Targeting Peptides: The New Generation of Targeted Drug Delivery Systems

Peptides can act as targeting molecules, analogously to oligonucleotide aptamers and antibodies. They are particularly efficient in terms of production and stability in physiological environments; in recent years, they have been increasingly studied as targeting agents for several diseases, from tumors to central nervous system disorders, also thanks to the ability of some of them to cross the blood–brain barrier. In this review, we will describe the techniques employed for their experimental and in silico design, as well as their possible applications. We will also discuss advancements in their formulation and chemical modifications that make them even more stable and effective. Finally, we will discuss how their use could effectively help to overcome various physiological problems and improve existing treatments

Is Raman the best strategy towards the development of non-invasive continuous glucose monitoring devices for diabetes management?

Diabetes has no well-established cure; thus, its management is critical for avoiding severe health complications involving multiple organs. This requires frequent glycaemia monitoring, and the gold standards for this are fingerstick tests. During the last decades, several blood-withdrawal-free platforms have been being studied to replace this test and to improve significantly the quality of life of people with diabetes (PWD). Devices estimating glycaemia level targeting blood or biofluids such as tears, saliva, breath and sweat, are gaining attention; however, most are not reliable, user-friendly and/or cheap. Given the complexity of the topic and the rise of diabetes, a careful analysis is essential to track scientific and industrial progresses in developing diabetes management systems. Here, we summarize the emerging blood glucose level (BGL) measurement methods and report some examples of devices which have been under development in the last decades, discussing the reasons for them not reaching the market or not being really non-invasive and continuous. After discussing more in depth the history of Raman spectroscopy-based researches and devices for BGL measurements, we will examine if this technique could have the potential for the development of a user-friendly, miniaturized, non-invasive and continuous blood glucose-monitoring device, which can operate reliably, without inter-patient variability, over sustained periods

A Prognostic Model for Estimating the Time to Virologic Failure in HIV-1 Infected Patients Undergoing a New Combination Antiretroviral Therapy Regimen

<p>Abstract</p> <p>Background</p> <p>HIV-1 genotypic susceptibility scores (GSSs) were proven to be significant prognostic factors of fixed time-point virologic outcomes after combination antiretroviral therapy (cART) switch/initiation. However, their relative-hazard for the time to virologic failure has not been thoroughly investigated, and an expert system that is able to predict how long a new cART regimen will remain effective has never been designed.</p> <p>Methods</p> <p>We analyzed patients of the Italian ARCA cohort starting a new cART from 1999 onwards either after virologic failure or as treatment-naïve. The time to virologic failure was the endpoint, from the 90^thday after treatment start, defined as the first HIV-1 RNA > 400 copies/ml, censoring at last available HIV-1 RNA before treatment discontinuation. We assessed the relative hazard/importance of GSSs according to distinct interpretation systems (Rega, ANRS and HIVdb) and other covariates by means of Cox regression and random survival forests (RSF). Prediction models were validated via the bootstrap and c-index measure.</p> <p>Results</p> <p>The dataset included 2337 regimens from 2182 patients, of which 733 were previously treatment-naïve. We observed 1067 virologic failures over 2820 persons-years. Multivariable analysis revealed that low GSSs of cART were independently associated with the hazard of a virologic failure, along with several other covariates. Evaluation of predictive performance yielded a modest ability of the Cox regression to predict the virologic endpoint (c-index≈0.70), while RSF showed a better performance (c-index≈0.73, p < 0.0001 vs. Cox regression). Variable importance according to RSF was concordant with the Cox hazards.</p> <p>Conclusions</p> <p>GSSs of cART and several other covariates were investigated using linear and non-linear survival analysis. RSF models are a promising approach for the development of a reliable system that predicts time to virologic failure better than Cox regression. Such models might represent a significant improvement over the current methods for monitoring and optimization of cART.</p

Ingénierie de systèmes biomoléculaires pour l’immunothérapie anti-tumorale

The Antibody Recruiting Molecules (ARMs) are belongs to the promising alternative in immunotherapy against cancer and pathogens. In the tumoral contest, an ARM has the singular ability to interface between the target cell and components of the immune system present on the environment leading to an immune response. In this Ph.D. work, we reported the design and the synthesis by click chemistry of several ARMs able to target over-expressed proteins on cancer cell surface through peptides-based tumoral binding modules (TBMs) and to engage natural endogenous antibodies through carbohydrate-based antibody binding modules (ABMs). Next, we demonstrated the formation of a ternary complex between cell-ARM-antibodies and the specific killing of cancer cells by our agents only in the presence of human serum as unique source of immune effectors, without pre-immunization. In addition, we established that the molecule flexibility, the length of the linker between ABM and TBM, the nature of the haptens (carbohydrates and peptides) and their valency play a significant role. Due to the efficiency of the synthetic process, a large diversity of ARMs could be easily created, opening new outlooks in diverse therapeutic fields.Les "Antibody Recruiting Molecules" (ARMs) font partie des pistes prometteuses en immunothérapie contre le cancer et les pathogènes. Dans le contexte tumoral, un ARM a la capacité de relier la cellule cible et des composants du système immunitaire pour conduire à une réponse cytotoxique. Dans ce travail de thèse, nous avons décrit la conception et la synthèse par chimie click de plusieurs ARMs capables de cibler des protéines surexprimées à la surface des cellules cancéreuses par de "tumoral binding modules" (TBMs) basés sur des peptides et d’engager des anticorps endogènes naturels par l’intermédiaire de "antibody binding modules" basés sur des glucides. Nous avons ensuite démontré la formation d’un complexe ternaire cellule-ARM-anticorps et la destruction spécifique des cellules cancéreuses par nos agents uniquement en présence de sérum humain, comme seule source de d’effecteurs immunitaires, sans pré-immunisation. Nous avons également établi que la flexibilité de la molécule, la longueur de la liaison entre ABM et TBM, la nature des haptens (glucides et peptides) et leur valence jouent un rôle important. Compte tenu de la grande efficacité du processus de synthèse, une large gamme de ARM pourrait être facilement créée, ouvrant de nouvelles perspectives dans différents domaines thérapeutiques

Engineering of biomolecular systems for anti-tumoral immunotherapy

Les "Antibody Recruiting Molecules" (ARMs) font partie des pistes prometteuses en immunothérapie contre le cancer et les pathogènes. Dans le contexte tumoral, un ARM a la capacité de relier la cellule cible et des composants du système immunitaire pour conduire à une réponse cytotoxique. Dans ce travail de thèse, nous avons décrit la conception et la synthèse par chimie click de plusieurs ARMs capables de cibler des protéines surexprimées à la surface des cellules cancéreuses par de "tumoral binding modules" (TBMs) basés sur des peptides et d’engager des anticorps endogènes naturels par l’intermédiaire de "antibody binding modules" basés sur des glucides. Nous avons ensuite démontré la formation d’un complexe ternaire cellule-ARM-anticorps et la destruction spécifique des cellules cancéreuses par nos agents uniquement en présence de sérum humain, comme seule source de d’effecteurs immunitaires, sans pré-immunisation. Nous avons également établi que la flexibilité de la molécule, la longueur de la liaison entre ABM et TBM, la nature des haptens (glucides et peptides) et leur valence jouent un rôle important. Compte tenu de la grande efficacité du processus de synthèse, une large gamme de ARM pourrait être facilement créée, ouvrant de nouvelles perspectives dans différents domaines thérapeutiques.The Antibody Recruiting Molecules (ARMs) are belongs to the promising alternative in immunotherapy against cancer and pathogens. In the tumoral contest, an ARM has the singular ability to interface between the target cell and components of the immune system present on the environment leading to an immune response. In this Ph.D. work, we reported the design and the synthesis by click chemistry of several ARMs able to target over-expressed proteins on cancer cell surface through peptides-based tumoral binding modules (TBMs) and to engage natural endogenous antibodies through carbohydrate-based antibody binding modules (ABMs). Next, we demonstrated the formation of a ternary complex between cell-ARM-antibodies and the specific killing of cancer cells by our agents only in the presence of human serum as unique source of immune effectors, without pre-immunization. In addition, we established that the molecule flexibility, the length of the linker between ABM and TBM, the nature of the haptens (carbohydrates and peptides) and their valency play a significant role. Due to the efficiency of the synthetic process, a large diversity of ARMs could be easily created, opening new outlooks in diverse therapeutic fields

Characterization and Functionalization Approaches for the Study of Polymeric Nanoparticles: The State of the Art in Italian Research

Polymeric nanoparticles (PNPs) are a group of nanocarriers employed in a wide range of applications. Characterization is a fundamental step in PNPs formulation and many basic techniques are available to provide chemical-physical information such as dimensions, surface potential, stability and solubility. Recently, these techniques have been implemented with more innovative ones to obtain more precise knowledge of the nanomaterials. In this review we analyzed the state of the art in the field of polymeric nanoparticles produced by Italian laboratories. We described all methods available for PNPs characterization with their applications as drug delivery systems. We also reported the different types of molecules that were recently used for PNPs functionalization, a fundamental step in delivering drugs specifically to their targets and then resulting in reduced side effects in patients

Pioglitazone-Loaded PLGA Nanoparticles: Towards the Most Reliable Synthesis Method

Recent findings have proved the benefits of Pioglitazone (PGZ) against atherosclerosis and type 2 diabetes. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this drug in nanoparticles (NPs) can minimize uncontrolled issues. In this context, drug delivery approaches based on several poly(lactic-co-glycolic acid) (PLGA) nanoparticles have been rising in popularity due to their promising capabilities. However, a fully reliable and reproducible synthetic methodology is still lacking. In this work, we present a rational optimization of the most critical formulation parameters for the production of PGZ-loaded PLGA NPs by the single emulsification-solvent evaporation or nanoprecipitation methods. We examined the influence of several variables (e.g., component concentrations, phases ratio, injection flux rate) on the synthesis of the PGZ-NPs. In addition, a comparison of these synthetic methodologies in terms of nanoparticle size, polydispersity index (PDI), zeta potential (&zeta;p), drug loading (DL%), entrapment efficiency (EE%), and stability is offered. According to the higher entrapment efficiency content, enhanced storage time and suitable particle size, the nanoprecipitation approach appears to be the simplest, most rapid and most reliable synthetic pathway for these drug nanocarriers, and we demonstrated a very slow drug release in PBS for the best formulation obtained by this synthesis

Nanogels: Recent Advances in Synthesis and Biomedical Applications

In the context of advanced nanomaterials research, nanogels (NGs) have recently gained broad attention for their versatility and promising biomedical applications. To date, a significant number of NGs have been developed to meet the growing demands in various fields of biomedical research. Summarizing preparation methods, physicochemical and biological properties, and recent applications of NGs may be useful to help explore new directions for their development. This article presents a comprehensive overview of the latest NG synthesis methodologies, highlighting advances in formulation with different types of hydrophilic or amphiphilic polymers. It also underlines recent biomedical applications of NGs in drug delivery and imaging, with a short section dedicated to biosafety considerations of these innovative nanomaterials. In conclusion, this article summarizes recent innovations in NG synthesis and their numerous applications, highlighting their considerable potential in the biomedical field