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Antibody-Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds that are widely used in the treatment of hematologic malignancies and solid tumors. Unlike conventional chemotherapeutic drug-based therapies, that are mainly associated with modest specificity and therapeutic benefit, the three key components that form an ADC (a monoclonal antibody bound to a cytotoxic drug via a chemical linker moiety) achieve remarkable improvement in terms of targeted killing of cancer cells and, while sparing healthy tissues, a reduction in systemic side effects caused by off-tumor toxicity. Based on their beneficial mechanism of action, 15 ADCs have been approved to date by the market approval by the Food and Drug Administration (FDA), the European Medicines Agency (EMA) and/or other international governmental agencies for use in clinical oncology, and hundreds are undergoing evaluation in the preclinical and clinical phases. Here, our aim is to provide a comprehensive overview of the key features revolving around ADC therapeutic strategy including their structural and targeting properties, mechanism of action, the role of the tumor microenvironment and review the approved ADCs in clinical oncology, providing discussion regarding their toxicity profile, clinical manifestations and use in novel combination therapies. Finally, we briefly review ADCs in other pathological contexts and provide key information regarding ADC manufacturing and analytical characterization.

Nanoparticles (NPs) are versatile candidates for nanomedical applications due to their unique physicochemical properties. However, their clinical applicability is hindered by their undesirable recognition by the immune system and the consequent immunotoxicity, as well as their rapid clearance in vivo. After injection, NPs are usually covered with layers of proteins, called protein coronas (PCs), which alter their identity, biodistribution, half-life, and efficacy. Therefore, the characterization of the PC is for in predicting the fate of NPs in vivo. The aim of this review was to summarize the state of the art regarding the intrinsic factors closely related to the NP structure, and extrinsic factors that govern PC formation in vitro. In addition, well-known opsonins, including complement, immunoglobulins, fibrinogen, and dysopsonins, such as histidine-rich glycoprotein, apolipoproteins, and albumin, are described in relation to their role in NP detection by immune cells. Particular emphasis is placed on their role in mediating the interaction of NPs with innate and adaptive immune cells. Finally, strategies to reduce PC formation are discussed in detail.

BackgroundAnticancer drugs are notoriously characterized by a low therapeutic index, the introduction of therapeutic drug monitoring (TDM) in oncologic clinical practice could therefore be fundamental to improve treatment efficacy. In this context, an attractive technique to overcome the conventional venous sampling limits and simplify TDM application is represented by dried blood spot (DBS). Despite the significant progress made in bioanalysis exploiting DBS, there is still the need to tackle some challenges that limit the application of this technology: one of the main issues is the comparison of drug concentrations obtained from DBS with those obtained from reference matrix (e.g., plasma). In fact, the use of DBS assays to estimate plasma concentrations is highly dependent on the chemical-physical characteristics of the measured analyte, in particular on how these properties determine the drug partition in whole blood.MethodsIn the present review, we introduce a critical investigation of the DBS-to-plasma concentration conversion methods proposed in the last ten years and applied to quantitative bioanalysis of anticancer drugs in DBS matrix. To prove the concordance between DBS and plasma concentration, the results of statistical tests applied and the presence or absence of trends or biases were also considered.

Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with.

In this work, a surface plasmon resonance (SPR)-based assay for the quantification of antineoplastic drug irinotecan in human plasma samples has been developed for the first time. The selective binding of irinotecan with an aptamer receptor, operating in human plasma, allowed to set-up a novel analytical methodology to detect the drug in the analytical range of interest by using SPR as detection technique. After hybridizing the aptamer to the sensing platform and optimizing the sample preparation procedure, a quantitative assay was validated according to FDA regulatory guidelines. The analytical working range was found between 100 and 7500 ng mL−1 with negligible interferences from plasma components and co-medication associated with the administration of irinotecan. The utility of the new SPR assay was confirmed by analyzing plasma samples in parallel with LC-MS as reference technique, providing a new analytical tool for the therapeutic drug monitoring of irinotecan in patients under chemotherapy regimens.

To test the efficacy and toxicity of exosomal doxorubicin (exoDOX) compared with free doxorubicin. The cytotoxic effects of exoDOX were tested and in nude mice by measuring the tumor volume. The toxic effects were evaluated by measuring the bodyweight and through histopathologic analyses. The biodistribution of DOX was assessed by MS. and studies showed that exosomes did not decrease the efficacy of DOX. Surprisingly, exoDOX showed no cardiotoxicity as observed in DOX-treated mice and MS studies confirmed that the accumulation of exoDOX in the heart was reduced by approximately 40%. We demonstrated that exoDOX was less toxic than DOX through its altered biodistribution.

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits marked resistance to immunotherapy. Beyond its characteristically low tumor mutational burden, post-translational modifications (PTMs) remodel the immunopeptidome and promote immune escape through reversible, enzyme-driven programs. Subject Matter: We synthesize evidence that aberrant glycosylation, O-GlcNAcylation, phosphorylation, and citrullination constitute core determinants of antigen visibility operating within spatially discrete tumor niches and a desmoplastic stroma. In hypoxic regions, HIF-linked hexosamine metabolism and OGT activity stabilize immune checkpoints and attenuate antigen processing; at tumor margins, sialylated mucins engage inhibitory Siglec receptors on innate and adaptive lymphocytes; within the stroma, PAD4-dependent NET formation enforces T cell exclusion. We also delineate technical barriers to discovering PTM antigens labile chemistry, low stoichiometry, and method-embedded biases and outline practical solutions: ETD/EThcD/AI-ETD fragmentation, PTM-aware database searching and machine-learning models, and autologous validation in patient-derived organoid–T cell co-cultures. Finally, we highlight therapeutic strategies that either immunize against PTM neoepitopes or inhibit PTM machinery (e.g., PAD4, OGT, ST6GAL1), with stromal remodeling as an enabling adjunct. Conclusions: PTM biology, spatial omics, and patient sample models can uncover targetable niches and speed up PDAC vaccination, TCR, and enzyme-directed treatment development.

Over the past two decades, Next-Generation Sequencing (NGS) has revolutionized the approach to cancer research. Applications of NGS include the identification of tumor specific alterations that can influence tumor pathobiology and also impact diagnosis, prognosis and therapeutic options. Pharmacogenomics (PGx) studies the role of inheritance of individual genetic patterns in drug response and has taken advantage of NGS technology as it provides access to high-throughput data that can, however, be difficult to manage. Machine learning (ML) has recently been used in the life sciences to discover hidden patterns from complex NGS data and to solve various PGx problems. In this review, we provide a comprehensive overview of the NGS approaches that can be employed and the different PGx studies implicating the use of NGS data. We also provide an excursus of the ML algorithms that can exert a role as fundamental strategies in the PGx field to improve personalized medicine in cancer.

Irinotecan is currently used in several cancer regimens mainly in colorectal cancer (CRC). This drug has a narrow therapeutic range and treatment can lead to side effects, mainly neutropenia and diarrhea, frequently requiring discontinuing or lowering the drug dose. A wide inter-individual variability in irinotecan pharmacokinetic parameters and pharmacodynamics has been reported and associated to patients' genetic background. In particular, a polymorphism in the UGT1A1 gene (UGT1A1*28) has been linked to an impaired detoxification of SN-38 (irinotecan active metabolite) to SN-38 glucuronide (SN-38G) leading to increased toxicities. Therefore, therapeutic drug monitoring of irinotecan, SN-38 and SN-38G is recommended to personalize therapy. In order to quantify simultaneously irinotecan and its main metabolites in patients' plasma, we developed and validated a new, sensitive and specific HPLC-MS/MS method applicable to all irinotecan dosages used in clinic. This method required a small plasma volume, addition of camptothecin as internal standard and simple protein precipitation. Chromatographic separation was done on a Gemini C18 column (3 μM, 100 mm x 2.0 mm) using 0.1% acetic acid/bidistilled water and 0.1% acetic acid/acetonitrile as mobile phases. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring. The standard curves were linear (R2 ≥0.9962) over the concentration ranges (10-10000 ng/mL for irinotecan, 1-500 ng/mL for SN-38 and SN-38G and 1-5000 ng/mL for APC) and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy, determined on three quality control levels for all the analytes, were always <12.3% and between 89.4% and 113.0%, respectively. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method was successfully applied to a pharmacokinetic study in metastatic CRC patients enrolled in a genotype-guided phase Ib study of irinotecan administered in combination with 5-fluorouracil/leucovorin and bevacizumab.

Ultrasensitive detection of low-quantity drugs is important for personalized therapeutic approaches in several diseases and, in particular, for cancer treatment. In this field, surface-enhanced Raman scattering (SERS) can be very useful for its ability to precisely identify analytes from their unique vibrational spectra, with very high sensitivity. Here, we report a study about SERS detection of sunitinib, paclitaxel and irinotecan, i.e. three commonly used antineoplastic drugs, and of SN-38, i.e. the metabolite of irinotecan, dissolved in methanol solutions. By using commercial Klarite substrates, we found that sunitinib, irinotecan and SN-38 have detection limits of 20–70 ng, which is below the threshold for applications in cancer therapy. Conversely, the SERS signal was not appreciable with paclitaxel, and this is explained by the absence of optical resonances in the visible range. Overall, our results show that ultrasensitive SERS detection of sunitinib, irinotecan and SN-38 is feasible, encouraging further development of this technology also for other drugs with similar molecular structure especially for those analytes with absorption bands in the visible range.