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.
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Triblock copolymers of poly(ethylene oxide) and poly(propylene oxide)-based matrices, such as Poloxamer 407 (P407) or Pluronic® F127, are extensively utilized in drug delivery and ...permeation systems due to their FDA approval and listing in the US and European Pharmacopoeias. The study hypothesizes that incorporating 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and the celecoxib-HP-β-CD inclusion complex into a 16 wt% P407 and chitosan blend in an aqueous acetic acid solution will affect the system's rheological and structural properties.
Rheological, small-angle X-ray scattering (SAXS), and dynamic light scattering (DLS) experiments were conducted to assess the impact of acetic acid and chitosan on the 16 wt% P407 and chitosan blend. Additionally, in vitro drug release studies were performed to monitor the drug release profile over time.
The addition of HP-β-CD was found to inhibit gel formation in the 16 wt% P407 and chitosan blend. However, the presence of the celecoxib-HP-β-CD inclusion complex showed no significant structural effects compared to P407 blended with chitosan alone. Rheological and SAXS analyses demonstrated that acetic acid led to the formation of a lamellar phase due to the lower pH, facilitating injectability. The presence of chitosan in acetic acid resulted in the detection of a hexagonal phase, affecting the release of celecoxib.
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•Cyclodextrin-based deep eutectic solvents (CycloDES) could be exploit for poorly soluble drug solubilization.•The improved performance of CycloDES against equimolar ...hydroxypropyl-β-cyclodextrin water solution was observed through solubility studies.•CycloDES resulted to maintain the drug in solution once diluted in water, while a significant loss of solubilized drug was observed in the model Choline Chloride:Glucose DES.
The aim of this work was to develop a new class of deep eutectic solvent (DES) composed of a complexation agent, namely hydroxy-propyl-β-cyclodextrin (HPβCD), to exploit a synergic solubilization-enhancing approach. For this purpose, cyclodextrin-based supramolecular DES (CycloDES) were physical-chemical characterized and loaded with three different BCS class II model drugs, specifically Cannabidiol, Indomethacin, and Dexamethasone, evaluating the influence of different factors on the observed solubility and permeation compared with the only HPβCD/drug complexation.
Hence, CycloDESs were presented as a possible vehicle for drugs and represent a novel potential approach for solving BCS class II and IV solubility issues, demonstrating at least a 100-fold improvement in the investigated drug solubilities. Furthermore, CycloDESs demonstrated a significantly improved resistance to dilution preserving a high percentage of drug in solution (i.e. 93% for Indomethacin) when water is added to the DES if compared with a glucose-choline chloride DES, used as a standard. This evidence guarantees the solubility-enhancing effect useful for the delivery of BCS class II and IV drugs converting solid raw material to advantageous liquid vehicles bypassing the rate-determining dissolution step.
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Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with ...sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R.
Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of ...interleukin-1(IL-1)β that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients' quality of life. IL-1β blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1β antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting.
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.
The aim of this study was to characterize new nanoparticles (NPs) containing chitosan (CS), or CS/cyclodextrin (CDs), and evaluate their potential for the oral delivery of the peptide glutathione ...(GSH). More precisely, NP formulations composed of CS, CS/α-CD and CS/sulphobutyl ether-β-cyclodextrin (SBE
7m-β-CD) were investigated for this application. CS/CD NPs showed particle sizes ranging from 200 to 500
nm. GSH was loaded more efficiently in CS/SBE
7m-β-CD NPs by forming a complex between the tripeptide and the CD. X-ray Photoelectron Spectroscopy (XPS) analysis suggested that GSH is located in the core of CS/SBE
7m-β-CD NPs and that it is almost absent from the NP surface. Release studies performed
in vitro at pH 1.2 and pH 6.8 showed that NP release properties can be modulated by selecting an appropriate CD. Transport studies performed in the frog intestine model confirmed that both CS and CS/CD nanoparticles could induce permeabilization of the intestinal epithelia. However, CS/SBE
7m-β-CD NPs provided absorption-enhancing properties in all segments of the duodenum, whereas CS NPs effect was restricted to the first segment of the duodenum. From the data obtained, we believe that CS/CD nanoparticles might represent an interesting technological platform for the oral administration of small peptides.
The transport of dopamine across the blood brain barrier represents a challenge for the management of Parkinson's disease. The employment of central nervous system targeted ligands functionalized ...nanocarriers could be a valid tactic to overcome this obstacle and avoid undesirable side effects. In this work, transferrin functionalized dopamine-loaded liposomes were made by a modified dehydration-rehydration technique from hydrogenated soy phosphatidylcoline, cholesterol and 1,2-stearoyl-
-glycero-3-phosphoethanolamine-
-carboxy(poly(ethylene glycol)-2000). The physical features of the prepared liposomes were established with successive determination of their endothelial permeability across an
model of the blood-brain barrier, constituted by human cerebral microvascular endothelial cells (hCMEC/D3). Functionalized dopamine-loaded liposomes with encapsulation efficiency more than 35% were made with sizes in a range around 180 nm, polydispersity indices of 0.2, and positive zeta potential values (+7.5 mV). Their stability and drug release kinetics were also evaluated. The apparent permeability (P
) values of encapsulated dopamine in functionalized and unfunctionalized liposomes showed that transferrin functionalized nanocarriers could represent appealing non-toxic candidates for brain delivery, thus improving benefits and decreasing complications to patients subjected to L-dopa chronical treatment.
This paper provides a mini-review of some recent approaches for the treatment of brain pathologies examining both medicinal chemistry and pharmaceutical technology contributions. Medicinal ...chemistry-based strategies are essentially aimed at the chemical modification of low molecular weight drugs in order to increase their lipophilicity or the design of appropriate prodrugs, although this review will focus primarily on the use of prodrugs and not analog development. Recently, interest has been focused on the design and evaluation of prodrugs that are capable of exploiting one or more of the various endogenous transport systems at the level of the blood brain barrier (BBB). The technological strategies are essentially non-invasive methods of drug delivery to malignancies of the central nervous system (CNS) and are based on the use of nanosystems (colloidal carriers) such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, polymeric micelles and dendrimers. The biodistribution of these nanocarriers can be manipulated by modifying their surface physico-chemical properties or by coating them with surfactants and polyethylene-glycols (PEGs). Liposomes, surfactant coated polymeric nanoparticles, and solid lipid nanoparticles are promising systems for delivery of drugs to tumors of the CNS. This mini-review discusses issues concerning the scope and limitations of both the medicinal chemistry and technological approaches. Based on the current findings, it can be concluded that crossing of the BBB and drug delivery to CNS is extremely complex and requires a multidisciplinary approach such as a close collaboration and common efforts among researchers of several scientific areas, particularly medicinal chemists, biologists and pharmaceutical technologists.
A new fluorine-substituted ligand, compound 1 (CB251), with a very high affinity (Ki = 0.27 ± 0.09 nM) and selectivity for the 18-kDa translocator protein (TSPO), is presented as an attractive ...biomarker for the diagnosis of neuroinflammation, neurodegeneration and tumour progression. To test compound 1 as a TSPO PET imaging agent in vivo, 2-(2-(4-(2-(18)Ffluoroethoxy)phenyl)-6,8-dichloroimidazo1,2-apyridin-3-yl)-N,N-dipropylacetamide ((18)F1; (18)FCB251) was synthesized by nucleophilic aliphatic substitution in a single-step radiolabelling procedure with a 11.1 ± 3.5% (n = 14, decay corrected) radiochemical yield and over 99% radiochemical purity. In animal PET imaging studies, (18)FCB251 provided a clearly visible image of the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND 1.83 ± 0.18), in a neuroinflammation rat model based on the unilateral stereotaxic injection of lipopolysaccharide (LPS), comparable to that of (11)CPBR28 (BPND 1.55 ± 0.41). (18)FCB251 showed moderate tumour uptake (1.96 ± 0.11%ID/g at 1 h post injection) in human glioblastoma U87-MG xenografts. These results suggest that (18)FCB251 is a promising TSPO PET imaging agent for neuroinflammation and TSPO-rich cancers.
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