Thiolated polymeric hydrogels for biomedical application: Cross-linking mechanisms

This review focuses on the synthesis of hydrogel networks using thiomers such as thiolated hyaluronic acid, chitosan, cyclodextrin, poly(ethylene glycol) and dextran that are cross-linked via their thiol substructures. Thiomers have been widely investigated as matrix of hydrogels due to the high reactivity of these sulfhydryl moieties. They are well known for their in situ gelling properties due to the formation of inter- and intra-chain disulfide bonds. Furthermore, as thiol groups on the polymeric backbone of thiomers cannot only react with each other but also with different other functional groups, several “click” methods such as thiol-ene/yne, Michael type addition and thiol-epoxy reactions have been developed within the last decades to fabricate thiomer hydrogels. These hydrogels are meanwhile used as scaffolds for tissue engineering, regenerative medicine, diagnostics and as matrix for drug and protein delivery

Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18-kDa Translocator Protein TSPO.

An interesting mitochondrial biomarker is the 18‐kDa mitochondrial translocator protein (TSPO). Decades of study have shown that this protein plays an important role in a wide range of cellular functions, including opening of the mitochondrial permeability transition pore as well as programmed cell death and proliferation. Variations in TSPO expression have been correlated to different diseases, from tumors to endocrine and neurological disorders. TSPO has therefore become an appealing target for both early diagnosis and selective mitochondrial drug delivery. The number of structurally different TSPO ligands examined has increased over time, highlighting the scientific community′s growing understanding of the roles of TSPO in normal and pathological conditions. However, only few TSPO ligands are characterized by the presence of groups that are potentially derivatizable; therefore only few such ligands are well suited for the preparation of targeted prodrugs or nanocarriers able to deliver therapeutics and/or diagnostic agents to mitochondria. This review provides an overview of the very few examples of drug delivery systems characterized by moieties that target TSPO

Bcr-abl tyrosine kinase inhibitors in the treatment of pediatric cml

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy

Stability data of extemporaneous suspensions of hydroxychloroquine sulphate in oral liquid bases after tablet manipulation

Hydroxychloroquine is a well-known anti-malarial and anti-rheumatic drug that has garnered recently unprecedented attention as potential therapeutic agent against virus infections. Hydroxychloroquine sulphate is authorized in the EU as film-coated tablets (i.e. Plaquenil®), which cannot be administered to non-cooperative patients, such as those in intensive care units or, more in general, unable to swallow solid dosage forms. Therefore, the hospital pharmacist must manipulate the solid dosage form for the preparation of suspension, even if it can strongly affect the product quality. In this scenario, it is crucial to offer useful information and advice to assist hospital pharmacists in their activity. The data presented in this article suggest that extemporaneous suspensions of hydroxychloroquine sulphate in oral liquid bases after tablet manipulation are stable for at least 30 days

Hydroxy-propil-β-cyclodextrin inclusion complexes of two biphenylnicotinamide derivatives: Formulation and anti-proliferative activity evaluation in pancreatic cancer cell models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy

Microfluidic preparation and in vitro evaluation of iRGD-functionalized solid lipid nanoparticles for targeted delivery of paclitaxel to tumor cells

Solid lipid nanoparticles (SLNs) can combine the advantages of different colloidal carriers and prevent some of their disadvantages. The production of nanoparticles by means of microfluidics represents a successful platform for industrial scale-up of nanoparticle manufacture in a reproducible way. The realisation of a microfluidic technique to obtain SLNs in a continuous and reproducible manner encouraged us to create surface functionalised SLNs for targeted drug release using the same procedure. A tumor homing peptide, iRGD, owning a cryptic C-end Rule (CendR) motif is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. In this study, the Paclitaxel loaded-SLNs produced by microfluidics were functionalized with the iRGD peptide. The SLNs proved to be stable in aqueous medium andwere characterized by a Z-average under 150 nm, a polydispersity index below 0.2, a zeta-potential between -20 and -35 mV and a drug encapsulation efficiency around 40%. Moreover, in vitro cytotoxic effects and cellular uptake have been assessed using 2D and 3D tumour models of U87 glioblastoma cell lines. Overall, these results demonstrate that the surface functionalization of SLNs with iRGD allow better cellular uptake and cytotoxicity ability.Peer reviewe

Induced expression of P-gp and BCRP transporters on brain endothelial cells using transferrin functionalized nanostructured lipid carriers:A first step of a potential strategy for the treatment of Alzheimer's disease

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two transporters expressed in human neural stem/progenitor cells and at the Blood-Brain Barrier (BBB) level with decreased activity in the early stage of Alzheimer's disease (AD). Both proteins, have a protective role for the embryonic stem cells in the early developmental step, maintaining them in an undifferentiated state, and limit the access of exogenous and endogenous agents to the brain. Recently, MC111 selected from a P-gp/BCRP ligands library was investigated as multitarget strategy for AD treatment, considering its ability to induce the expression and activity of both proteins. However, MC111 clinical use could be limited for the ubiquitous physiological expression of efflux transporters and its moderate toxicity towards endothelial cells. Therefore, a selective MC111 delivery system based on nanostructured lipid carriers (NLC) functionalized with transferrin were developed. The results proved the formation of NLC with average size about 120 nm and high drug encapsulation efficiency (EE% greater than 50). In vitro studies on hCMEC/D3 cells revealed that the MC111 was selectively released by NLC at BBB level and then inducing the activity and expression of BCRP and P-gp, involved in the clearance of amyloid p peptide on brain endothelial cells