The Spicy Science of Dendrimers in the Realm of Cancer Nanomedicine: A Report from the COST Action CA17140 Nano2Clinic

: COST Action CA17140 Cancer Nanomedicine-from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, preclinical testing of efficacy, pharmacokinetics and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation, and innovative solutions, the action aims at providing a timely instrument to rationalize and focus research efforts at the European level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and societal-burdening human pathologies. Within CA17140, dendrimers in all their forms (from covalent to self-assembling dendrons) play a vital role as powerful nanotheranostic agents in oncology; therefore, the purpose of this review work is to gather and summarize the major results in the field stemming from collaborative efforts in the framework of the European Nano2Clinic COST Action

Perceptions and Misconceptions in Molecular Recognition: Key Factors in Self-Assembling Multivalent (SAMul) Ligands/Polyanions Selectivity

Biology is dominated by polyanions (cell membranes, nucleic acids, and polysaccharides just to name a few), and achieving selective recognition between biological polyanions and synthetic systems currently constitutes a major challenge in many biomedical applications, nanovectors-assisted gene delivery being a prime example. This review work summarizes some of our recent efforts in this field; in particular, by using a combined experimental/computation approach, we investigated in detail some critical aspects in self-assembled nanomicelles and two major polyanions-DNA and heparin

Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled In Silico-Experimental Studies. Part I: Covalent siRNA Nanocarriers

Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the clinical translation of RNA interference (RNAi) requires safe and efficient vectors for siRNA delivery into cells. Dendrimers are attractive nanovectors to serve this purpose, as they present a unique, well-defined architecture and exhibit cooperative and multivalent effects at the nanoscale. This short review presents a brief introduction to RNAi-based therapeutics, the advantages offered by dendrimers as siRNA nanocarriers, and the remarkable results we achieved with bio-inspired, structurally flexible covalent dendrimers. In the companion paper, we next report our recent efforts in designing, characterizing and testing a series of self-assembled amphiphilic dendrimers and their related structural alterations to achieve unprecedented efficient siRNA delivery both in vitro and in vivo

Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled in Silico-Experimental Studies. Part II: Self-Assembled siRNA Nanocarriers

In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing

Chiral recognition at self-assembled multivalent (SAMul) nanoscale interfaces – enantioselectivity in polyanion binding

Self-assembled multivalent (SAMul) ligands based on palmitic acid functionalised with cationic L/D-lysine bind polyanionic heparin or DNA with no chiral preference. Inserting a glycine spacer unit switches on chiral discrimination – a rare example of controlled chiral recognition at a SAMul nanoscale interface

Thermoplastic Materials for the Metal Replacement of Non-Structural Components in Marine Engines

Metal replacements for automotive and aerospace components are already a consolidated reality, in light of the advantages offered by fibre-reinforced polymers, consisting of reduced costs, weight, and environmental impact. As a result, engineering has been studying the possibility of replacing currently used metallic alloys with alternative materials, such as thermoplastic fibre-reinforced polymers, in the manufacturing of non-structural sections of marine engines. Given the peculiar characteristics of the working environment of such parts, i.e., ship engine spaces, and the strict requirements regarding safety, the selection of the polymer must be properly performed through a tailored material design process. Consequently, the redesign of the components must be carried out with the aim of exploiting the best of the materials’ properties while ensuring the correct resistance and simplifying installation operations. In this framework, finite element simulations may represent a suitable approach to validate the conformity of the proposed material and design. In this paper, this methodology is applied to a camshaft cover of a four-stroke marine engine, currently made of aluminium alloy. A 30% wt GFs/PA6,6 was identified as the most promising material and the novel plastic cover proved to guarantee the correct resistance while ensuring an important reduction in weight, processing costs, and required energy

Biophysical and docking study on the interaction of anticancer drugs encorafenib and binimetinib with human serum albumin

The utilization of BRAF and MEK inhibitors in combination therapy has demonstrated superior outcomes in the treatment of melanoma as compared to monotherapy. In the present scenario, the combination therapy of Encorafenib (ENC), a BRAF inhibitor, and Binimetinib (BINI), a MEK inhibitor, has been identified as one of the most efficacious treatment modalities for this malignancy. Investigations of protein binding, particularly with human serum albumin (HSA), are essential to understand drug performance and enhance therapeutic outcomes. The investigation of the interplay between small molecule drugs and HSA is of paramount importance, given that such interactions can exert a substantial influence on the pharmacokinetics of these therapeutic agents. The present study aims to bridge these lacunae by implementing a comprehensive approach that integrates fluorescence spectroscopy (FS), isothermal titration calorimetry (ITC), far-ultraviolet circular dichroism (far-UV CD), and molecular simulations. Through analysis of the fluorescence quenching of HSA at three distinct temperatures, it was ascertained that the association constants for the complexes formed between drugs and HSA were of the magnitude of 104 M−1. This suggests that the interactions between the compounds and albumin were moderate and comparable. Simultaneously, the investigation of fluorescence indicated a contrasting binding mechanism for the two inhibitors: ENC predominantly binds to HSA through enthalpic interaction, while BINI/HSA is stabilized by entropic contributions. The data obtained was confirmed through experimental procedures conducted using the ITC method. The results of ligand-competitive displacement experiments indicate that ENC and BINI can bind to HSA within subdomain IIA, specifically Sudlow site I. However, far-UV CD studies show that there are no notable alterations in the structure of HSA upon binding with either of the two inhibitors. Ultimately, the results were supported by computational molecular analysis, which identified the key interactions that contribute to the stabilization of the two ligand/HSA complexes

Highly grafted polystyrene/polyvinylpyridine polymer gold nanoparticles in a good solvent: effects of chain length and composition

In this work, the structural features of spherical gold nanoparticles (NPs) decorated with highly grafted poly(styrene) (PS), poly(vinylpyridine) (PVP) and PS\u2013PVP diblock copolymer brushes immersed in a good solvent are investigated by means of Dissipative Particle Dynamics (DPD) simulations as a function of grafted chain length and of homopolymer and copolymer chain composition. For NPs grafted either by PS or PVP homopolymer brushes (selected as a proof of concept), good agreement between the Daoud\u2013Cotton theory, experimental evidence, and our DPD simulations is observed in the scaling behavior of single chain properties, especially for longer grafted chains, and in brush thickness prediction. On the other hand, for grafted chain lengths comparable to NP dimensions parabolic-like profiles of the end-monomer distributions are obtained. Furthermore, a region of high concentration of polymer segments is observed in the monomer density distribution for long homopolymers. In the case of copolymer-decorated NPs, the repulsion between PS and PVP blocks is found to substantially influence the radius of gyration and the shape of the end-monomer distribution of the relevant polymer shell. Moreover, for diblock chains, the un-swollen region is observed to be thinner (and, correspondingly, the swollen layer thicker) than that of a NP modified with a homopolymer of the same length. Finally, the lateral segregation of PS and PVP blocks is evidenced by our calculations and a detailed analysis of the corona behavior is reported, thus revealing the key parameters in controlling the surface properties and the response of diblock copolymer modified nanoparticles

Novel epigenetic therapeutic strategies and targets in cancer

The critical role of dysregulated epigenetic pathways in cancer genesis, development, and therapy has typically been established as a result of scientific and technical innovations in next generation sequencing. RNA interference, histone modification, DNA methylation and chromatin remodelling are epigenetic processes that control gene expression without causing mutations in the DNA. Although epigenetic abnormalities are thought to be a symptom of cell tumorigenesis and malignant events that impact tumor growth and drug resistance, physicians believe that related processes might be a key therapeutic target for cancer treatment and prevention due to the reversible nature of these processes. A plethora of novel strategies for addressing epigenetics in cancer therapy for immuno-oncological complications are currently available - ranging from basic treatment to epigenetic editing. - and they will be the subject of this comprehensive review. In this review, we cover most of the advancements made in the field of targeting epigenetics with special emphasis on microbiology, plasma science, biophysics, pharmacology, molecular biology, phytochemistry, and nanoscience

Nanomedicine-driven molecular targeting, drug delivery, and therapeutic approaches to cancer chemoresistance

Cancer cell resistance to chemotherapeutics (chemoresistance) poses a significant clinical challenge that oncology research seeks to understand and overcome. Multiple anticancer drugs and targeting agents can be incorporated in nanomedicines, in addition to different treatment modalities, forming a single nanoplatform that can be used to address tumor chemoresistance. Nanomedicine-driven molecular assemblies using nucleic acids, small interfering (si)RNAs, miRNAs, and aptamers in combination with stimuli-responsive therapy improve the pharmacokinetic (PK) profile of the drugs and enhance their accumulation in tumors and, thus, therapeutic outcomes. In this review, we highlight nanomedicine-driven molecular targeting and therapy combination used to improve the 3Rs (right place, right time, and right dose) for chemoresistant tumor therapies