Molecularly matched targeted therapy: a promising approach for refractory metastatic melanoma.

BACKGROUND: Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported. MATERIALS AND METHODS: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. RESULTS: We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations. CONCLUSIONS: High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.

Cytidine deaminase status as a marker of response to azacytidine treatment in MDS and AML patients.

Azacitidine (Aza) is a mainstay of treatment for patients with acute myeloid leukaemia (AML) ineligible for induction chemotherapy and other high-risk myelodysplastic syndromes (MDS). Only half of patients respond, and almost all will eventually relapse. There are no predictive markers of response to Aza. Aza is detoxified in the liver by cytidine deaminase (CDA). Here, we investigated the association between CDA phenotype, toxicity and efficacy of Aza in real-world adult patients. Median overall survival (OS) was 15 months and 13 months in AML and high-risk MDS patients respectively. In addition, our data suggest that delaying Aza treatment was not associated with lack of efficacy and should not be considered a signal to switch to an alternative treatment. Half of the patients had deficient CDA activity (i.e. <2 UA/mg), with a lower proportion of deficient patients in MDS patients (34%) compared to AML patients (67%). In MDS patients, CDA deficiency correlated with longer landmark OS (14 vs. 8 months; p = 0.03), but not in AML patients. Taken together, our data suggest that CDA is an independent covariate and may therefore be a marker for predicting clinical outcome in MDS patients treated with Aza.

Anticancer drug delivery by focused ultrasound-mediated blood-brain/tumor barrier disruption for glioma therapy: From benchside to bedside.

The therapeutic management of gliomas remains particularly challenging. Brain tumors present multiple obstacles that make therapeutic innovation complex, mainly due to the presence of blood-tumor and blood-brain barriers (BTB and BBB, respectively) which prevent penetration of anticancer agents into the brain parenchyma. Focused ultrasound-mediated BBB disruption (FUS-BBBD) provides a physical method for non-invasive, local, and reversible BBB disruption. The safety of this technique has been demonstrated in small and large animal models. This approach promises to enhance drug delivery into the brain tumor and therefore to improve survival outcomes by repurposing existing drugs. Several clinical trials continue to be initiated in the last decade. In this review, we provide an overview of the rationale behind the use of FUS-BBBD in gliomas and summarize the preclinical studies investigating different approaches (free drugs, drug-loaded microbubbles and drug-loaded nanocarriers) in combination with this technology in in vivo glioma models. Furthermore, we discuss the current state of clinical trials and devices developed and review the challenges to overcome for clinical use of FUS-BBBD in glioma therapy.

Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model.

Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain and tumor concentration of drugs administered systemically. Non-invasive, sensitive, and reliable imaging approaches are required to better understand the impact of FUS on the BBB and brain microenvironment. In this study, nuclear imaging (SPECT/CT and PET/CT) was used to quantify neuroinflammation 48 h post-FUS and estimate the influence of FUS on BBB opening and tumor growth in vivo. BBB disruptions were performed on healthy and GBM-bearing mice (U-87 MG xenograft orthotopic model). The BBB recovery kinetics were followed and quantified by [99mTc]Tc-DTPA SPECT/CT imaging at 0.5 h, 3 h and 24 h post-FUS. The absence of neuroinflammation was confirmed by [18F]FDG PET/CT imaging 48 h post-FUS. The presence of the tumor and its growth were evaluated by [68Ga]Ga-RGD2 PET/CT imaging and post-mortem histological analysis, showing that tumor growth was not influenced by FUS. In conclusion, molecular imaging can be used to evaluate the time frame for systemic treatment combined with transient BBB opening and to test its efficacy over time.

Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives.

The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIß inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC50 = 2.49 ± 1.33 µM and IC50 = 3.96 ± 2.03 µM for compound 11a and IC50 = 5.3 ± 2.12 µM and IC50 = 7.12 ± 1.59 µM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties.

Acceptance, efficacy, and safety of COVID-19 vaccination in older patients with cancer.

PURPOSE: The COVID-19 vaccination campaign began in December 2020, in France, and primarily targeted the oldest people. Our study aimed to determine the level of acceptance of vaccination in a population of older patients with cancer. METHODS: From January 2021, we offered vaccination with the BNT162b2 COVID-19 vaccine to all patients 70 years and older referred to our geriatric oncology center in Marseille University Hospital (AP-HM) for geriatric assessment before initiation of an oncological treatment. Objectives were to evaluate acceptance rate of COVID-19 vaccination and to assess vaccine safety, reactogenicity, and efficacy two months after the first dose. RESULTS: Between January 18, 2021 and May 7, 2021, 150 older patients with cancer were offered vaccination after a geriatric assessment. The majority were men (61.3%), with a mean age of 81 years. The two most frequent primary tumors were digestive (29.4%) and thoracic (18%). The vaccine acceptance rate was 82.6% and the complete vaccination rate (2 doses) reached 75.3%. Among the vaccinated patients, 15.9% reported mild side effects after the first dose and 23.4% after the second dose, mostly arm pain and fatigue. COVID-19 cases were observed in 5.1% of vaccinated patients compared with 16.7% in unvaccinated patients. Of the 22 vaccinated patients who agreed to have their serum tested, 15 had antibodies against the spike protein at day 21 after the first dose. CONCLUSION: Our study showed a high acceptance rate of COVID-19 vaccination, with good tolerance in this frail population. These results highlight the benefits of organizing vaccination campaigns at the very beginning of oncological management in older patients. CLINICAL TRIAL REGISTRATION: This study was registered May 23, 2019 in ClinicalTrials.gov (NCT03960593).

Telemedication Reviews to Optimize Medication Prescription for Older People in Nursing Homes.

Introduction: Older people living in nursing homes (NH) are at a higher risk of preventable drug-related adverse events because of age-related physiological changes, polypathology, and polypharmacy. NH residents are particularly exposed to potentially inappropriate medications (PIMs). Many strategies have been developed to improve the quality and the safety of drug prescription in NH, including medication reviews (MRs). Methods: In the context of the application of telemedicine, we developed and are currently implementing a novel hospital expert-based MRs through tele-expertise (or "telemedication review," telemedication reviews hereafter [TMR]) in French NH residents. The impact of these TMR on unplanned hospitalizations 3 months after implementation is assessed. TMR consider all available sociodemographic, clinical, biological, and pharmaceutical data pertaining to the patient and are performed in accordance with their health care objectives. Results: The preliminary results for the 39 TMRs performed to date (September 2021) showed that a total of 402 PIMs were detected, and all residents had at least one PIM. We also present the feasibility and the usefulness of this novel TMR for NH, illustrating these preliminary results with two concrete TMR experiences. Among the 39 TMR performed, the average acceptance rate of expert recommendations made to general practitioners (GP) working in NH was ∼33%. Discussion and Conclusions: The success of this novel TMR depends on how the proposed prescription adjustments made by the hospital expert team are subsequently integrated into health care practices. The low acceptance rate by GP highlights the need to actively involve these professionals in the process of developing TMR, with a view to encouraging them to act on proposed adjustments.

Development of a multi-functional preclinical device for the treatment of glioblastoma.

Glioblastoma multiforme (GBM) is one of the most common and aggressive malignant primary brain tumors in adults. The treatment of GBM is limited by the blood-brain barrier (BBB), which limits the diffusion of appropriate concentrations of therapeutic agents at the tumor site. Among experimental therapies, photo-thermal therapy (PTT) mediated by nanoparticles is a promising strategy. To propose a preclinical versatile research instrument for the development of new PTT for GBM, a multipurpose integrated preclinical device was developed. The setup is able to perform: i) BBB permeabilization by focused ultrasound sonication (FUS); ii) PTT with continuous wave laser; iii) in situ temperature monitoring with photo-acoustic (PA) measurements. In vivo preliminary subcutaneous and transcranial experiments were conducted on healthy or tumor-bearing mice. Transcranial FUS-induced BBB permeabilization was validated using single photon emission computed tomography (SPECT) imaging. PTT capacities were monitored by PA thermometry, and are illustrated through subcutaneous and transcranial in vivo experiments. The results show the therapeutic possibilities and ergonomy of such integrated device as a tool for the validation of future treatments.

Acceptability of a Novel Telemedication Review for Older Adults in Nursing Homes in France: A Qualitative Study.

PURPOSE: In France, polypharmacy among older people living in nursing homes (NH) is a major public health concern. In this context, the randomized controlled trial TEM-EHPAD was recently launched in various NH in southern France to evaluate the impact of implementing a novel telemedication review (TMR) on hospital admission rates of NH residents at high risk of iatrogenic disease. A qualitative study was integrated into the main trial study to assess general practitioners' (GP) and other NH healthcare professionals' (HP) acceptability of the proposed TMR before its implementation. MATERIAL AND METHODS: A qualitative study using face-to-face semi-structured interviews was conducted with 16 HP before the beginning of the intervention. A manual thematic analysis was performed on the transcribed interviews. RESULTS: Four main themes emerged from the thematic analysis: HP perceptions of the TMR, difficulties related to medication management for NH residents, HP perceptions of the roles of different professionals, and facilitators of good practices. Most participants were favorable to the TMR, but some GP expressed fears about loss of control over their prescription writing. CONCLUSION: This study fulfilled its objective to assess pre-intervention acceptability by GP and other HP. Results provided important information about how to adapt the TMR intervention to make it more acceptable to HP who will be involved in TEM-EHPAD. One of the main recommendations is the importance of providing participating GP with the opportunity to take part in the process of reviewing prescriptions.

Octogenarians treated for thoracic and lung cancers: Impact of comprehensive geriatric assessment.

BACKGROUND: Lung cancer affects older and older old adults and is the leading cause of death by cancer. Comprehensive Geriatric Assessment (CGA) is recommended before and during cancer treatment to guide therapy management in this population. METHODS: This study was conducted between September 2015 and January 2019 at Marseille University Hospital (AP-HM). During this period, all consecutive outpatients 70 years or older referred for a CGA before initiation of lung cancer treatment were enrolled. The objective of this study was to compare lung and thoracic cancer management of octogenarians (≥80 years) and their geriatric profile versus patients aged 70 to 79 years (<80 years). FINDINGS: In our study, 228 patients were recruited. The median age was 78.7 ± 5 years. There were 94 octogenarians (41.2%), 36.2% of them were diagnosed with stage IV neoplasm and the most common treatment was chemotherapy (43.6%). The logistic regression analysis highlights that handgrip strength was the most commonly impaired domain (OR 2.3; 95% CI [1.3-4.3]) in octogenarians and that they are more likely than their younger counterparts to be treated by targeted therapy (OR 9.8; 95% CI [1.0-92.9]). Overall survival (OS) was similar in both age groups (log rank = 0,95). INTERPRETATION: In our study, octogenarians and patients <80 years had equivalent survival, across the different thoracic cancer treatments and tumor stages. Measure of muscle strength in CGA could be very useful in a clinical setting to help improve the management of older old patients treated for lung or thoracic cancer.

Prognostic Value of the B12/CRP Index in Older Systemically Treatable Cancer Patients.

BACKGROUND: While comprehensive geriatric assessment (CGA) in older patients treated for cancer assesses several related domains, it does not include standardized biological tests. The present study aimed to: (1) assess the prognosis value of the B12/CRP index (BCI) in a population of systemically treatable older patients with cancer and (2) analyze the association between BCI value and pre-existing geriatric frailty. METHOD: We conducted a retrospective observational study between January 2016 and June 2020 at Marseille University Hospital. All consecutive cancer patients aged 70 years and over before initiating systemic therapy were included. RESULTS: Of the 863 patients included, 60.5% were men and 42.5% had metastatic stage cancer. Mean age was 81 years. The low-BCI group (≤10,000) had a significantly longer survival time than the mid-BCI (10,000 < BCI ≤ 40,000) and high-BCI (BCI > 40,000) groups (HR = 0.327, CI95% [0.26-0.42], p-value = 0.0001). Mid- and high-BCI (BCI > 40,000) values were associated with impaired functional status and malnutrition. CONCLUSION: A BCI > 10,000 would appear to be a good biological prognostic factor for poor survival times and pre-existing geriatric impairment in older cancer patients before they initiate systemic treatment.

Older Patients Treated for Lung and Thoracic Cancers: Unplanned Hospitalizations and Overall Survival.

BACKGROUND: Lung cancer affects older adults and is the leading solid tumor in terms of death. A Comprehensive Geriatric Assessment (CGA) is recommended before cancer treatment to guide therapy management. PATIENTS AND METHODS: This study was conducted between September 2015 and January 2019. During this period of time, all consecutive older outpatients referred for a CGA before initiation of lung or thoracic tumor treatment were included. The objectives were to describe the impact of geriatric factors on unplanned hospitalizations and overall survival (OS). The study was approved by a local ethics committee. RESULTS: Overall, 228 patients were recruited. The median age was 78.7 ± 5 years. The majority (82%) of patients were diagnosed with non-small-cell lung cancer, and the most common (40.4%) treatment was systemic therapy. In multivariate analysis, factors associated with unplanned hospitalizations within the first 3 months were male gender (adjusted odds ratio [aOR], 3.3; 95% confidence interval [CI], 1.5-7.2), systemic therapy (aOR, 2.6; 95% CI, 1.1-6.2), and fall history (aOR, 3.6; 95% CI, 1.6-8.2). Factors associated with a decrease in OS in the multivariate Cox model analysis were male gender (hazard ratio [HR], 3.9; 95% CI, 2.1-7.3), stage IV (HR, 1.6; 95% CI, 1.0-2.6), G8 ≤ 14 (HR, 3.5; 95% CI, 1.1-11.4), systemic therapy (HR, 2.6; 95% CI, 1.2-5.5), Eastern Cooperative Oncology Group performance status ≥ 2 (HR, 2.0; 95% CI, 1.2-3.4), and impaired handgrip strength (HR, 1.6; 95% CI, 1.0-2.5). CONCLUSION: G8 score and handgrip strength are important to predict OS in older adults treated for thoracic tumors. In the CGA, fall history was associated with unplanned hospitalization.

Medication Reconciliation Associated with Comprehensive Geriatric Assessment in Older Patients with Cancer: ChimioAge Study.

BACKGROUND: Polymorbidity induces polypharmacy in older patients may lead to potential drug-drug interactions (DDI) which can modify the tolerance and safety of oncological treatments and alter the intended therapeutic effect. The objective of our study was to describe the decision-making process for oncological treatment and related outcomes, in a population of older adults undergoing a comprehensive geriatric assessment (CGA) associated to a comprehensive medication reconciliation (CMR) prior to initiating oncological treatment. METHODS: ChimioAge is a prospective observational study conducted between 01/2017 and 07/2018 at Marseille University Hospital and approved by the French National Ethics Committee. It comprised all consecutive patients aged 70 years and over who were referred for a CGA as part of CMR, before initiating systemic treatment. RESULTS: One hundred and seventy-one cancer patients were included. Mean age was 79.2 years, over half had metastatic cancers, 75% had an ECOG performance status zero or one, and two-thirds were independent in daily activities. Two-thirds of the patients had polypharmacy and the CMR identified potential DDI with systemic treatment in 43.3% of patients. Following the CGA, the CMR and the hospital oncologists decision, 30% of the patients received adapted systemic treatment with reduced doses at initiation. They presented fewer toxicities - irrespective of grade and type - than patients who received standard treatment (p<0.001) and had comparable overall survival (Log rank p=0.21). CONCLUSION: This is one of the first studies to highlight the value in conducting CMR and a CGA simultaneously before initiating systemic treatment in older patients with cancer. These two evaluations could give oncologists decisive information to personalize cancer treatment of older patients and optimize treatment dose to offer the best efficacy and minimize toxicity.

Hydrophilic Fluorescent Nanoprodrug of Paclitaxel for Glioblastoma Chemotherapy.

Highly water-soluble, nontoxic organic nanoparticles on which paclitaxel (PTX), a hydrophobic anticancer drug, has been covalently bound via an ester linkage (4.5% of total weight) have been prepared for the treatment of glioblastoma. These soft fluorescent organic nanoparticles (FONPs), obtained from citric acid and diethylenetriamine by microwave-assisted condensation, show suitable size (Ø = 17-30 nm), remarkable solubility in water, softness as well as strong blue fluorescence in an aqueous environment that are fully retained in cell culture medium. Moreover, these FONPs were demonstrated to show in vitro safety and preferential internalization in glioblastoma cells through caveolin/lipid raft-mediated endocytosis. The PTX-conjugated FONPs retain excellent solubility in water and remain stable in water (no leaching), while they showed anticancer activity against glioblastoma cells in two-dimensional and three-dimensional culture. PTX-specific effects on microtubules reveal that PTX is intracellularly released from the nanocarriers in its active form, in relation with an intracellular-promoted lysis of the ester linkage. As such, these hydrophilic prodrug formulations hold major promise as biocompatible nanotools for drug delivery.

Delaying Anticancer Drug Delivery by Self-Assembly and Branching Effects of Minimalist Dendron-Drug Conjugates.

Self-assembly of a covalently-bound lipophilic drug to a dendronic scaffold for making organic nanoparticles is reported as a proof of concept in nanovectorization. A minimalist structural approach with a small PEG-dendron conjugated to paclitaxel (PTX), incorporating safe succinic and gallic acids, is efficient to provide the expected anticancer bioactivity, but also significantly retards and targets intracellular delivery of PTX in 2D and 3D lung cancer cell cultures. A branching effect of dendrons is crucial, when compared to linear PTX conjugates. Transmission electron microscopy (TEM) and dynamic light-scattering (DLS) studies indicate the formation of stable, low-disperse nanoparticles at 10-5 m in H2 0, which could also be responsible for the biological effects. An ultrasensitive LC-MS/MS method was used for the determination of intracellular PTX concentration over time, along with the survival rates of cancer cells. Similarly, cell survival assays were successfully correlated to a 3D cell culture with spheroids for mimicking tumors, when treated with PTX conjugates. Our work opens the way to a full evaluation program required for new chemical entities.

Docetaxel-trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer.

BACKGROUND: Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab. METHODS: Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy. RESULTS: ANC-1 showed a greater docetaxel encapsulation rate (73%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The IC50s for docetaxel combined to free trastuzumab were 8.7±4, 2±0.7 and 6±2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The IC50s for ANC-1 were 2.5±1, 1.8±0.6 and 3.4±0.8 nM and for ANC-2 were 1.8±0.3 nM, 2.8±0.8 nM and 6.8±1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake. CONCLUSION: In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles.

Stability of a highly concentrated solution of epirubicin for conventional transcatheter arterial chemoembolization.

INTRODUCTION: Epirubicin is widely used for conventional transcatheter arterial chemoembolization (cTACE) in patients with hepatocellular-carcinoma. However, there is no data about its stability in solution at concentration higher than 2 mg/L, yet needed when mixing it with a standard volume of Lipiodol(®) to produce an efficient water-in-oil emulsion. The aim of this study was therefore to evaluate the stability of a highly concentrated solution of epirubicin for cTACE and verify whether epirubicin solution could be prepared in advance. MATERIALS AND METHODS: Fifty milligrams of epirubicin were dissolved in 6 mL of 0.9% sodium chloride and conditioned in brown polypropylene syringe. Physical and chemical stability assays including particles and HPLC-DAD analysis were performed in triplicate, using series of 5 syringes stored over 72 h at 4±2 °C followed by 4h at 22±4°C. RESULTS: Neither weight loss nor pH or spectrum change occurred. No haze or turbidity was observed and the number of subvisible particles was below the recommended limits. Epirubicin concentration remained above 95% of the initial value over the 72 h of storage at +4 °C followed by 4h at 22±4 °C and no degradation was observed. CONCLUSION: Epirubicin at 50mg/6 mL in 0.9% NaCl conditioned in brown propylene syringe is stable for at least 72 h at 4±2 °C with additional 4h at 22±4 °C allowing its preparation in advance for programmed cTACE and the standardization of its use in clinical practice.

An ultrasensitive LC-MS/MS method with liquid phase extraction to determine paclitaxel in both cell culture medium and lysate promising quantification of drug nanocarriers release in vitro.

The quantification of paclitaxel, a chemotherapy drug used to treat different types of cancers, has been performed from complete cell culture medium and cell lysate samples using a simple liquid-liquid extraction procedure in conjunction with liquid chromatography tandem mass spectrometry (LC-MS/MS). A simple sample preparation using methanol and acetic acid as a weaker acid was applied to avoid paclitaxel destruction and to achieve recovery exceeding 80 % from both matrices spiked with paclitaxel and docetaxel used as internal standard. This rapid, simple, selective and sensitive method enabled the quantification of paclitaxel within the linear range of 1-250nM in culture medium and 5-250nM in cell lysate. The lower limit of quantification was achieved in cell culture medium and cell lysates at 0.2 and 1pmol, respectively. This method was successfully applied to human non-small cell lung carcinoma cells (A549 cells) in order to quantify the amount of paclitaxel in both cell culture medium and lysate after incubation with 5, 50 and 100nM of paclitaxel. This ultra-sensitive method promises the quantification of ultra-low concentrations of paclitaxel released from any nanocarriers, allowing the determination of the kinetic profile of drug release, which is an essential parameter to validate the use of nanocarriers for drug delivery in cancer therapy.

Gold nanoparticles prepared by laser ablation in aqueous biocompatible solutions: assessment of safety and biological identity for nanomedicine applications.

Due to excellent biocompatibility, chemical stability, and promising optical properties, gold nanoparticles (Au-NPs) are the focus of research and applications in nanomedicine. Au-NPs prepared by laser ablation in aqueous biocompatible solutions present an essentially novel object that is unique in avoiding any residual toxic contaminant. This paper is conceived as the next step in development of laser-ablated Au-NPs for future in vivo applications. The aim of the study was to assess the safety, uptake, and biological behavior of laser-synthesized Au-NPs prepared in water or polymer solutions in human cell lines. Our results showed that laser ablation allows the obtaining of stable and monodisperse Au-NPs in water, polyethylene glycol, and dextran solutions. The three types of Au-NPs were internalized in human cell lines, as shown by transmission electron microscopy. Biocompatibility and safety of Au-NPs were demonstrated by analyzing cell survival and cell morphology. Furthermore, incubation of the three Au-NPs in serum-containing culture medium modified their physicochemical characteristics, such as the size and the charge. The composition of the protein corona adsorbed on Au-NPs was investigated by mass spectrometry. Regarding composition of complement C3 proteins and apolipoproteins, Au-NPs prepared in dextran solution appeared as a promising drug carrier. Altogether, our results revealed the safety of laser-ablated Au-NPs in human cell lines and support their use for theranostic applications.