Search

Zahid Hussain,1,2 Lama Abdulrahim Abdul Moti,1 Jayalakshmi Jagal,2 Hnin Ei Thu,3 Shahzeb Khan,4 Mohsin Kazi5 1Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; 2Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; 3Department of Pharmacology, Faculty of Dentistry, Universiti Teknologi MARA, Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia; 4Center for Pharmaceutical Engineering Science, Faculty of Life Sciences, School of Pharmacy and Medical Sciences, University of Bradford, West Yorkshire Bradford, BD7 1DP, UK; 5Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451 Saudi ArabiaCorrespondence: Zahid Hussain, Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates, Email zhussain@sharjah.ac.aeIntroduction: Owing to its high prevalence, colossal potential of chemoresistance, metastasis, and relapse, breast cancer (BC) is the second leading cause of cancer-related fatalities in women. Several treatments (eg, chemotherapy, surgery, radiations, hormonal therapy, etc.) are conventionally prescribed for the treatment of BC; however, these are associated with serious systemic aftermaths. In this research, we aimed to design a multiprong targeting strategy for concurrent action against different phenotypes of BC (MCF-7 and SK-BR-3) and tumor-associated macrophages (TAMs) for relapse-free treatment of BC.Methods: Paclitaxel (PTX) and tamoxifen (TMX) co-loaded chitosan (CS) nanoparticles (NPs) were prepared using the ionic-gelation method and optimized using the Design Expert® software by controlling different material attributes. For selective targeting through CD44-receptors that are heavily expressed on the BC cells and TAMs, the fabricated NPs (PTX-TMX-CS-NPs) were functionalized with hyaluronic acid (HA) as a targeting ligand.Results: The optimized HA-PTX-TMX-CS-NPs exhibited desired physicochemical properties (PS ~230 nm, PDI 0.30, zeta potential ~21.5 mV), smooth spherical morphology, high encapsulation efficiency (PTX ~72% and TMX ~97%), good colloidal stability, and biphasic release kinetics. Moreover, the lowest cell viability depicted in MCF-7 (~25%), SK-BR-3 (~20%), and RAW 264.7 cells (~20%), induction of apoptosis, cell cycle arrest, enhanced cell internalization, and alleviation of MCF-7 and SK-BR-3 migration proved the superior anticancer potential of HA-PTX-TMX-CS-NPs compared to unfunctionalized NPs and other control medicines.Conclusion: HA-functionalization of NPs is a promising multiprong strategy for CD44-receptors-mediated targeting of BC cells and TAMs to mitigate the progression, metastasis, and relapse in the BC. Keywords: paclitaxel, tamoxifen, hyaluronic acid, polymeric nanoparticles, CD44-receptors, breast cancer, cell uptake, anticancer efficacy

Wael Talaat,1– 3 Smriti Aryal AC,1,2 Sausan Al Kawas,1,2 AB Rani Samsudin,1,2 Nadia G Kandile,4 David RK Harding,5 Mohamed M Ghoneim,6 Waleed Zeiada,7,8 Jayalakshmi Jagal,2 Ahmed Aboelnaga,9 Mohamed Haider2,10,11 1Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; 2Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; 3Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Suez Canal University, Ismaillia 41522, Egypt; 4Department of Chemistry, Faculty of Women, Ain Shams University, Heliopolis, Cairo 11757, Egypt; 5School of Fundamental Sciences, Massey University, Palmerston North 4442, New Zealand; 6Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Sinai University, Arish 45511, Egypt; 7Department of Civil and Environmental Engineering, College of Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates; 8Public Works Engineering Department, College of Engineering, Mansoura University, Mansoura 35516, Egypt; 9Department of Surgery, Faculty of Medicine, Suez Canal University, Ismaillia 41522, Egypt; 10Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; 11Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 71526, EgyptCorrespondence: Wael TalaatOral and Maxillofacial Surgery, College of Dental Medicine, University of Sharjah, Sharjah, United Arab EmiratesTel +971 65057605Fax +971 65057606Email wtaha@sharjah.ac.aePurpose: Several scaffolds and cell sources are being investigated for cartilage regeneration. The aim of the study was to prepare nanocellulose-based thermosensitive injectable hydrogel scaffolds and assess their potential as 3D scaffolds allowing the chondrogenic differentiation of embedded human dental pulp stem and progenitor cells (hDPSCs).Materials and Methods: The hydrogel-forming solutions were prepared by adding β-glycerophosphate (GP) to chitosan (CS) at different ratios. Nanocellulose (NC) suspension was produced from hemp hurd then added dropwise to the CS/GP mixture. In vitro characterization of the prepared hydrogels involved optimizing gelation and degradation time, mass-swelling ratio, and rheological properties. The hydrogel with optimal characteristics, NC-CS/GP-21, was selected for further investigation including assessment of biocompatibility. The chondrogenesis ability of hDPSCs embedded in NC-CS/GP-21 hydrogel was investigated in vitro and compared to that of bone marrow-derived mesenchymal stem cells (BMSCs), then was confirmed in vivo in 12 adult Sprague Dawley rats.Results: The selected hydrogel showed stability in culture media, had a gelation time of 2.8 minutes, showed a highly porous microstructure by scanning electron microscope, and was morphologically intact in vivo for 14 days after injection. Histological and immunohistochemical analyses and real-time PCR confirmed the chondrogenesis ability of hDPSCs embedded in NC-CS/GP-21 hydrogel.Conclusion: Our results suggest that nanocellulose–chitosan thermosensitive hydrogel is a biocompatible, injectable, mechanically stable and slowly degradable scaffold. hDPSCs embedded in NC-CS/GP-21 hydrogel is a promising, minimally invasive, stem cell-based strategy for cartilage regeneration.Keywords: tissue regeneration, cartilage, scaffolds, stem cells, nanocellulose, chitosan, hydrogel

Head and neck squamous cell carcinoma (HNSCC) remain a major oncological challenge with significant morbidity and mortality rates. Erlotinib (Er) and Curcumin (Cm) are potential therapeutic agents for HNSCC, yet they are hindered by poor solubility and bioavailability. This study explored the optimization of poly(lactic-co-glycolic acid) nanoparticles co-loaded with Er and Cm (Er/Cm-NP), prepared via a D-optimal response surface design-guided nanoprecipitation process. The optimized formulation, optEr/Cm-NP, was then incorporated into chitosan/β-glycerophosphate hydrogels (optEr/Cm-NP-HG) to create an injectable intratumoral (IT) nanocomposite hydrogel (HG) delivery system. Physicochemical properties of the formulations, including gelation time, injectability, mechanical strength and drug release profiles were assessed alongside hemolytic activity. Compared to optEr/Cm-NP alone, the NP-loaded HG formulation exhibited a more pronounced modulation effect, enabling sustained and controlled drug release. The cytotoxicity of the developed formulations was evaluated using the FaDu HNSCC cancer cell line. Both optEr/Cm-NP and optEr/Cm-NP-HG21 displayed enhanced cytotoxicity compared to free drugs. Confocal laser microscopy and flow cytometry confirmed superior cellular uptake of Er and Cm when delivered via NPs or NP-loaded HG. Furthermore, a significant increase in apoptotic cell death upon treatment with optEr/Cm-NP was observed, highlighting its potential for HNSCC therapy. In vivo studies conducted on a xenograft HNSCC mouse model revealed the significant capacity of the intratumorally-injected optEr/Cm-NP-HG21 formulation to retard the tumor growth. Conclusively, the results presented herein report the successful development of a nanocomposite HG system incorporating NPs co-loaded with Er and Cm that could be efficiently utilized in the treatment of HNSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Psoriasis (Ps) is a chronic inflammatory disorder marked by skin plaque formation, driven by immune dysregulation and genetic factors. Despite the available treatments, incidence of Ps is increasing in the dermatology patients. Novel strategies are crucial due to current treatment limitations. The interleukin 17 (IL-17) pathway is pivotal in Ps pathogenesis, however the expression of its putative target gene placenta expressed transcript 1 (Plet1) remains unstudied in Ps. Considering the potential anti-inflammatory properties of N-Acetylglucosamine (GlcNAc), our study explored its role in modulating Plet1 expression in an imiquimod (IMQ)-induced Ps mouse model. Our data demonstarted a significant reduction of inflammation and Psoriasis Area and Severity Index (PASI) scores, downregulation of growth factors (GFs), IL-17 A, and MAPK expression after GlcNAc treatment. In addition, GlcNAc treatment reduced neutrophils, monocyte-dendritic cells (Mo-DC) and conventional T cells (Tcons) while increasing monocyte-macrophages (Mo-Macs) and regulatory T cells (Tregs). GlcNAc treatment also downregulated Plet1 overexpression in psoriatic mouse skin and in vitro, reduced proliferation and apoptosis in IL-17 A stimulated human dermal fibroblasts (HDF), along with IL-17 A and TGF-β mRNA expression. Together, these data suggest that, GlcNAc interferes with downstream mechanisms in IL-17 pathway and downregulating Plet1 expression, presenting a promising strategy for Ps treatment., Competing Interests: Declarations. Competing interests: All the authors declare that they have no competing interests. Conflict of interest: All authors declare, no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Curcumin (CUR) exhibits anti-inflammatory and anti-cancer activities. However, its poor solubility and bioavailability limit its therapeutic applications. Several CUR nano-formulations have been developed to enhance its solubility and uptake, thereby improving its anti-cancer activity. Despite this, studies comparing the effect of enhanced CUR solubility versus cellular uptake on its anti-cancer efficacy are lacking. Therefore, CUR nanofibers (CUR NF) were synthesized by electrospinning using a water-soluble polymer to enhance CUR solubility. While CUR nanoparticles (CUR NP) were synthesized by nanoprecipitation method using a water-insoluble polymer to enhance CUR cellular uptake. Both nano-formulations aim to improve CUR cellular concentration and anti-cancer activity against various cancer cells. CUR NF and CUR NP were successfully synthesized at drug load (DL%) of 10 %, 20 %, and 40 % w/w. Both nano-formulations were characterized, and CUR dissolution, release, cytotoxicity, IC50, and cellular uptake were assessed. A gradual increase in NF diameter and NP size was observed as the drug load% increased compared to the placebo. NF showed a rapid CUR release and increased solubility by 16-38 fold. In contrast, NP sustained CUR release and resulted in only a 2-fold increase in solubility. Both formulations significantly reduced cell viability and IC50 compared to free CUR. However, CUR NP demonstrated higher cell toxicity (70-80 %) than CUR NF (60 %) and reduced IC50 up to 4 μM compared to 11 μM for NF. Enhancing CUR solubility or uptake can significantly increase its cellular concentration and anti-cancer activity. However, enhancing CUR cellular uptake by NP demonstrated superior anti-cancer effect compared to enhancing its solubility by NF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Carvedilol (CV), a β-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster T max and higher C max compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Traditional treatments for head and neck squamous cell carcinoma (HNSCC) such as surgery, radiation therapy, and chemotherapy, often have severe side effects. Local delivery of chemotherapeutic agents can be a promising approach to minimise systemic toxicity and improve efficacy. Lauric acid (LA), was explored as a novel injectable thermosensitive drug reservoir as a depot for sustained release of anticancer drugs to treat HNSCC. LA was characterised in terms of melting temperature and gelation time. The efficacy of LA-based drug formulations was tested in vitro in a HNSCC cell line and in vivo in a mouse model of HNSCC. LA was modified to have a melting point of 38.5 °C and a gelation time of 40 s at 37.5 °C, rendering it suitable for injection at body temperature. LA- based doxorubicin (DOXO) formulation showed slow release with a maximum of 18% release after 3 days. The in vitro study showed that LA enhanced the cytotoxic effect of DOXO. LA combined with DOXO prevented tumour progression and LA alone significantly reduced the original tumour volume compared to the untreated control group. These findings confirmed that LA can function as practical carrier for the local delivery of chemotherapeutics and provides a safe and simple strategy for the delivery of hydrophobic anticancer drugs and warrant further testing in clinical trials.

Aim: The therapeutic potential of senolytic drugs in osteoarthritis (OA) is poorly known. Quercetin, a senolytic agent exhibits promising potential to treat OA, having limited bioavailability. We investigated the effects of Quercetin-loaded nanoparticles (Q-NP) with enhanced bioavailability in human chondrocytes mimicking OA phenotype. Materials & methods: The C-20/A4 chondrocytes were exposed to ferric ammonium citrate to induce OA phenotype, followed by treatment with free Quercetin/Q-NP for 24 and 48-h. Q-NP were synthesized by nanoprecipitation method. Following treatment chondrocytes were assessed for drug cellular bioavailability, viability, cell cycle, apoptosis, oxidative stress and expression of key senescence markers. Results: Q-NP exhibited 120.1 ± 1.2 nm particle size, 81 ± 2.4% encapsulation efficiency, increased cellular bioavailability and selective apoptosis of senescent chondrocytes compared with free Quercetin. Q-NP treatment also induced oxidative stress and reduced the expressions of senescence markers, including TRB3, p16, p62 and p21 suggesting their ability to eliminate senescent cells. Last, Q-NP arrested the cell cycle in the sub-G0 phase, potentially creating a beneficial environment for tissue repair. Conclusion: Q-NP propose a promising delivery system for treating OA by eliminating senescent chondrocytes through apoptosis. Furthermore, their enhanced cellular bioavailability and capacity to modify cell cycle and senescent pathways warrant further investigations.

Helicobacter pylori (H. pylori) is a causative agent of various gastrointestinal diseases and eradication mainly relies on antibiotic treatment, with (AMX) being a key component. However, rising antibiotic resistance in H. pylori necessitates the use of antibiotics combination therapy, often disrupting gut microbiota equilibrium leading to further health complications. This study investigates a novel strategy utilizing AMX-loaded chitosan nanoparticles (AMX-CS NPs), co-administered with prebiotic inulin to counteract H. pylori infection while preserving microbiota health. Following microbroth dilution method, AMX displayed efficacy against H. pylori, with a MIC 50 of 48.34 ± 3.3 ng/mL, albeit with a detrimental impact on Lactobacillus casei (L. casei). The co-administration of inulin (500 μg/mL) with AMX restored L. casei viability while retaining the lethal effect on H. pylori. Encapsulation of AMX in CS-NPs via ionic gelation method, resulted in particles of 157.8 ± 3.85 nm in size and an entrapment efficiency (EE) of 86.44 ± 2.19 %. Moreover, AMX-CS NPs showed a sustained drug release pattern over 72 h with no detectable toxicity on human dermal fibroblasts cell lines. Encapsulation of AMX into CS NPs also reduced its MIC 50 against H. pylori, while its co-administration with inulin maintained L. casei viability. Interestingly, treatment with AMX-CS NPs also reduced the expression of the efflux pump gene hefA in H. pylori. This dual treatment strategy offers a promising approach for more selective antimicrobial treatment, minimizing disruption to healthy microbial communities while effectively addressing pathogenic threats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The increasing resistance to antiparasitic drugs and limited availability of new agents highlight the need to improve the efficacy of existing treatments. Ivermectin (IVM) is commonly used for parasite treatment in humans and animals, however its efficacy is not optimal and the emergence of IVM-resistant parasites presents a challenge. In this context, the physico-chemical characteristics of IVM were modified by nanocrystallization to improve its equilibrium water-solubility and skin penetration, potentially improving its therapeutic effectiveness when applied topically. IVM-nanocrystals (IVM-NC) were prepared using microfluidization technique. The impact of several process/formulation variables on IVM-NC characteristics were studied using D-optimal statistical design. The optimized formulation was further lyophilized and evaluated using several in vitro and ex vivo tests. The optimal IVM-NC produced monodisperse particles with average diameter of 186 nm and polydispersity index of 0.4. In vitro results showed an impressive 730-fold increase in the equilibrium solubility and substantial 24-fold increase in dissolution rate. Ex vivo permeation study using pig's ear skin demonstrated 3-fold increase in dermal deposition of IVM-NC. Additionally, lyophilized IVM-NC was integrated into topical cream, and the resulting drug release profile was superior compared to that of the marketed product. Overall, IVM-NC presents a promising approach to improving the effectiveness of topically applied IVM in treating local parasitic infections., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Published by Elsevier B.V.)

The use of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) as carriers for chemotherapeutic drugs is regarded as an actively targeted nano-therapy for the specific delivery of anti-cancer drugs to target cells. However, the exact mechanism by which PLGA NPs boost anticancer cytotoxicity at the molecular level remains largely unclear. This study employed different molecular approaches to define the response of carcinoma FaDu cells to different types of treatment, specifically: paclitaxel (PTX) alone, drug free PLGA NPs, and PTX-loaded PTX-PLGA NPs. Functional cell assays revealed that PTX-PLGA NPs treated cells had a higher level of apoptosis than PTX alone, whereas the complementary, UHPLC-MS/MS (TIMS-TOF) based multi-omics analyses revealed that PTX-PLGA NPs treatment resulted in increased abundance of proteins associated with tubulin, as well as metabolites such as 5-thymidylic acid, PC(18:1(9Z)/18:1(9Z0), vitamin D, and sphinganine among others. The multi-omics analyses revealed new insights about the molecular mechanisms underlying the action of novel anticancer NP therapies. In particular, PTX-loaded NPs appeared to exacerbate specific changes induced by both PLGA-NPs and PTX as a free drug. Hence, the PTX-PLGA NPs' molecular mode of action, seen in greater detail, depends on this synergy that ultimately accelerates the apoptotic process, resulting in cancer cell death., (© 2023 Wiley-VCH GmbH.)

Functionalized metal oxide nanoparticles (NPs) have demonstrated specific binding affinity to antigens or receptors presented on the cancer cell surface, favouring selective targeting and minimizing side effects during the chemotherapy. Placenta-specific protein 1 (PLAC-1) is a small cell surface protein overexpressed in certain types of breast cancer (BC); therefore, it can be used as a therapeutic target. The objective of this study is to develop NPs that can bind PLAC-1 and hence can inhibit the progression and metastatic potential of BC cells. Zinc oxide (ZnO) NPs were coated with a peptide (GILGFVFTL), which possesses a strong binding ability to PLAC-1. The physical attachment of the peptide to ZnO NPs was verified through various physicochemical and morphological characterization techniques. The selective cytotoxicity of the designed NPs was investigated using PLAC-1-bearing MDA-MB 231 human BC cell line and compared to LS-180 cells that do not express PLAC-1. The anti-metastatic and pro-apoptotic effects of the functionalized NPs on MDA-MB 231 cells were examined. Confocal microscopy was used to investigate the mechanism of NPs uptake by MDA-MB 231 cells. Compared to non-functionalized NPs, peptide functionalization significantly improved the targeting and uptake of the designed NPs by PLAC-1-expressing cancer cells with significant pro-apoptotic and anti-metastatic effects. The uptake of peptide functionalized ZnO NPs (ZnO-P NPs) occurred via peptide-PLAC1 interaction-assisted clathrin-mediated endocytosis. These findings highlight the potential targeted therapy of ZnO-P NPs against PLAC-1-expressing breast cancer cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pathogenic Acanthamoeba produce keratitis and fatal granulomatous amoebic encephalitis. Treatment remains problematic and often ineffective, suggesting the need for the discovery of novel compounds. For the first time, here we evaluated the effects of the anticancer drugs Irosustat and STX140 alone, as well as their nanoformulations, against A. castellanii via amoebicidal, excystment, cytopathogenicity, and cytotoxicity assays. Nanoformulations of the compounds were successfully synthesized with high encapsulation efficiency of 94% and 82% for Irosustat and STX140, respectively. Nanoparticles formed were spherical in shape and had a unimodal narrow particle size distribution, mean of 145 and 244 nm with a polydispersity index of 0.3, and surface charge of -14 and -15 mV, respectively. Irosustat and STX140 exhibited a biphasic release profile with almost 100% drug released after 48 h. Notably, Irosustat significantly inhibited A. castellanii viability and amoebae-mediated cytopathogenicity and inhibited the phenotypic transformation of amoebae cysts into the trophozoite form, however their nanoformulations depicted limited effects against amoebae but exhibited minimal cytotoxicity when tested against human cells using lactate dehydrogenase release assays. Accordingly, both compounds have potential for further studies, with the hope of discovering novel anti- Acanthamoeba compounds, and potentially developing targeted therapy against infections of the central nervous system.

Colorectal cancer (CRC) accounts for approximately 10% of all new cancer cases worldwide with significant morbidity and mortality. The current imaging techniques are lacking diagnostic precision while traditional chemotherapeutic strategies are limited by their adverse side effects and poor response in advanced stages. Targeted nanoparticles (NPs) can specifically bind to surface antigens on cancer cells and provide effective delivery of diagnostic and chemotherapeutic agent. Placenta-specific protein 1 (PLAC-1) is overexpressed in CRC and can be used as a target for detection and treatment of the disease. The aim of this work was to develop a targeted nanotheranostic agent for early diagnosis and inhibition of the malignant progression and metastasis of CRC. Graphene oxide quantum dots (QD) were covalently labeled with a peptide (GILGFVFTL) having high affinity to PLAC-1. The covalent coupling between the QD and the peptide was confirmed using a series of physicochemical and morphological characterization techniques. Confocal microscopy was used to evaluate the uptake of QD and QD-P in HCT-29, HT-116 and LS-180 CRC cell lines. Selective targeting of antigen PLAC-1 overexpressed on HT-29 and HCT-116 cells was measured by immunofluorescence. Cell proliferation, cell invasion and extent of PLAC-1 expression in CRC cells after treatment with QD and QD-P were determined. The prepared QD-P showed a significant increase in targeting and specific uptake in cells expressing the antigen PLAC-1 compared to non-functionalized QD. Treatment with QD-P also increased the cell cytotoxicity, reduced the invasiveness of HT-29 and HCT-116 cells by 38% and 62%, respectively, and downregulated the expression of PLAC-1 by 53% and 33%, respectively. These results highlight the potential use of QD-P as a theranostic agent for the detection and treatment of CRC cells expressing the antigen PLAC-1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Rhizopus delemar , the main causative pathogen for the lethal mucormycosis and a severe threat during the COVID-19 pandemic, is resistant to most antifungals, including fluconazole, a known selective antifungal drug. On the other hand, antifungals are known to enhance fungal melanin synthesis. Rhizopus melanin plays an important role in fungal pathogenesis and in escaping the human defense mechanism, thus complicating the use of current antifungal drugs and fungal eradication. Because of drug resistance and the slow discovery of effective antifungals, sensitizing the activity of older ones seems a more promising strategy., Methods: In this study, a strategy was employed to revive the use and enhance the effectiveness of fluconazole against R. delemar . UOSC-13, a compound synthesized in-house to target the Rhizopus melanin, was combined with fluconazole either as is or after encapsulation in poly (lactic-coglycolic acid) nanoparticles (PLG-NPs). Both combinations were tested for the growth of R. delemar , and the MIC 50 values were calculated and compared., Results: The activity of fluconazole was found to be enhanced several folds following the use of both combined treatment and nanoencapsulation. The combination of fluconazole with UOSC-13 caused a 5-fold reduction in the MIC 50 value of fluconazole. Furthermore, encapsulating UOSC-13 in PLG-NPs enhanced the activity of fluconazole by an additional 10 folds while providing a wide safety profile., Conclusion: Consistent with previous reports, the encapsulation of fluconazole without sensitization showed no significant difference in activity. Collectively, sensitization of fluconazole represents a promising strategy to revive the use of outdated antifungal drugs back in the market., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Intratumoral (IT) injection of chemotherapeutics into needle-accessible solid tumors can directly localize the anticancer drug in the tumor site, thus increasing its local bioavailability and reducing its undesirable effects compared to systemic administration. In this study, graphene oxide (GO)-based chitosan/β-glycerophosphate (CS/GP) thermosensitive injectable composite hydrogels (CH) were prepared and optimized for the localized controlled delivery of doxorubicin (DOX). A quality-by-design (QbD) approach was used to study the individual and combined effects of several formulation variables to produce optimal DOX-loaded GO/CS/GP CH with predetermined characteristics, including gelation time, injectability, porosity, and swelling capacity. The surface morphology of the optimal formulation (DOX/opt CH), chemical interaction between its ingredients and in vitro release of DOX in comparison to GO-free CS/GP CH were investigated. Cell viability and cellular uptake after treatment with DOX/opt CH were studied on MCF 7, MDB-MB-231 and FaDu cell lines. The statistical analysis of the measured responses revealed significant effects of the concentration of GO, the concentration of CS, and the CS:GP ratio on the physicochemical characteristics of the prepared GO/CS/GP CH. The optimization process showed that DOX-loaded GO/CS/GP CH prepared using 0.1% GO and 1.7% CS at a CS: GO ratio of 3:1 ( v/v ) had the highest desirability value. DOX/opt CH showed a porous microstructure and chemical compatibility between its ingredients. The incorporation of GO resulted in an increase in the ability of the CH matrices to control DOX release in vitro. Finally, cellular characterization showed a time-dependent increase in cytotoxicity and cellular uptake of DOX after treatment with DOX/opt CH. The proposed DOX/opt CH might be considered a promising injectable platform to control the release and increase the local bioavailability of chemotherapeutics in the treatment of solid tumors.

Magnetically soft-soft MnFe 2 O 4 -Fe 3 O 4 core-shell nanoparticles were synthesized through a seed-mediated method using the organometallic decomposition of metal acetyl acetonates. Two sets of core-shell nanoparticles (S1 and S2) of similar core sizes of 5.0 nm and different shell thicknesses (4.1 nm for S1 and 5.7 nm for S2) were obtained by changing the number of nucleating sites. Magnetic measurements were conducted on the nanoparticles at low and room temperatures to study the shell thickness and temperature dependence of the magnetic properties. Interestingly, both core-shell nanoparticles showed similar saturation magnetization, revealing the ineffective role of the shell thickness. In addition, the coercivity in both samples displayed similar temperature dependencies and magnitudes. Signatures of spin glass (SG) like behavior were observed from the field-cooled temperature-dependent magnetization measurements. It was suggested to be due to interface spin freezing. We observed a slight and non-monotonic temperature-dependent exchange bias in both samples with slightly higher values for S2. The effective magnetic anisotropy constant was calculated to be slightly larger in S2 than that in S1. The magnetothermal efficiency of the chitosan-coated nanoparticles was determined by measuring the specific absorption rate (SAR) under an alternating magnetic field (AMF) at 200-350 G field strengths and frequencies (495.25-167.30 kHz). The S2 nanoparticles displayed larger SAR values than the S1 nanoparticles at all field parameters. A maximum SAR value of 356.5 W/g was obtained for S2 at 495.25 kHz and 350 G for the 1 mg/mL nanoparticle concentration of ferrogel. We attributed this behavior to the larger interface SG regions in S2, which mediated the interaction between the core and shell and thus provided indirect exchange coupling between the core and shell phases. The SAR values of the core-shell nanoparticles roughly agreed with the predictions of the linear response theory. The concentration of the nanoparticles was found to affect heat conversion to a great extent. The in vitro treatment of the MDA-MB-231 human breast cancer cell line and HT-29 human colorectal cancer cell was conducted at selected frequencies and field strengths to evaluate the efficiency of the nanoparticles in killing cancer cells. The cellular cytotoxicity was estimated using flow cytometry and an MTT assay at 0 and 24 h after treatment with the AMF. The cells subjected to a 45 min treatment of the AMF (384.50 kHz and 350 G) showed a remarkable decrease in cell viability. The enhanced SAR values of the core-shell nanoparticles compared to the seeds with the most enhancement in S2 is an indication of the potential for tailoring nanoparticle structures and hence their magnetic properties for effective heat generation.

Aims: Breast cancer (BC) is the third leading cause of death among other cancer types. Worldwide, it is the most common harmful disease in women, representing 1/4 of all cancers. Treatment of BC remains an ongoing challenge to most researchers. Understanding how cancer cells differ from normal cells can enhance drug targeting and overall disease progression. Endocytosis is a major physiological process modified in cancer cells and affects the cellular uptake of chemotherapeutic agents. MCF-7 breast cancer cells exhibit constitutive macropinocytic activity in comparison to normal non-macropinocytic MCF-10A breast cells. Therefore, we hypothesized that blocking the macropinocytosis mechanism in MCF-7 cells may inhibit the cancer progression while maintaining the safety of normal cells., Main Methods: Using nano-precipitation technique, paclitaxel-PLGA-NPs were successfully prepared in the size range and charge required to opt for macropinocytosis in MCF-7 cells., Key Findings: Uptake and endocytosis inhibitor assays indicated that the developed NPs acquired size and surface charges that efficiently target macropinocytosis of MCF-7 cells. Paclitaxel-loaded PLGA-NPs showed higher efficacy against MCF-7 cells, while providing no toxicity on normal MCF-10A cells. Metabolomics analysis indicated the nutrients deprivation because of occupying the macropinocytosis. However, treatment of fresh MCF-7 cancer cells by metabolites secreted from PLGA-NPs-treated MCF-7 cells showed a potential metastatic activity. Thus, co- administration with an anti-metastatic drug is advised., Significance: Collectively, adjusting the size and surface characteristics of a drug can critically control its cellular uptake, affecting the efficacy of drugs and the microenvironment of cancer cells., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Generic drugs or generic medicines are pharmaceutical products manufactured to be equivalent to the brand/innovator drug products. They represent the majority of worldwide prescribed medicines; therefore, their quality is critical to maximize patients' therapeutic outcomes. This study aimed to evaluate the pharmaceutical equivalency of locally and regionally manufactured generic pharmaceutical products being sold in the United Arab Emirates (UAE) market to enhance public confidence, promote their utilization, and reduce treatment costs. Three drugs (tadalafil, rosuvastatin, and acetaminophen) from three different pharmacological classes were selected from the UAE market as representatives for generic drugs. At least two generic products for each locally (L) and regionally (R) manufactured generic were evaluated according to the USP criteria in comparison to the brand (B) comparator product. All comparative tests were performed before storage and 3 and 6 months after storage during the accelerated stability study performed under the conditions for climatic zone IV (40 °C ± 2 °C /75% RH ± 5% RH). Although results were statistically different from the comparators using ANOVA and Tukey's Kremer post hoc tests, all tests were within the USP acceptance limits, except one, for friability, disintegration, content uniformity, and dissolution. Significant changes were observed following their storage over 6 months during accelerated stability studies, however, without failing the USP limits. Only one locally manufactured acetaminophen generic failed the USP dissolution tests before and after its storage and failed the disintegration test following its storage under accelerated conditions for zone IV. In conclusion, the majority of the locally and regionally manufactured generic products being sold in the UAE market were of good quality and performed similarly to their comparators. However, a continuous independent quality evaluation for the marketed generic drugs is essential to enhance public confidence., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Local anesthetics are commonly used for the management of intraoperative and postoperative acute and chronic pain caused by small invasive procedures. However, their short half-life and duration of action limit their clinical benefits. In this study, we proposed the incorporation of graphene oxide (GO) nanosheets to chitosan (CS)/β-glycerophosphate (GP) thermosensitive hydrogel system to form an injectable nanocomposite hydrogel (NCH) with improved mechanical properties and better control over the release of bupivacaine hydrochloride (BH). The prepared NCHs were characterized for their gelation time, porosity, swelling ratio, injectability, mechanical strength and in vitro drug release. In vivo, the efficacy of the prepared NCH containing 0.5 % w/v BH was evaluated using a thermal nociceptive assay in a rat model. The incorporation of GO significantly enhanced the physicochemical and mechanical properties of the hydrogel scaffolds in a concentration-dependent manner. Inclusion of 0.1% w/v GO resulted in 84% reduction in gelation time and 16% and 40% decrease in the porosity and swelling ratio of the NCHs, respectively. The mechanical strength of the CS/GP hydrogel scaffolds was also significantly improved in presence of GO. BH was slowly released from the NCHs containing 0.1% w/v GO and resulted in a 55% and 86.43% drug release after 6 and 24 h, respectively. In vivo studies showed that BH-loaded NCH significantly prolonged the local anesthetic effect and resulted in a 6.5-fold increase in blocking the pain sensory reflex compared to BH solution. These results indicate that the incorporation of GO significantly improved the physical and mechanical properties of CS/GP thermosensitive hydrogels and successfully sustained the effect of local anesthesia for more effective pain management., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Quantum dots (QDs) are a promising tool to detect and monitor tumors. However, their small size allows them to accumulate in large quantities inside the healthy cells (in addition to the tumor cells), which increases their toxicity. In this study, we synthesized stealth liposomes encapsulating hydrophilic graphene quantum dots and triggered their release with ultrasound with the goal of developing a safer and well-controlled modality to deliver fluorescent markers to tumors. Our results confirmed the successful encapsulation of the QDs inside the core of the liposomes and showed no effect on the size or stability of the prepared liposomes. Our results also showed that low-frequency ultrasound is an effective method to release QDs encapsulated inside the liposomes in a spatially and temporally controlled manner to ensure the effective delivery of QDs to tumors while reducing their systemic toxicity.

The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide- co -glycolide) NPs (PTX-PLGA-NPs) with ultra-small sizes were prepared and optimized by adopting the principles of quality by design (QbD) approach. The optimized PTX-PLGA-NPs showed ultra-small spherical particles of about 53 nm with EE% exceeding 90%, a relatively low polydispersity index (PDI) of 0.221, an effective surface charge of -10.1 mV, and a 10-fold increase in the in vitro drug release over 72 h relative to free drug. The cellular viability of pharynx carcinoma cells decreased by almost 50% in 24 h following treatment with optimized PTX-PLGA-NPs, compared to only 20% from the free drug. The intracellular uptake of PTX-PLGA-NPs was highly favored, and the antitumor activity of PTX was remarkably improved with a reduction in its half maximal inhibitory concentration (IC 50 ), by almost 50% relative to free drug solution. These results suggest that the optimal critical formulation parameters, guided by QbD principles, could produce PLGA-NPs with remarkably high EE% and ultra-small PS, resulting in enhanced cellular uptake and efficacy of PTX.