

Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.

Background: CBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy. Patients and methods: Germ-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided. Results: Median progression-free survival (PFS) was 7.73 [95% confidence interval (CI) 6.46-9.00] months for GP arm and 6.07 (95% CI 5.32-6.83) months for GT arm (P = 0.005). No significant difference in overall survival (OS) was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher objective response rate (ORR) and longer PFS in GP arm than in GT arm (71.9% versus 38.7%, P = 0.008; 10.37 versus 4.30 months, P = 0.011). There was no significant interaction between germ-line BRCA1/2 (gBRCA1/2) status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP arm than in GT arm (83.3% versus 37.5%, P = 0.086; 8.90 versus 3.20 months, P = 0.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks. Conclusions: GP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients. Trial registration: ClinicalTrials.gov, NCT01287624.

Assessment of Three-Drug Combination Pharmacodynamic Interactions in Pancreatic Cancer Cells.

The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term. TFP fully inhibited growth of cells (Imax = 1) with an IC50 = 9887 nM. Near-maximum inhibition was achieved for GEM (Imax = 0.825) and PTX (Imax= 0.844) with an IC50 = 17.4 nM for GEM and IC50 = 7.08 nM for PTX. Estimates of an interaction term ψ revealed that the combination of TFP-GEM was apparently synergistic; close to additivity, the combination TFP-PTX was antagonistic. The interaction of GEM-PTX was additive, and TFP-GEM-PTX was synergistic but close to additive. The combination of TFP IC60-GEM IC60-PTX IC60 seemed optimal in producing inhibition of PANC-1 cells with an inhibitory effect of 82.1-90.2%. The addition of ψ terms to traditional interaction equations allows assessment of the degree of perturbation of assumed mechanisms.

Impact of treatment regimen on acute care use during and after adjuvant chemotherapy for early-stage breast cancer.

PURPOSE: The Oncology Care Model was developed, in part, to reduce acute care use during the 6 months after chemotherapy initiation. However, little is known about the impact of chemotherapy regimen on acute care needs, or about later acute care. We sought to assess acute care use over 2 years in patients receiving four contemporary adjuvant chemotherapy regimens for breast cancer. METHODS: Administrative claims data from a large U.S. commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify women with early-stage breast cancer who received adjuvant doxorubicin-cyclophosphamide (AC), AC followed or preceded by docetaxel or paclitaxel (AC-T), AC concurrent with docetaxel or paclitaxel (TAC), or docetaxel-cyclophosphamide (TC) between 2008 and 2014. Rates of hospitalizations and emergency department (ED) visits that did not lead to hospitalizations were compared during four sequential 6-month periods among recipients of these four regimens using negative binomial regression (TC = reference). RESULTS: We identified 8621 eligible patients, 87.2% younger than 65. Over 6 months, 11.9% were hospitalized and 17.1% had ED visits. Over 24 months, 17.9% were hospitalized and 28.3% visited the ED. Adjusted rates of hospitalizations/100 patients were significantly higher in AC-T and TAC compared to TC recipients in the first 6 months (14.9, 21.9, and 11.3, respectively, p < 0.001). There were no hospitalization rate differences among regimens later. ED visit rates did not differ significantly by regimen during any 6-month period. CONCLUSION: Higher rates of hospitalizations in recipients of AC-T and TAC were restricted to the chemotherapy administration period, and did not persist afterwards.

Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment.

The present investigation was aimed at developing various ligands-anchored dendrimers and comparing their brain targeting potential at one platform. Sialic acid (S), glucosamine (G) and concanavalin A (C) anchored poly(propyleneimine) (PPI) dendritic nanoconjugates were developed and evaluated for delivery of anti-cancer drug, paclitaxel (PTX) to the brain. MTT assay on U373MG human astrocytoma cells indicated IC50 values of 0.40, 0.65, 0.95, 2.00 and 3.50µM for PTX loaded SPPI, GPPI, CPPI, PPI formulations, and free PTX, respectively. The invivo pharmacokinetics and biodistribution studies in rats showed significantly higher accumulation of PTX in brain as compared to free PTX. The order of targeting potential of various ligands under investigation was found as sialic acid>glucosamine>concanavalin A. Thus, it can be concluded that sialic acid, glucosamine and Con A can be used as potential ligands to append PPI dendrimers for enhanced delivery of anticancer drugs to the brain for higher therapeutic outcome.

Quantitative and Mechanistic Assessment of Model Lipophilic Drugs in Micellar Solutions in the Transport Kinetics Across MDR1-MDCK Cell Monolayers.

An approach to characterizing P-glycoprotein (Pgp) interaction potential for sparingly water-soluble compounds was developed using bidirectional transport kinetics in MDR1-MDCK cell monolayers. Paclitaxel, solubilized in a dilute polysorbate 80 (PS80) micellar solution, was used as a practical example. Although the passage of paclitaxel across the cell monolayer was initially governed by the thermodynamic activity of the micelle-solubilized drug solution, Pgp inhibition was sustained by the thermodynamic activity (i.e., critical micelle concentration) of the PS80 micellar solution bathing the apical (ap) membrane. The mechanistic understanding of the experimental strategies and treatment of data was supported by a biophysical model expressed in the form of transport events occurring at the ap and basolateral (bl) membranes in series whereas the vectorial directions of the transcellular kinetics were accommodated. The derived equations permitted the stepwise quantitative delineation of the Pgp efflux activity (inhibited and uninhibited by PS80) and the passive permeability coefficient of the ap membrane, the passive permeability at the bl membrane and, finally, the distinct coupling of these with efflux pump activity to identify the rate-determining steps and mechanisms. The Jmax/KM(∗) for paclitaxel was in the order of 10(-4) cm/s and the ap- and bl-membrane passive permeability coefficients were asymmetric, with bl-membrane permeability significantly greater than ap.