A three-gene expression score for predicting clinical benefit to anti-PD-1 blockade in advanced renal cell carcinoma.

In the advanced renal cell carcinoma (RCC) scenario, there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade (ICB). Taking this into consideration, herein, we conducted a retrospective study in order to develop and validate a gene expression score for predicting clinical benefit to the anti-PD-1 antibody nivolumab in the context of patients diagnosed with advanced clear cell RCC enrolled in the CheckMate-009, CheckMate-010, and CheckMate-025 clinical trials. First, a three-gene expression score (3GES) with prognostic value for overall survival integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Its prognostic value was then validated in the TCGA-KIRC cohort. Second, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 phase 3 clinical trial. Lastly, we explored the correlation of our 3GES with different clinical, molecular, and immune tumor characteristics. If the results of this study are definitively validated in other retrospective and large-scale, prospective studies, the 3GES will represent a valuable tool for guiding the design of ICB-based clinical trials in the aRCC scenario in the near future.

Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists.

The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.

Electrospraying as a Technique for the Controlled Synthesis of Biocompatible PLGA@Ag2S and PLGA@Ag2S@SPION Nanocarriers with Drug Release Capability.

Ag2S nanoparticles are near-infrared (NIR) probes providing emission in a specific spectral range (~1200 nm), and superparamagnetic iron oxide nanoparticles (SPION) are colloidal systems able to respond to an external magnetic field. A disadvantage of Ag2S NPs is the attenuated luminescent properties are reduced in aqueous media and human fluids. Concerning SPION, the main drawback is the generation of undesirable clusters that reduce particle stability. Here, we fabricate biocompatible hybrid nanosystems combining Ag2S NPs and SPION by the electrospraying technique for drug delivery purposes. These nanostructures are composed of poly(lactic-co-glycolic acid) (PLGA) as the polymeric matrix in connection with both Ag2S NPs and SPIONs. Initially, we fabricate a hybrid colloidal nanosystem composed of Ag2S NPs in connection with PLGA (PLGA@Ag2S) by three different routes, showing good photoluminescent (PL) properties with relatively high average decay times. Then, we incorporate SPIONs, obtaining a PLGA polymeric matrix containing both Ag2S NPs and SPION (PLGA@Ag2S@SPION). Interestingly, in this hybrid system, the location of Ag2S NPs and SPIONs depends on the synthesis route performed during electrospraying. After a detailed characterization, we demonstrate the encapsulation and release capabilities, obtaining the kinetic release using a model chemotherapeutic drug (maslinic acid). Finally, we perform in vitro cytotoxicity assays using drug-loaded hybrid systems against several tumor cell lines.

Nanomedicine to Overcome Multidrug Resistance Mechanisms in Colon and Pancreatic Cancer: Recent Progress.

The development of drug resistance is one of the main causes of cancer treatment failure. This phenomenon occurs very frequently in different types of cancer, including colon and pancreatic cancers. However, the underlying molecular mechanisms are not fully understood. In recent years, nanomedicine has improved the delivery and efficacy of drugs, and has decreased their side effects. In addition, it has allowed to design drugs capable of avoiding certain resistance mechanisms of tumors. In this article, we review the main resistance mechanisms in colon and pancreatic cancers, along with the most relevant strategies offered by nanodrugs to overcome this obstacle. These strategies include the inhibition of efflux pumps, the use of specific targets, the development of nanomedicines affecting the environment of cancer-specific tissues, the modulation of DNA repair mechanisms or RNA (miRNA), and specific approaches to damage cancer stem cells, among others. This review aims to illustrate how advanced nanoformulations, including polymeric conjugates, micelles, dendrimers, liposomes, metallic and carbon-based nanoparticles, are allowing to overcome one of the main limitations in the treatment of colon and pancreatic cancers. The future development of nanomedicine opens new horizons for cancer treatment.

Biomimetic Magnetoliposomes as Oxaliplatin Nanocarriers: In Vitro Study for Potential Application in Colon Cancer.

Current chemotherapy for colorectal cancer (CRC) includes the use of oxaliplatin (Oxa), a first-line cytotoxic drug which, in combination with irinotecan/5-fluorouracil or biologic agents, increases the survival rate of patients. However, the administration of this drug induces side effects that limit its application in patients, making it necessary to develop new tools for targeted chemotherapy. MamC-mediated biomimetic magnetic nanoparticles coupled with Oxa (Oxa-BMNPs) have been previously demonstrated to efficiently reduce the IC50 compared to that of soluble Oxa. However, their strong interaction with the macrophages revealed toxicity and possibility of aggregation. In this scenario, a further improvement of this nanoassembly was necessary. In the present study, Oxa-BMNPs nanoassemblies were enveloped in phosphatidylcholine unilamellar liposomes (both pegylated and non-pegylated). Our results demonstrate that the addition of both a lipid cover and further pegylation improves the biocompatibility and cellular uptake of the Oxa-BMNPs nanoassemblies without significantly reducing their cytotoxic activity in colon cancer cells. In particular, with the pegylated magnetoliposome nanoformulation (a) hemolysis was reduced from 5% to 2%, being now hematocompatibles, (b) red blood cell agglutination was reduced, (c) toxicity in white blood cells was eliminated. This study represents a truly stepforward in this area as describes the production of one of the very few existing nanoformulations that could be used for a local chemotherapy to treat CRC.

Magnetically active pNIPAM nanosystems as temperature-sensitive biocompatible structures for controlled drug delivery.

Here, temperature-sensitive hybrid poly(N-isopropylacrylamide) (pNIPAM) nanosystems with magnetic response are synthesised and investigated for controlled release of 5-fluorouracil (5FU) and oxaliplatin (OXA). Initially, magnetic nanoparticles (@Fe3O4) are synthesised by co-precipitation approach and functionalised with acrylic acid (AA), 3-butenoic acid (3BA) or allylamine (AL) as comonomers. The thermo-responsive polymer is grown by free radical polymerisation using N-isopropylacrylamide (NIPAM) as monomer, N,N'-methylenbisacrylamide (BIS) as cross-linker, and 2,2'-azobis(2-methylpropionamidene) (V50) as initiator. We evaluate particle morphology by transmission electron microscopy (TEM) and particle size and surface charge by dynamic light scattering (DLS) and Z-potential (ZP) measurements. These magnetically active pNIPAM@ nanoformulations are loaded with 5-fluorouracil (5FU) and oxaliplatin (OXA) to determine loading efficiency, drug content and release as well as the cytotoxicity against T-84 colon cancer cells. Our results show high biocompatibility of pNIPAM nanoformulations using human blood cells and cultured cells. Interestingly, the pNIPAM@Fe3O4-3BA + 5FU nanoformulation significantly reduces the growth of T-84 cells (57% relative inhibition of proliferation). Indeed, pNIPAM-co-AL@Fe3O4-AA nanosystems produce a slight migration of HCT15 cells in suspension in the presence of an external magnetic field. Therefore, the obtained hybrid nanoparticles can be applied as a promising biocompatible nanoplatform for the delivery of 5FU and OXA in the improvement of colon cancer treatments.

Bengamide Analogues Show A Potent Antitumor Activity against Colon Cancer Cells: A Preliminary Study.

The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC.

Novel MicroRNA Sponges to Specifically Modulate Gene Expression in Colon Cancer Cells.

MicroRNA (miRNA) sponges allow the selective blockade of a complete family of associated miRNAs, which induce post-transcriptional gene silencing in their target through binding to 3'UTR mRNA. miRNA-365 and miRNA-145 are downregulated in colorectal cancer (CRC) but not in healthy tissues. Based on this, we constructed two vectors by inserting miRNA sponges (one for miRNA-365 and other for miRNA-145), and used enhanced green fluorescent protein (EGFP) as a 3'UTR reporter gene to analyze the ability of each sponge to catch its respective miRNA. Quantitative polymerase chain reaction (qPCR) results corroborated that the expression levels of both miRNAs were lower in CRC cell lines than in normal colon cell lines. Flow cytometry analysis revealed a decrease of the EGFP expression levels in the cell lines transfected with both sponges, being higher on the normal cell line while CRC cell lines presented a minimal decline. Also, this decrease was inversely proportional to the levels of expression of both miRNAs obtained by qPCR. These results were corroborated by fluorescence microscopy, showing a similar decrease in fluorescence. We propose a new vector system to carry in a specific way the expression of genes to CRC cells without affecting healthy cells, preventing damage to healthy tissues.

Nanoformulations for glioblastoma multiforme: a new hope for treatment.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, associated with a high mortality rate and a survival of between 12 and 15 months after diagnosis. Due to current treatment limitations involving surgery, radiotherapy and chemotherapy with temozolamide, there is a high rate of treatment failure and recurrence. To try to overcome these limitations nanotechnology has emerged as a novel alternative. Lipid, polymeric, silica and magnetic nanoparticles, among others, are being developed to improve GBM treatment and diagnosis. These nanoformulations have many advantages, including lower toxicity, biocompatibility and the ability to be directed toward the tumor. This article reviews the progress that have been made and the large variety of nanoparticles currently under study for GBM.

Oxaliplatin-Biomimetic Magnetic Nanoparticle Assemblies for Colon Cancer-Targeted Chemotherapy: An In Vitro Study.

Conventional chemotherapy against colorectal cancer (CRC), the third most common cancer in the world, includes oxaliplatin (Oxa) which induces serious unwanted side effects that limit the efficiency of treatment. Therefore, alternative therapeutic approaches are urgently required. In this work, biomimetic magnetic nanoparticles (BMNPs) mediated by MamC were coupled to Oxa to evaluate the potential of the Oxa-BMNP nanoassembly for directed local delivery of the drug as a proof of concept for the future development of targeted chemotherapy against CRC. Electrostatic interactions between Oxa and BMNPs trigger the formation of the nanoassembly and keep it stable at physiological pH. When the BMNPs become neutral at acidic pH values, the Oxa is released, and such a release is greatly potentiated by hyperthermia. The coupling of the drug with the BMNPs improves its toxicity to even higher levels than the soluble drug, probably because of the fast internalization of the nanoassembly by tumor cells through endocytosis. In addition, the BMNPs are cytocompatible and non-hemolytic, providing positive feedback as a proof of concept for the nanoassembly. Our study clearly demonstrates the applicability of Oxa-BMNP in colon cancer and offers a promising nanoassembly for targeted chemotherapy against this type of tumor.

Lipid-Based Nanoparticles: Application and Recent Advances in Cancer Treatment.

Many therapeutically active molecules are non-soluble in aqueous systems, chemically and biologically fragile or present severe side effects. Lipid-based nanoparticle (LBNP) systems represent one of the most promising colloidal carriers for bioactive organic molecules. Their current application in oncology has revolutionized cancer treatment by improving the antitumor activity of several chemotherapeutic agents. LBNPs advantages include high temporal and thermal stability, high loading capacity, ease of preparation, low production costs, and large-scale industrial production since they can be prepared from natural sources. Moreover, the association of chemotherapeutic agents with lipid nanoparticles reduces active therapeutic dose and toxicity, decreases drug resistance and increases drug levels in tumor tissue by decreasing them in healthy tissue. LBNPs have been extensively assayed in in vitro cancer therapy but also in vivo, with promising results in some clinical trials. This review summarizes the types of LBNPs that have been developed in recent years and the main results when applied in cancer treatment, including essential assays in patients.