An Innovative Formulation Based on Nanostructured Lipid Carriers for Imatinib Delivery: Pre-Formulation, Cellular Uptake and Cytotoxicity Studies

Imatinib (IMT) is a tyrosine kinase enzyme inhibitor and extensively used for the treatment of gastrointestinal stromal tumors (GISTs). A nanostructured lipid carrier system (NLCS) containing IMT was developed by using emulsification–sonication methods. The characterization of the developed formulation was performed in terms of its particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, loading capacity, sterility, syringeability, stability, in vitro release kinetics with mathematical models, cellular uptake studies with flow cytometry, fluorescence microscopy and cytotoxicity for CRL-1739 cells. The particle size, PDI, loading capacity and zeta potential of selected NLCS (F16-IMT) were found to be 96.63 ± 1.87 nm, 0.27 ± 0.15, 96.49 ± 1.46% and −32.7 ± 2.48 mV, respectively. F16-IMT was found to be stable, thermodynamic, sterile and syringeable through an 18 gauze needle. The formulation revealed a Korsmeyer–Peppas drug release model of 53% at 8 h, above 90% of cell viability, 23.61 µM of IC50 and induction of apoptosis in CRL-1739 cell lines. In the future, F16-IMT can be employed to treat GISTs. A small amount of IMT loaded into the NLCSs will be better than IMT alone for therapy for GISTs. Consequently, F16-IMT could prove to be useful for effective GIST treatment.

Controlled Release of Epigenetically-Enhanced Extracellular Vesicles from a GelMA/Nanoclay Composite Hydrogel to Promote Bone Repair

Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs’ potential for bone regeneration has been shown, issues associated with their therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (p ≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (p ≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (p ≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (p ≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration.

Design of Oral Sustained-Release Pellets by Modeling and Simulation Approach to Improve Compliance for Repurposing Sobrerol

Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.

Crosslinking-Dependent Drug Kinetics in Hydrogels for Ophthalmic Delivery

Drug-diffusion kinetics in 2-hydroxyethyl methacrylate hydrogels were studied as a function of the crosslinking density and porosity. By varying the concentration of the crosslinker, tetraethylene glycol dimethacrylate, we demonstrated how the release of Timolol maleate could be optimized to allow for efficient drug delivery. FTIR and spectrophotometry supplied optical inferences into the functional groups present. By studying the swelling and degradation of hydrogels, supplemented with drug-release kinetics studies, the relationship between these two tenets could be formulated.

Oil Phase Solubility Rather Than Diffusivity Determines the Release of Entrapped Amino Acids and Di-Peptides from Water-in-Oil-in-Water Emulsions

The permeation of amino acids and di-peptides with different hydrophobicities across the oil phase in W/O/W double emulsions was investigated at different concentrations, considering the pH of the aqueous phase. Moreover, the particle size, yield of entrapped water and release kinetics of the double emulsions was evaluated as a function of time. Regarding the release of the entrapped amino acids and di-peptides, their hydrophobicity and the pH had a significant effect, whereas the concentration of the dissolved compound did not lead to different release kinetics. The release of the amino acids and di-peptides was faster at neutral pH as compared to acidic pH values due to the increased solute solubility in the oil phase for more hydrophobic molecules at neutral pH. Regarding the effect of the type of oil, much faster amino acid transport was observed through MCT oil as compared to LCT oil, which might be due to its higher solubility and/or higher diffusivity. As di-peptides released faster than amino acids, it follows that the increased solubility overruled the effect from the decreased diffusion coefficient of the dissolved compound in the oil phase.

Prolonged release of VEGF and Ang1 from intralesionally implanted hydrogel promotes perilesional vascularization and functional recovery after experimental ischemic stroke

Injectable hydrogels can generate and support pro-repair environments in injured tissue. Here we used a slow-releasing drug carrying in situ-forming hydrogel to promote post-stroke recovery in a rat model. Release kinetics were measured in vitro and in vivo with MRI, using gadolinium-labeled albumin (Galbumin), which demonstrated prolonged release over multiple weeks. Subsequently, this hydrogel was used for long-term delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) (Gel VEGF + Ang1, n = 14), in a photothrombotically induced cortical stroke lesion in rats. Control stroke animals were intralesionally injected with saline (Saline, n = 10), non-loaded gel (Gel, n = 10), or a single bolus of VEGF + Ang1 in saline (Saline VEGF + Ang1, n = 10). MRI was executed to guide hydrogel injection. Functional recovery was assessed with sensorimotor function tests, while tissue status and vascularization were monitored by serial in vivo MRI. Significant recovery from sensorimotor deficits from day 28 onwards was only measured in the Gel VEGF + Ang1 group. This was accompanied by significantly increased vascularization in the perilesional cortex. Histology confirmed (re)vascularization and neuronal sparing in perilesional areas. In conclusion, intralesional injection of in situ-forming hydrogel loaded with pro-angiogenic factors can support prolonged brain tissue regeneration and promote functional recovery in the chronic phase post-stroke.

Host-guest stoichiometry affects the physicochemical properties and releases kinetics of beta-cyclodextrin/ ferulic acid inclusion complexes

An inclusion system of embedding ferulic acid into β-cyclodextrin (FACD) with different host-guest stoichiometry was prepared by a co-precipitation method. Then, the physicochemical properties and release kinetics of the FACD...