MSIpixel: a fully automated pipeline for compound annotation and quantitation in mass spectrometry imaging experiments.

Mass spectrometry imaging (MSI) is commonly used to map the spatial distribution of small molecules within complex biological matrices. One of the major challenges in imaging MS-based spatial metabolomics is molecular identification and metabolite annotation, to address this limitation, annotation is often complemented with parallel bulk LC-MS2-based metabolomics to confirm and validate identifications. Here we applied MSI method, utilizing data-dependent acquisition, to visualize and identify unknown molecules in a single instrument run. To reach this aim we developed MSIpixel, a fully automated pipeline for compound annotation and quantitation in MSI experiments. It overcomes challenges in molecular identification, and improving reliability and comprehensiveness in MSI-based spatial metabolomics.

THE SPACE DIMENSION AT THE MICRO LEVEL: MASS SPECTROMETRY IMAGING OF DRUGS IN TISSUES.

Mass spectrometry imaging (MSI) has seen remarkable development in recent years. The possibility of getting quantitative or semiquantitative data, while maintaining the spatial component in the tissues has opened up unique study possibilities. Now with a spatial window of few tens of microns, we can characterize the events occurring in tissue subcompartments in physiological and pathological conditions. For example, in oncology-especially in preclinical models-we can quantitatively measure drug distribution within tumors, correlating it with pharmacological treatments intended to modify it. We can also study the local effects of the drug in the tissue, and their effects in relation to histology. This review focuses on the main results in the field of drug MSI in clinical pharmacology, looking at the literature on the distribution of drugs in human tissues, and also the first preclinical evidence of drug intratissue effects. The main instrumental techniques are discussed, looking at the different instrumentation, sample preparation protocols, and raw data management employed to obtain the sensitivity required for these studies. Finally, we review the applications that describe in situ metabolic events and pathways induced by the drug, in animal models, showing that MSI makes it possible to study effects that go beyond the simple concentration of the drug, maintaining the space dimension. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.

Drug-Homogeneity Index in Mass-Spectrometry Imaging.

Enhancing drug penetration in solid tumors is an interesting clinical issue of considerable importance. In preclinical research, mass-spectrometry imaging is a promising technique for visualizing drug distribution in tumors under different treatment conditions and its application in this field is rapidly increasing. However, in view of the huge variability among MSI data sets, drug homogeneity is usually manually assessed by an expert, and this approach is biased by interobserver variability and lacks reproducibility. We propose a new texture-based feature, the drug-homogeneity index (DHI), which provides an objective, automated measure of drug homogeneity in MSI data. A simulation study on synthetic data sets showed that previously known texture features do not give an accurate picture of intratumor drug-distribution patterns and are easily influenced by the tumor-tissue morphology. The DHI has been used to study the distribution profile of the anticancer drug paclitaxel in various xenograft models, which were either pretreated or not pretreated with antiangiogenesis compounds. The conclusion is that drug homogeneity is better in the pretreated condition, which is in agreement with previous experimental findings published by our group. This study shows that DHI could be useful in preclinical studies as a new parameter for the evaluation of protocols for better drug penetration.

Molecular and Pharmacological Mechanisms of Drug Resistance:An Evolving Paradigm.

The high heterogeneity and genomic instability of malignant tumors explains why even responsive tumors contain cell clones that are resistant for many possible mechanisms involving intracellular drug inactivation, low uptake or high efflux of anticancer drugs from cancer cells, qualitative or quantitative changes in the drug target. Many tumors, however, are resistant because of insufficient exposure to anticancer drugs, due to pharmacokinetic reasons and inefficient and heterogeneous tumor drug distribution, related to a deficient vascularization and high interstitial pressure. Finally, resistance can be related to the activation of anti-apoptotic and cell survival pathways by cancer cells and often enhanced by tumor microenvironment.

High Penetration of Paclitaxel in Abdominal Wall of Rabbits after Hyperthermic Intraperitoneal Administration of Nab-Paclitaxel Compared to Standard Paclitaxel Formulation.

PURPOSE: Paclitaxel (PTX) is currently used in combination with cisplatin for Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis. Albumin-bound PTX is a promising new drug for HIPEC because of its easy solubility in aqueous perfusion medium and possibly because of the tendency of albumin to cross physiological barriers and accumulate in tumor tissue. METHODS: We tested the feasibility of using nab-paclitaxel in rabbits treated by HIPEC for 60 min compared with the classical formulation at an equivalent PTX dose. Samples of perfusate and blood were collected at different time points and peritoneal tissues were collected at the end of perfusion. PTX concentrations were determined by HPLC. The depth of paclitaxel penetration through the peritoneal barrier was assessed by mass spectrometry imaging. RESULTS: PTX after nab-paclitaxel treatment penetrated up to 0.63 mm in the peritoneal wall, but after CRE-paclitaxel, it was not detectable in the peritoneum. Moreover, the peritoneal concentration after nab-paclitaxel was five times that after paclitaxel classical formulation. Despite the high levels reached in the peritoneum, systemic exposure of PTX was low. CONCLUSIONS: Our results show that nab-paclitaxel penetrates into the abdominal wall better than CRE-paclitaxel, in terms of effective penetration and peritoneal tissue concentration.

PEGylated Nanoparticles Obtained through Emulsion Polymerization as Paclitaxel Carriers.

Polymer nanoparticles (NPs) represent a promising way to deliver poorly water-soluble anticancer drugs without the use of unwanted excipients, whose presence can be the cause of severe side effects. In this work, a Cremophor-free formulation for paclitaxel (PTX) has been developed by employing PEGylated polymer nanoparticles (NPs) as drug delivery carriers based on modified poly(ε-caprolactone) macromonomers and synthesized through free radical emulsion polymerization. Paclitaxel was loaded in the NPs in a postsynthesis process which allowed to obtain a drug concentration suitable for in vivo use. In vivo experiments on drug biodistribution and therapeutic efficacy show comparable behavior between the NPs and the Cremophor formulation, also showing good tolerability of the new formulation proposed.

Preclinical Activity of Two Paclitaxel Nanoparticle Formulations After Intraperitoneal Administration in Ovarian Cancer Murine Xenografts.

Background: Epithelial ovarian cancer is associated with high mortality due to diagnosis at later stages associated with peritoneal involvement. Several trials have evaluated the effect of intraperitoneal treatment. In this preclinical study, we report the efficacy, pharmacokinetics and pharmacodynamics of intraperitoneal treatment with two approved nanomolecular formulations of paclitaxel (nab-PTX and mic-PTX) in a murine ovarian cancer xenograft model. Methods: IC50 was determined in vitro on three ovarian cancer cell lines (OVCAR-3, SK-OV-3 and SK-OV-3-Luc IP1). EOC xenografts were achieved using a modified subperitoneal implantation technique. Drug treatment was initiated 2 weeks after engraftment, and tumor volume and survival were assessed. Pharmacokinetics and drug distribution effects were assessed using UHPLC-MS/MS and MALDI imaging mass spectrometry, respectively. Pharmacodynamic effects were analyzed using immunohistochemistry and transmission electron microscopy using standard protocols. Results: We demonstrated sub-micromolar IC50 concentrations for both formulations on three EOC cancer cell lines in vitro. Furthermore, IP administration of nab-PTX or mic-PTX lead to more than 2-fold longer survival compared to a control treatment of IP saline administration (30 days in controls, 66 days in nab-PTX treated animals, and 76 days in mic-PTX animals, respectively). We observed higher tissue uptake of drug following nab-PTX administration when compared to mic-PTX, with highest uptake after 4 hours post-treatment, and confirmed this lower uptake of mic-PTX using HPLC on digested tumor samples. Furthermore, apoptosis was not increased in tumor implants up to 24h post-treatment. Conclusion: Intraperitoneal administration of both nab-PTX and mic-PTX results in a significant anticancer efficacy and survival benefit in a mouse OC xenograft model.

A hyphenated microLC-Q-TOF-MS platform for exosomal lipidomics investigations: application to RCC urinary exosomes.

Urinary exosomes are released from every renal epithelial cell type facing the urinary space and therefore, they may carry molecular markers of renal dysfunction and structural injury. Here, we present a hyphenated microLC-Q-TOF-MS platform for lipidomics studies applied to investigate the urinary exosome lipid repertoire. Lipids were separated by reversed-phase chromatography using a linear gradient of formic acid 0.2% and tetrahydrofuran, in 40 min of analysis. Features (m/z with associated own retention time) were extracted by MarkerLynx(TM) (Waters) and processed, demonstrating good analytical performance in terms of repeatability and mass accuracy of the microLC Q-TOF MS platform. In particular, a stable retention time (RSD less than 4%) and relative intensity (RSD from 2.9% to 11%) were observed. Moreover, the method takes advantages by the use of a lock spray interface (Waters) that allows readjusting the m/z data after acquisition, obtaining inaccuracy below 6 ppm in measuring the m/z value of the reference compound during chromatographic run. The method was employed in a preliminary application to perform comparative analysis from healthy control subjects and renal cell carcinoma (RCC) patients, in order to possibly highlight differences in lipid composition to be exploited as potential tumor biomarker. Differential lipid composition in RCC urinary exosomes was achieved and tentatively identified by accurate mass, providing a preliminary indication of a relationship between lipid composition of urinary exosomes and RCC disease. Among the total features significantly different in RCC exosomes, the ion at m/z 502.3 was taken as an example for molecular confirmation by MS/MS fragmentation analysis.

Quantitative measurement of pioglitazone in neoplastic and normal tissues by AP-MALDI mass spectrometry imaging.

Pioglitazone is a Peroxisome Proliferator-Activated Receptor (PPAR) agonist of the thiazolidinedione class of compounds with promising anticancer activity. An innovative quantitative mass spectrometry imaging (MSI) method and a HPLC-UV method were developed and validated to investigate its distribution in tumor and liver tissues. The MSI method is based on stable isotope normalization and resulted highly specific and sensitive (0.2 pmol/spot). The correct identification of the drug ion signal is confirmed by MS/MS analysis on tissue. The method shows an optimal lateral resolution (25 µm) relying on the ionization efficiency and fine laser diameter of the atmospheric pressure MALDI source. The HPLC-UV method is simple and straightforward involving quick protein precipitation and shows good sensitivity (50ng/sample) using a small starting volume of biological sample. Thus, it is applicable to samples obtained from both preclinical models and clinical surgical procedures. MSI and HPLC-UV assays were validated assessing linearity, intra- and inter-day precision and accuracy, limit of quantification, selectivity and recovery. These are the first methods developed and validated for the analysis of pioglitazone in tissues, and they were applied successfully to myxoid liposarcoma xenograft-bearing mice, which received clinically relevant drug doses. Pioglitazone was measured by either method in sections of tumor and liver 2, 6 and 24 h post-treatment. Drug distribution was relatively homogeneous.

Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery.

Exosomes are membranous vesicles released by cells in extracellular fluids: they have been found and analyzed in blood, urine, amniotic fluid, breast milk, seminal fluid, saliva and malignant effusions, besides conditioned media from different cell lines. Several recent papers show that exosome proteomes of different origin include both a common set of membrane and cytosolic proteins, and specific subsets of proteins, likely correlated to cell-type associated functions. This is particularly interesting in relation to their possible involvement in human diseases. The knowledge of exosome proteomics can help not only in understanding their biological roles but also in supplying new biomarkers to be searched for in patients' fluids. This review offers an overview of technical and analytical issues in exosome proteomics, and it highlights the significance of proteomic studies in terms of biological and clinical usefulness.

Betulinic acid and its spray dried microparticle formulation: In vitro PDT effect against ovarian carcinoma cell line and in vivo plasma and tumor disposition.

The race against ovarian cancer continue to motivate the research worldwide. It is known that many antitumor drugs have limited penetration into solid tumor tissues due to its microenvironment, thus contributing to their low efficacy. Therapeutic modalities have been exploited to elicit antitumor effects based on microenvironment of tumor, including Photodynamic therapy (PDT). Prospection of natural small molecules and nanotechnology are important tools in the development of new ways of obtaining photoactive compounds that are biocompatible. The Betulinic acid (BA) has shown potential biological effect as bioactive drug, but it has low water solubility. Thus, in the present study, owing to the poor solubility of the BA, its free form (BAF) was compared to a spray dried microparticle betulinic acid/HP-ß-CD formulation (BAC) aiming to assess the BAF and BAC efficacy as a photosensitizer in PDT for application in ovarian cancer. BAF and BAC were submitted to assays in the presence of LED (λ = 420 nm) under different conditions (2.75 J/cm2, 5.5 J/cm2, and 11 J/cm2) and in absence of irradiation, after 5 min or 4 h of contact with ovarian carcinoma cells (A2780) or fibroblast murine cells (3T3). Furthermore, HPLC-MS/MS and MALDI-MSI methods were developed and validated in plasma and tumor of mice proving suitable for in vivo studies. The results found a greater photoinduced cytotoxic effect for the BAC at low concentration for A2780 when irradiated with LED with similar results for fluorescence microscopy. The results motivate us to continue the studies with the BA as a potential antitumor bioactive compound.

Tumor vascular remodeling by thrombospondin-1 enhances drug delivery and antineoplastic activity.

The disorganized and inefficient tumor vasculature is a major obstacle to the delivery and efficacy of antineoplastic treatments. Antiangiogenic agents can normalize the tumor vessels, improving vessel function and boosting the distribution and activity of chemotherapy. The type III repeats (T3R) domain of thrombospondin-1 contains different potential antiangiogenic sequences. We therefore hypothesized that it might affect the tumor vasculature. Ectopic expression of the T3R domain by the tumor cells or by the host, or administration of recombinant T3R, delayed the in vivo growth of experimental tumors. Tumors presented marked reorganization of the vasculature, with abundant but smaller vessels, associated with substantially less necrosis. Mechanistically, the use of truncated forms of the domain, containing different active sequences, pointed to the FGF2/FGFR/ERK axis as a target for T3R activity. Along with reduced necrosis, the expression of T3R promoted tumor distribution of chemotherapy (paclitaxel), with a higher drug concentration and more homogeneous distribution, as assessed by HPLC and MALDI imaging mass spectrometry. T3R-expressing tumors were more responsive to paclitaxel and cisplatin. This study shows that together with its known role as a canonical inhibitor of angiogenesis, thrombospondin-1 can also remodel tumor blood vessels, affecting the morphological and functional properties of the tumor vasculature. The ability of T3R to reduce tumor growth and improve the response to chemotherapy opens new perspectives for therapeutic strategies based on T3R to be used in combination therapies.

PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models.

BACKGROUND: Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs. METHODS: We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry. RESULTS: Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model. CONCLUSION: Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.

Human sialidase NEU4 long and short are extrinsic proteins bound to outer mitochondrial membrane and the endoplasmic reticulum, respectively.

Sialidases are widely distributed glycohydrolytic enzymes removing sialic acid residues from glycoconjugates. In mammals, several sialidases with different subcellular localizations and biochemical features have been described. NEU4, the most recently identified member of the human sialidase family, is found in two forms, NEU4 long and NEU4 short, differing in the presence of a 12-amino-acid sequence at the N-terminus. Contradictory data are present in the literature about the subcellular distribution of these enzymes, their membrane anchoring mechanism being still unclear. In this work, we investigate the human NEU4 long and NEU4 short membrane anchoring mechanism and their subcellular localization. Protein extraction with Triton X-114 and sodium carbonate and cross-linking experiments demonstrate that both forms of NEU4 are extrinsic membrane proteins, anchored via protein-protein interactions. Moreover, through confocal microscopy and subcellular fractionation, we show that the long form localizes in mitochondria, while the short form is also associated with the endoplasmic reticulum. Finally, mitochondria subfractionation experiments suggest that NEU4 long is bound to the outer mitochondrial membrane.

Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging.

Rationale: Optimal intratumor distribution of an anticancer drug is fundamental to reach an active concentration in neoplastic cells, ensuring the therapeutic effect. Determination of drug concentration in tumor homogenates by LC-MS/MS gives important information about this issue but the spatial information gets lost. Targeted mass spectrometry imaging (MSI) has great potential to visualize drug distribution in the different areas of tumor sections, with good spatial resolution and superior specificity. MSI is rapidly evolving as a quantitative technique to measure the absolute drug concentration in each single pixel. Methods: Different inorganic nanoparticles were tested as matrices to visualize the PARP inhibitors (PARPi) niraparib and olaparib. Normalization by deuterated internal standard and a custom preprocessing pipeline were applied to achieve a reliable single pixel quantification of the two drugs in human ovarian tumors from treated mice. Results: A quantitative method to visualize niraparib and olaparib in tumor tissue of treated mice was set up and validated regarding precision, accuracy, linearity, repeatability and limit of detection. The different tumor penetration of the two drugs was visualized by MSI and confirmed by LC-MS/MS, indicating the homogeneous distribution and higher tumor exposure reached by niraparib compared to olaparib. On the other hand, niraparib distribution was heterogeneous in an ovarian tumor model overexpressing the multidrug resistance protein P-gp, a possible cause of resistance to PARPi. Conclusions: The current work highlights for the first time quantitative distribution of PAPRi in tumor tissue. The different tumor distribution of niraparib and olaparib could have important clinical implications. These data confirm the validity of MSI for spatial quantitative measurement of drug distribution providing fundamental information for pharmacokinetic studies, drug discovery and the study of resistance mechanisms.

A methodological approach to correlate tumor heterogeneity with drug distribution profile in mass spectrometry imaging data.

BACKGROUND: Drug mass spectrometry imaging (MSI) data contain knowledge about drug and several other molecular ions present in a biological sample. However, a proper approach to fully explore the potential of such type of data is still missing. Therefore, a computational pipeline that combines different spatial and non-spatial methods is proposed to link the observed drug distribution profile with tumor heterogeneity in solid tumor. Our data analysis steps include pre-processing of MSI data, cluster analysis, drug local indicators of spatial association (LISA) map, and ions selection. RESULTS: The number of clusters identified from different tumor tissues. The spatial homogeneity of the individual cluster was measured using a modified version of our drug homogeneity method. The clustered image and drug LISA map were simultaneously analyzed to link identified clusters with observed drug distribution profile. Finally, ions selection was performed using the spatially aware method. CONCLUSIONS: In this paper, we have shown an approach to correlate the drug distribution with spatial heterogeneity in untargeted MSI data. Our approach is freely available in an R package 'CorrDrugTumorMSI'.

Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

OBJECTIVE: Evidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreductive surgery (MI-SCS). METHODS: Cisplatin levels were assessed at 0, 20, 40, 60, and 120 minutes in: 1) blood samples, 2) peritoneal perfusate, and 3) peritoneal biopsies at the end of HIPEC. Median Cmax has been used to identify women with high and low drug levels. Progression-free survival (PFS) was calculated as the time elapsed between SCS+HIPEC and secondary recurrence or last follow-up visit. RESULTS: Nine (45.0%) women received MI-SCS, and 11 (55.0%) O-SCS. At 60 minutes, median cisplatin Cmax in peritoneal tissue was higher in patients treated with MI-SCS compared to O-SCS (Cmax=8.262 µg/mL vs. Cmax=4.057 µg/mL). Furthermore, median cisplatin plasma Cmax was higher in patients treated with MI-SCS compared to O-SCS (Cmax=0.511 vs. Cmax=0.254 µg/mL; p-value=0.012) at 120 minutes. With a median follow-up time of 24 months, women with higher cisplatin peritoneal Cmax showed a longer PFS compared to women with low cisplatin peritoneal levels (2-years PFS=70% vs. 35%; p-value=0.054). CONCLUSIONS: We demonstrate for the first time that minimally invasive route enhances cisplatin peritoneal tissue uptake during HIPEC, further evaluations are needed to confirm the correlation between peritoneal cisplatin levels after HIPEC and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01539785.

Monitoring the Fate of Orally Administered PLGA Nanoformulation for Local Delivery of Therapeutic Drugs.

One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract; (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells; (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure; (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders.

Past-in-the-Future. Peak detection improves targeted mass spectrometry imaging.

Mass spectrometry imaging is a valuable tool for visualizing the localization of drugs in tissues, a critical issue especially in cancer pharmacology where treatment failure may depend on poor drug distribution within the tumours. Proper preprocessing procedures are mandatory to obtain quantitative data of drug distribution in tumours, even at low intensity, through reliable ion peak identification and integration. We propose a simple preprocessing and quantification pipeline. This pipeline was designed starting from classical peak integration methods, developed when "microcomputers" became available for chromatography, now applied to MSI. This pre-processing approach is based on a novel method using the fixed mass difference between the analyte and its 5 d derivatives to set up a mass range gate. We demonstrate the use of this pipeline for the evaluating the distribution of the anticancer drug paclitaxel in tumour sections. The procedure takes advantage of a simple peak analysis and allows to quantify the drug concentration in each pixel with a limit of detection below 0.1 pmol mm-2 or 10 µg g-1. Quantitative images of paclitaxel distribution in different tumour models were obtained and average paclitaxel concentrations were compared with HPLC measures in the same specimens, showing <20% difference. The scripts are developed in Python and available through GitHub, at github.com/FrancescaFalcetta/Imaging_of_drugs_distribution_and_quantifications.git.

Self-Assembling PCL-Based Nanoparticles as PTX Solubility Enhancer Excipients.

The advent of nanotechnology in medicine has allowed to eliminate the toxic excipients that are often necessary to formulate lipophilic drugs in clinics. An example is paclitaxel, one of the most important chemotherapeutic drugs developed so far, where the Cremophor EL has been eliminated in the Genexol and Abraxane formulations. However, the complex procedures to synthesize these formulations hamper their cost-effective use and, in turn, their distribution among the patient population. For this reason, a simplified method to formulate this drug directly at the bed of the patient has been adopted. It requires only the use of a syringe and it starts from a native dry amphiphilic biodegradable and biocompatible block-copolymer obtained via the combination of the reversible addition-fragmentation chain transfer polymerization and ring-opening polymerization. In this way, a novel paclitaxel formulation with the same drug pharmacological properties, but without the use of the Cremophor EL, can be produced. In addition, as long as these nanoparticles are engineered to act as solubility enhancers, a lower burden for its approval from the pharmaceutical regulatory agencies is also expected.