Samar Mansour

Liposomal carriers are widely used for anticancer drug delivery due to their biocompatible nature in the biological milieu. Liposome-based drugs often face premature leakage, uncontrolled release, and insufficient control over long-term drug availability. Here, we present poly(lactic-co-glycolic acid) (PLGA)-coated mesoporous silica nanocarriers (PLGA–mSiO2, polysilomes) as an efficient and stable alternative to PEGylated liposomes. Such hybrid transporters are capable of efficiently encapsulating both hydrophilic [doxorubicin (DOX)] and hydrophobic [tamoxifen (TAM)] drugs. Investigation on drug loading, release kinetics, cellular uptake, and therapeutic response confirms the superior drug encapsulation and delivery of polysilomes efficiently. In liposomes, TAM was localized within the lipid bilayer, whereas DOX was actively loaded into the aqueous core through a transmembrane pH gradient. While this architecture enabled coloading, liposomes showed rapid drug release and pronounced cytotoxicity. In contrast, the core–shell structure of PLGA–mSiO2 polysilome carriers retained hydrophilic DOX within the mesoporous silica core and hydrophobic TAM within the PLGA shell. This compartmentalization ensures higher encapsulation efficiencies of both DOX (77.3%) and TAM (60.5%), with loading capacities of 59.3 and 50.4%, respectively. The PLGA–silica interface is a degradable diffusion barrier, enabling pH-responsive sustained release under acidic conditions. Moreover, PLGA–mSiO2 showed enhanced cellular uptake in MDA-MB-231 breast cancer cells and prolonged (up to 144 h) suppression of cell viability. These results present PLGA-coated mesoporous silica nanocarriers as a promising alternative to liposomal delivery by converting rapid drug release into sustained therapeutic activity.

1. Corneal injury is a critical ocular emergency that can threaten a patient’s sight, characterized by a breach in the corneal epithelium that extends into the underlying stroma. Even when medical ...

Silica nanocarriers are highly effective for drug delivery due to their tunable pore sizes, well-defined structures ( e.g. , mesoporous and hollow), and chemical stability across various physiological and chemical environments.

Background: Liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition, driven by activated hepatic stellate cells (aHSCs). Effective therapeutic strategies require targeting aHSCs and agents capable of reversing their activated phenotype. Methods: In this study, we developed chitosan nanoparticles loaded with atorvastatin (AS) and JQ1 and functionalized them with varying densities of retinol (Rt) to exploit aHSC targeting. Results: In vitro, Rt-NPs demonstrated enhanced uptake in GRX cells, with optimal performance observed at high Rt density (HRt-NPs). In vivo biodistribution in CCl₄-induced fibrotic and healthy mice revealed that LRt-NPs achieved superior hepatic accumulation in fibrotic livers compared to unmodified and HRt-NPs, underscoring the importance of optimal ligand density for targeting. Western blot analysis showed that treatment of GRX cells with Rt-AS-NPs and Rt-JQ1-NPs either individually or combined significantly reduced the expression of fibronectin, vimentin, and PDGFR-β, key markers of HSC activation, with combination therapy providing more significant effects. Conclusions: This work highlights the potential of Rt-chitosan NPs loaded with AS and JQ1 as an effective dual-drug system for targeted antifibrotic therapy, offering enhanced hepatic selectivity, improved safety, and potent aHSC deactivation.

Activated hepatic stellate cells (aHSCs) are key players in the fibrotic cascade in inflamed livers, with transforming growth factor-beta 1 (TGF-β₁) being the most potent pro-fibrotic cytokine. Therefore, TGF-β₁ downregulation in aHSCs may serve as an interesting therapeutic approach for the treatment of liver fibrosis. However, excessive collagen deposition in the extracellular matrix (ECM) hinders drug delivery to aHSCs. Chitosan nanoparticles (CS-NPs) show intrinsic affinity for collagen, holding potential for drug delivery to fibrotic livers. In this study, CS-NPs were used for the in vivo delivery of anti-TGF-β₁ siRNA. To promote delivery into aHSCs, CS-NPs were modified with different densities of platelet-derived growth factor receptor-β (PDGF-β) binding peptides as the targeting moiety. The CS-NPs showed an average hydrodynamic diameter of 103 ± 7 nm, a zeta potential of 24 ± 1 mV, and an siRNA encapsulation efficiency of 92.39 ± 6.4%. In healthy mice, biweekly treatment of siRNA-free unmodified CS-NPs up to a concentration of 120 mg/kg for 4 weeks was well tolerated and caused no organ-specific toxicity. The biodistribution of the unmodified and peptide-modified CS-NPs was carried out to identify potential sites of accumulation in healthy and fibrotic mice, and histopathological studies confirmed the safety of the formulations in nontarget sites in the case of fibrotic animals. Cell culture experiments confirmed the affinity of unmodified CS-NPs to the collagenated ECM, whereas collagen density reduction with collagenase-loaded CS-NPs (Coll-NPs) was necessary to promote cellular uptake of the peptide-modified CS-NPs. When loaded with anti-TGF-β₁ siRNA and used for the treatment of the CCl₄ liver fibrosis model in mice, CS-NPs decorated with a high density of PDGF-β binding peptide could significantly reduce the hepatic TGF-β₁ (by approximately 65%) and fibronectin (by approximately 63%) levels. Pretreatment with Coll-NPs could contribute to a further reduction of both markers by around 10%. Histopathological evaluations with Masson Trichrome staining revealed a reduction in the aggregation of the portal inflammatory cells, an absence in the proliferation of the fibroblastic cells in between hepatocytes, and a decrease in collagen deposition in the liver following treatment with anti-TGF-β₁ siRNA-loaded peptide-modified CS-NPs, both with and without Coll-NP pretreatment. Accordingly, the results demonstrate the plausibility of anti-TGF-β₁-siRNA delivery to aHSCs using PDGF-β binding peptide-modified CS-NPs for the treatment of liver fibrosis.

Transdermal drug delivery systems are a promising option for the treatment of rheumatoid arthritis (RA) because they can lower systemic adverse effects of immunosuppressants. Janus kinase (JAK) inhibitors were found to be effective for the treatment of RA by inhibiting the JAK-STAT pathway and preventing autoimmune joint destruction. The aim of this study is to deliver tofacitinib (a JAK 1 and 3 inhibitor) through mannose-decorated transferosomes (MDTs) directly to inflamed joints. Transferosomes are composed of phospholipids, Cremophor A25, PEG400, Labrafac lipophile, and oleic acid to enhance the permeation of tofacitinib and control nanovesicle size (similar to 70-200 nm). Permeation through rat skin was evaluated, where the skin permeation of MDTs (Q24: 38.8 +/- 9.82 mu g/cm(2)) and flux (0.5311 +/- 0.072 mu g/cm(2)/h) were significantly greater than those of the uncoated transferosomes (Q24 of T1: 1.522 +/- 0.329 mu g/cm(2), Q24 of T2: 3.5002 +/- 0.998 mu g/cm(2), and Q24 of T3: 18.226 +/- 5.25 mu g/cm(2)). In addition, MDTs seem to permeate the skin intact, as shown by the transmission electron microscopy (TEM) images of the recipient buffer removed from the Franz diffusion cell. A histopathology assay was performed during the in vivo evaluation of MDTs in an arthritic rat model, in which, significantly less inflammation was observed when MDTs were applied directly to the joint compared to when applied to the dorsal skin and untreated arthritic joints. Furthermore, significantly lower tumor necrosis factor-alpha (TNF alpha), IL-6, and IL-1 beta levels (P < 0.05) were detected by enzyme-linked immunosorbent assay (ELISA) in homogenates of the joints treated with MDTs than in untreated arthritic joints. In conclusion, this study proposed effective MDTs that could deliver tofacitinib directly to inflamed joints possibly by targeting the macrophages circulating in the proximity of the site of inflammation.

Activated hepatic stellate cells (aHSCs) are the main orchestrators of the fibrotic cascade in inflamed livers, with transforming growth factor-beta (TGF-β) being the most potent pro-fibrotic cytokine. Hence, aHSCs serve as interesting therapeutic targets. However, drug delivery to aHSCs is hindered by excessive collagen deposition in the extracellular matrix (ECM) and capillarization of liver sinusoids. Chitosan-nanoparticles (CS-NPs) show intrinsic affinity for collagen, holding potential for drug delivery to fibrotic livers. Here, we employed CS-NPs for anti-TGF-β siRNA delivery, promoting delivery into aHSCs via modification with platelet-derived growth factor receptor-beta binding peptides. In-vitro experiments using aHSCs demonstrated the association of unmodified CS-NPs to the collagen-rich ECM, with reduced intracellular accumulation. Peptide-modified CS-NPs showed a higher propensity to localize intracellularly; however, this was only the case upon ECM-collagen reduction via collagenase treatment. Peptide-modified CS-NPs were more potent than unmodified CS-NPs in reducing TGF-β expression, implying that while collagen binding promotes liver accumulation, it hinders cell-specific siRNA delivery. In-vivo, CS-NPs successfully accumulated in fibrotic livers via collagen binding. Similar to in-vitro findings, when mice were pretreated with collagenase-loaded CS-NPs, the accumulation of peptide-modified NPs increased. Our findings demonstrate the usefulness of NPs modification with targeting ligands and collagenase treatment for aHSCs targeting and highlight the importance of chitosan–collagen binding in drug delivery to fibrotic diseases.

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome-thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX-emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal^® suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution.