Stimuli-responsive Polymeric nanosystems for therapeutic applications

Background: Recent past decades have reported emerging of polymeric nanoparticles as a promising technique for controlled and targeted drug delivery. As nanocarriers, they have high drug loading and delivery to the specific site or targeted cells with an advantage of no drug leakage within en route and unloading of a drug in a sustained fashion at the site. These stimuli-responsive systems are functionalized in dendrimers, metallic nanoparticles, polymeric nanoparticles, liposomal nanoparticles, quantum dots. Purpose of Review: The authors reviewed the potential of smart stimuli-responsive carriers for therapeutic application and their behavior in external or internal stimuli like pH, temperature, redox, light, and magnet. These stimuli-responsive drug delivery systems behave differently in In vitro and In vivo drug release patterns. Stimuli-responsive nanosystems include both hydrophilic and hydrophobic systems. This review highlights the recent development of the physical properties and their application in specific drug delivery. Conclusion: The stimuli (smart, intelligent, programmed) drug delivery systems provide site-specific drug delivery with potential therapy for cancer, neurodegenerative, lifestyle disorders. As development and innovation, the stimuli-responsive based nanocarriers are moving at a fast pace and huge demand for biocompatible and biodegradable responsive polymers for effective and safe delivery.

Classification of Companion Diagnostics: A New Framework for Biomarker-Driven Patient Selection

Background Modern personalized medicine strategies builds on therapy companion diagnostics to stratify patients into subgroups with differential benefit/risk. In general, stratification for drug response implies a treatment-by-subgroup interaction. This interaction is usually suggested by the drug’s mechanism of action and investigated in pharmacological research or in clinical studies. In these candidate genes or pathway approaches, either biological reasons for a differential benefit/risk or statistical interaction regarding a pharmacological or clinical endpoint or both may be given. For successful drug approval, demonstration of a positive benefit/risk balance in the intended patient population is required. This also applies to situations with biomarker-selected populations. However, further regulatory considerations relate to the usefulness and plausibility of the selected patients and benefit/risk extrapolations or alternative therapy options in biomarker-negative populations. Methods To facilitate the specification of regulatory requirements and support the design of clinical development programmes, a systematic classification of biomarker-drug pairs is needed, in particular with regard to the expected underlying molecular mechanism and the clinical evidence. Results A classification of five biomarker-drug categories is proposed related to increasing evidence on the biomarker’s predictive value in relation to a specific drug. We classified biomarkers into five ascending categories with increasing evidence on the predictive nature of the biomarker in relation to a specific drug according to the comparative pharmacological and clinical evidence. Conclusions The proposed classification will facilitate regulatory decision-making and support drug development with respect to biomarker-related subgrouping, both, during clinical programme and at the time of marketing authorization application, since the grade of evidence on the differential power of the biomarker can be considered as an indicator for the usefulness of a biomarker-related subgrouping.

EUDRAGIT COATED ALGINATE BEADS BEARING OXALIPLATIN LOADED LIPOSOMES: FORMULATION, OPTIMIZATION AND IN VITRO CHARACTERIZATION

Objective: The present investigation aimed to develop and characterize Eudragit S-100 coated alginate beads bearing oxaliplatin loaded liposomes for colon-specific drug delivery. Methods: Liposomes were formulated by the thin-film hydration method. The process and formulation variables were optimized by Box-Behnken design (BBD) with the help of Design-Expert® Software. Three independent variables taken were HSPC: Chol molar ratio (X1), hydration time (X2), and sonication time (X3). The response variables selected were entrapment efficiency of oxaliplatin, polydispersity index, and vesicle size. Results: The liposomes possessed an average vesicle size of 110.1±2.8 nm, PDI 0.096±0.3, zeta potential of-6.70±1.4 mV, and entrapment efficiency of 27.65%. The beads were characterized for their size, in vitro drug release, and swelling index. The degree of swelling of the beads was found to be 2.3 fold higher at pH 7.4 than at pH 1.2. The in vitro drug release depicted a sustained drug release in 48 h. Conclusion: The outcomes of the study proposed that the developed system can be effectively used for site-specific drug delivery to the colon via the oral route.

How I Treat High-risk Multiple Myeloma

Survival of multiple myeloma (MM) has significantly improved over the last decade; however, a composed group of patients (15-20%), named high-risk (HR) MM, still experience reduced survival. Both tumor biology and suboptimal/absent responses to therapy may underlie HR definition and a clear uniform identification of risk factors is crucial for a proper management of these patients. In biologic-HRMM, MRD negativity attainment and sustain, inside and outside BM, should be the primary goal and therapy should be adapted in patients with frailty to reduce toxicity and improve quality of life. MM treatment has traditionally been tailored on age and more recently frailty or comorbidities, but very rarely on the biology of the disease, mainly because of the lack of a clear benefit derived from a specific drug/combination, inhomogeneity in HR definition and lack of data coming from prospective, properly designed clinical trials. Some attempts have been successfully made recently in this direction. In this review, we are discussing the current different definitions of HR and the need for a consensus, the results of available trials in HR patients and the way through risk-adapted treatment strategies. For this purpose, we are proposing several clinical cases of difficult-to-treat patients throughout different treatment phases.

DDRE-42. TOWARDS PRECISION MEDICINE: AUTOMATED DRUG SCREENING PLATFORM UTILIZING TUMOR-ORGANOIDS TO IDENTIFY PATIENT-SPECIFIC DRUG-RESPONSES IN MENINGIOMA

Tumor-organoids (TO) are mini-tumors generated from tumor tissue preserving its genotype and phenotype by maintaining the cellular heterogeneity and important components of the tumor microenvironment. We recently developed a protocol to reliably establish TOs from meningioma (MGM) in large quantities. The use of TOs in combination with lab automation holds great promise for drug discovery and screening of comprehensive drug libraries. This might help to tailor patient-specific therapy in the future. The aim of our study was to establish an automated drug screening platform utilizing TOs. For this purpose, we established TOs by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples in the high-throughput format of 384-well plates. The drug screening was performed fully automated by utilizing the robotic liquid handler Hamilton Microlab STAR and a drug library containing 166 FDA-approved oncology agents. Viability was assessed with CellTiterGlo3D. In total, we performed the drug screening with 166 drugs on TOs from 11 patients suffering from MGM (n=8 WHO°I, n=2 WHO°II, n=1 WHO°III). The top five most effective drugs resulted in a decrease of TO viability ranging from 84.6–63.3%. K-means clustering analysis resulted in groupings of drugs with similar modes of action. One cluster consisted of epigenetic drugs while another cluster consisted of several proteasome inhibitors. However, when looking at a patient-individual level, in 11 patients 44 of 166 drugs, were among the top 10 most effective drugs, providing strong evidence for heterogeneous drug-responses in MGM patients. Taken together, we successfully developed an automated drug screening platform pipeline utilizing TOs from MGM to identify patient-specific drug-responses. The observed intra-individual differences of drug responses mandate for a personalized testing of comprehensive drug libraries in TOs to tailor more effective therapies in MGM patients.

A Review of the Antimicrobial Activity of Selenium Nanoparticles

Antimicrobial resistance has become a severe problem for health systems worldwide, and counteractions are challenging because of the lack of interest of pharmaceutical companies in generating new and effective antimicrobial drugs. Selenium nanoparticles have attracted considerable interest in treating bacteria, fungi, parasites, and viruses of clinical importance due to their high therapeutic efficacy and almost zero generation of adverse effects. Some studies have revealed that the antimicrobial activity of these nanoparticles is due to the generation of reactive oxygen species, but more studies are needed to clarify their antimicrobial mechanisms. Other studies show that their antimicrobial activity is increased when the surface of the nanoparticles is functionalized with some biomolecules or when their surface carries a specific drug. This review addresses the existing background on the antimicrobial potential offered by selenium nanoparticles against viruses, bacteria, fungi, and parasites of clinical importance.