Triple negative breast cancer (TNBC) is an aggressive malignancy characterized by early recurrence, high metastatic burden, and resistance to conventional therapies, largely due to the absence of targetable receptors and an immunosuppressive tumor microenvironment. To address these limitations, our lab has engineered a multifunctional nanotherapeutic system iRGD-DOX-oHA-PLN comprising polymer-lipid nanoparticles co-loaded with doxorubicin (DOX) and oligomeric hyaluronic acid (oHA) and functionalized with the tumor-penetrating integrin-targeting iRGD peptide. This rationally designed platform capitalizes on the sequential targeting mechanism: integrin-mediated tumor penetration and endocytosis via iRGD, followed by CD44 engagement through oHA to enhance intracellular drug delivery and suppresses cell motility. iRGD-DOX-oHA-PLN significantly improved cellular uptake, intratumoral accumulation, and cytotoxic efficacy in TNBC cells and tumors. Notably, it enhanced immunogenic cell death, characterized by increased calreticulin exposure, ATP and HMGB1 levels, triggering potent anti-tumor immune responses. Intravenous treatment led to elevated CD8+ T-cell infiltration, granzyme B expression, and secretion of pro-inflammatory cytokines (TNF-α, IFN-γ), while concurrently suppressing immunosuppressive mediators including IL-6, regulatory T cells, and tumor-associated macrophages. Over a four-week treatment period, iRGD-DOX-oHA-PLN effectively inhibited primary tumor growth and systemic pulmonary metastases in a syngeneic orthotopic TNBC mouse model. These findings demonstrate the therapeutic potential of simultaneously targeting integrin-CD44 signaling and the immunosuppressive niche using a dual-functional nanomedicine to overcome drug resistance and immune evasion in TNBC, offering a promising strategy for metastatic cancer intervention.

The high mortality rate associated with metastatic breast cancer presents a significant global challenge. Inherent and chemotherapy-induced DNA damage repair, alongside immunosuppression, drastically contribute to triple-negative breast cancer (TNBC) relapse and metastasis. While poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib show effectiveness against BRCA1-mutant TNBC, they may lead to drug resistance and reduced efficacy due to increased programmed death-ligand 1 (PD-L1) expression. Our study explored the use of polymer-lipid nanoparticles (PLN) loaded with doxorubicin (DOX) and oligomeric hyaluronic acid (oHA), functionalized iRGD-peptide for integrins targeting (iRGD-DOX-oHA-PLN), to prevent TNBC immunosuppression, DNA repair, and metastasis. The results demonstrate that the iRGD-DOX-oHA-PLNs efficiently downregulated single and double-strand DNA repair proteins and enhanced DNA damage while decreasing PD-L1 expression compared to olaparib. Accordingly, iRGD-DOX-oHA-PLN treatment showed significantly higher efficiency in reducing levels of primary tumor growth and numbers of metastases to the lung and liver compared to olaparib in vitro and in vivo in both BRCA1-mutant and wild type TNBC orthotopic xenograft models.

Radiotherapy (RT) is one of major therapeutic modalities in combating breast cancer. In RT, ionizing radiation is employed to induce DNA double-strand breaks (DSBs) as a primary mechanism that causes cancer cell death. However, the induced DNA damage can also trigger the activation of DNA repair mechanisms, reducing the efficacy of RT treatment. Given the pivotal role of RAD50 protein in the radiation-responsive DNA repair pathways involving DSBs, we developed a novel polymer-lipid based nanoparticle formulation containing RAD50-silencing RNA (RAD50-siRNA-NPs) and evaluated its effect on the RAD50 downregulation as well as cellular and tumoral responses to ionizing radiation using human triple-negative breast cancer as a model. The RAD50-siRNA-NPs successfully preserved the activity of the siRNA, facilitated its internalization by cancer cells via endocytosis, and enabled its lysosomal escape. The nanoparticles significantly reduced RAD50 expression, whereas RT alone strongly increased RAD50 levels at 24 h. Pretreatment with RAD50-siRNA-NPs sensitized the cancer cells to RT with ∼2-fold higher level of initial DNA DSBs as determined by a γH2AX biomarker and a 2.5-fold lower radiation dose to achieve 50% colony reduction. Intratumoral administration of RAD50-siRNA-NPs led to a remarkable 53% knockdown in RAD50. The pretreatment with RAD50-siRNA-NPs followed by RT resulted in approximately a 2-fold increase in DNA DSBs, a 4.5-fold increase in cancer cell apoptosis, and 2.5-fold increase in tumor growth inhibition compared to RT alone. The results of this work demonstrate that RAD50 silencing by RAD50-siRNA-NPs can disrupt RT-induced DNA damage repair mechanisms, thereby significantly enhancing the radiation sensitivity of TNBC MDA-MB-231 cells in vitro and in orthotopic tumors as measured by colony forming and tumor regrowth assays, respectively.

Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment. Herein, we exploited the bioreactivity of novel polymer–lipid manganese dioxide nanoparticles (PLMDs) to remodel the tumor immune microenvironment (TIME) by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death. This study demonstrated that PLMD treatment sensitized hypoxic human and murine CRPC cells to radiation, significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death, which enhanced the secretion of damage-associated molecular patterns, attributable to the induction of autophagy and endoplasmic reticulum stress. Reoxygenation via PLMDs also polarized hypoxic murine RAW264.7 macrophages toward the M1 phenotype, enhancing tumor necrosis factor alpha release, and thus reducing the viability of murine CRPC TRAMP-C2 cells. In a syngeneic TRAMP-C2 tumor model, intravenous injection of PLMDs suppressed, while radiation alone enhanced recruitment of regulatory T cells and myeloid-derived suppressor cells. Pretreatment with PLMDs followed by radiation down-regulated programmed death-ligand 1 and promoted the infiltration of antitumor CD8 + T cells and M1 macrophages to tumor sites. Taken together, TIME modulation by PLMDs plus radiation profoundly delayed tumor growth and prolonged median survival compared with radiation alone. These results suggest that PLMDs plus radiation is a promising treatment modality for improving therapeutic efficacy in radioresistant and immunosuppressive solid tumors.

IntroductionRadiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT.Materials and methodsHuman PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT.ResultsPLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate.ConclusionPLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC.

Globally, a rising burden of complex diseases takesa heavy toll on human lives and poses substantial clinical andeconomic challenges. This review covers nanomedicine andnanotechnology-enabled advanced drug delivery systems (DDS)designed to address various unmet medical needs. Key nano-medicine and DDSs, currently employed in the clinic to tacklesome of these diseases, are discussed focusing on their versatility indiagnostics, anticancer therapy, and diabetes management. First-hand experiences from our own laboratory and the work of othersare presented to provide insights into strategies to design andoptimize nanomedicine- and nanotechnology-enabled DDS forenhancing therapeutic outcomes. Computational analysis is alsobriefly reviewed as a technology for rational design of controlledrelease DDS. Further explorations of DDS have illuminated the interplay of physiological barriers and their impact on DDS. It isdemonstrated how such delivery systems can overcome these barriers for enhanced therapeutic efficacy and how new perspectives ofnext-generation DDS can be applied clinically.

Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases.

Color is the main feature of any food item as it en ha ces the appeal and acceptability of food. Curren tly, there is increasing awareness among people towards natural d yes and dye yielding plants due to severe health pr oblems. Beet scientifically known as Beta vulgaris belongs to Chenopodiaceae family and locally known in Libya n markets as "Banjer". The present study aimed to study of be et from Libyan markets as coloring agent in food an cosmetic. Beet juice was prepared by hot extraction using met hanol and then examined for its activity against ba cteria by using the agar well diffusion method and also as an tioxidant by using 2,2, Diphenyl-1-picryhydrazyl (D PPH) assay. Beet juice also investigated phytochemically which indicated that beet is a rich source of flavonoids. Beet juice examined for the presence of aflatoxines (B1, B2, G 1and G2), the beet juice was free from mentioned to xic substances. Therefore, the juice is safe. Finally B eet juice was evaluated as a food (Cakes) and cosme tic (Hair dye) coloring agents. The juice showed a weak antioxidan t activity, good antimicrobial activity against gra m positive bacteria and accepted to many volunteers in color a nd taste questionnaires when it's added to homemade c k s. The ability of juice to augment of Henna color; the bes t mixture with long lasting coloring was a 50:50 mi xture.

Three Libyan plants namely Ballota pseudodictamnus, Hedera helix, Thapsia garganica were tested for anticancer activity. The plants, collected from Aljabal-Al-Akhdar area of Libya in April 2010 were shed dried and subjected to Soxhlet extraction by methanol. Phytochemical screening indicated the presence of 2-deoxy sugars, flavonoids, saponins and tannins but absence of alkaloids in all three plants under investigation. Antiproliferative activity was performed breast adenocarcinoma cell line (MCF7). At the concentration of 100µg/mL, B. pseudodictamnus, T. garganica and H. helix showed 90, 60 and 5% cell death, respectively as compared to the control. Key words: Antiproliferative; Breast adenocarcinoma; Cell l ine MCF-7

The medicinal plants have been considered a healthy source of life for all people and the therapeutical properties of the medical plants are very useful in curing range of diseases. The aims of the study are to evaluate the anti-oxidant, antimicrobial, anti-inflammatory and anti-ulcer properties of Helianthemum lippii (MHL) methanolic extracts. MHL samples were collected in the mountain region of Libya. The antioxidant properties of MHL were evaluated using free radical scavenging assay. Stomach ulcers were induced in rats by ethanol. Pretreatment with ranitidine and MHL samples were performed before the ulcer induction. Gastric mucosal histological changes in rat stomach tissue were evaluated. Antimicrobial efficacy of MHL was also studied against gram-positive bacteria S. aureus, gram-negative bacteria E. coli , and fungal strain C. albicans. The phytochemical screening of MHL showed presence of flavonoids, tannins, saponine and simple phenolic compounds. MHL exhibited a powerful anti-oxidant activity, where 31.17 ± 1.40 µg/ml of extract caused 50% inhibition on 2,2, Diphenyl-1-picryhydrazyl (DPPH) scavenging activity in comparison to standard ascorbic acid (15.35 ± 3.2 µg/ml). MHL also showed substantial anti-microbial activity against a strain of gram-positive bacteria, S. aureu, with zone of inhibition (21 mm) and MIC (12.25 mg/ml) and a fungal strain, C. albicans, with zone of inhibition (20 mm) and MIC (6.25 mg/ml) compared to ciprofloxacin or amphotericin B. MHL at doses of 250 and 500 mg/kg produced statistical significant anti-inflammatory activity (23.6%, 50%) in comparison to aspirin (60%). It further showed significant anti-ulcer activity in doses of 250mg/kg and 500mg/kg with percentage of gastric lesions inhibitions of 48.78% and 76.82%, respectively, in comparison to standard anti-ulcer ranitidine (50 mg/kg), which showed 69.78%. MHL has clearly a protective effect against ethanol-induced gastric mucosal lesion, and this effect, at least in part, depends on the increase of anti-oxidant activity. In conclusion, the MHL extract showed anti-oxidant, anti-ulcer, anti-microbial activities against tested microbes, antioxidant and anti-inflammatory; mightily due to combined mechanisms of MHL’s constituents. Keyword: gastric ulcer, Helianthemum lippii, Cistaceae, anti-oxidant, anti-microbial, anti-inflammatory, anti-ulcer. Abbreviations: DPPH: 2,2, Diphenyl-1-picryhydrazyl; MEHL: methanolic extract of H. lippii; MHL: Helianthemum lippii; MIC: Minimum inhibitory concentration

Four Libyan medicinal plants Olea Europaea (Oleacea), Cistus Incanus (Cistaceae), Launaea Residifolia (Asteraceae) , Cistus Parviflorus ,Lam(Cistaceae) were collected from EL –jabal EL-akhdar eastern Libya in April 2010 .after identified the plants were extracted using microwave technique by three solvents (methanol-ethyl acetate –hexane ) .these plants were studied for anti-inflammatory activity using carrageenan induced mice odema model. The plant extracts of different solvents were administered at dose 250 mg /kg of the body weight intraperitoneally. among these extracts, Cistus Parviflorus ,Lam extract especially methanolic and ethyl acetate extracts gave the most significant % inhibition of inflammation after 3 hr (57.4±1.9 65.5±2.5 respectively) this effect was better than standard reference aspirin (55.1±1.9)

Natural products are often a source for bioactive cwhich have great potential for developing novel therapeutic agents. In this study, two Libyan medic inal plants Helianthemum lippii (H. lippii ) and Launaea residifolia (L. residifolia ) were collected from El-Jabel El- Garbi (Gharian) in the Spring season (2010). They were extracted successively by using microwave technique with three different solvents of different polarities. The analgesic activity of these plant extracts was eval uated using the hot-plate method and the anti-infla mmatory activity was evaluated using Carrageenen-induced pa w edema method. The methanol and chloroform extracts exhibited significant analgesic activity at the dos es tested while the petroleum ether extracts of bot h plants did not show any significant effect. In addition, the anti- inflammatory activities of various extracts showed a significant percentage inhibition of paw edema for H. lippii extracts in methanol and chloroform but not in petr oleum ether. Moreover, the results exhibit different percentage inhibitions of paw edema for L. residifolia extract s in methanol, chloroform and petroleum ether. The analgesic and a effects produced by the extracts m ay be attributed individually or collectively to the flavonoids and tannins. H. lippii and L. residifolia ca n be introduced as new plant sources for analgesics and anti inflammat ory agents. The methanolic and chloroform extracts of both plants showed a significant analgesic activity due to an increase in the reaction time (p 0.05) and (14.56%, p>0.05) respectively compared to control.

Purpose: 2-(3-benzoyl phenyl)propanohydroxamic acid (2) and 2-{3-[(hydroxyimino)(phenyl)methyl]phenyl}propanoic acid (3) were synthesized from non-steroidal anti-inflammatory drug, ketoprofen as dual-mechanism drugs. Materials and Methods: Structures of the synthesized compounds were established by IR, 1H NMR, and mass spectroscopy. Both compounds were screened for their anti-inflammatory activity in rat paw edema model and in vitro antitumor activity against 60 human tumor cell lines. Flexible ligand docking studies were performed with different matrix metalloproteinases and cyclooxygenases to gain an insight into the structural preferences for their inhibition. Results: Compound (2) proved out to be more potent than ketoprofen in rat paw edema model. Both compounds showed moderate anticancer activity ranging from 1% to 23% inhibition of growth in 38 cell lines of 8 tumor subpanels at 10 μM concentration in a single dose experiment. Hydroxamic acid analogue was found to be more potent than ketoximic analogue in terms of its antitumor activity. Conclusion: Analysis of docking results together with experimental findings provide a good explanation for the biological activities associated with synthesized compounds which may be fruitful in designing dual-target-directed drugs that may inhibit cyclooxygenases and MMPs for the treatment of cancer.

Ballota pseudodictamnus (L.) Benth. (Lamiaceae), Salvia fruticosa Mill. (Lamiaceae) and Thapsia garganica L. (Apiaceae) are three well-known medicinal plants from the Libyan flora, which have long been used for the treatment of inflammations. The aim of the present study was to investigate, for the first time, the anti-inflammatory property of the methanol (MeOH) extracts of the aerial parts of these plants. Shade-dried and ground aerial parts of B. pseudodictamnus, S. fruticosa) and T. garganica were Soxhlet-extracted with MeOH. The extracts were concentrated by evaporation under reduced pressure at 40°C. The anti-inflammatory activity of the extracts was evaluated using the carrageenan-induced mice paw edema model. The administration of the extracts at a dose of 500 mg/kg body weight produced statistically significant inhibition (p < 0.05) of edema within 3 h of carrageenan administration. The results demonstrated significant anti-inflammatory properties of the test extracts. Among the extracts, the S. fruticosa extract exhibited the most significant inhibition of inflammation after 3 h (62.1%). Thus, S. fruticosa could be a potential source for the discovery and development of newer anti-inflammatory ‘leads’ for drug development. The anti-inflammatory activity of B. pseudodictamnus and S. fruticosa could be assumed to be related to high levels of phenolic compounds, e.g., flavonoids, present in these plants.