Aluminum Phthalocyanine tetrasulfonate conjugated to surface-modified Iron oxide nanoparticles as a magnetic targeting platform for photodynamic therapy of Ehrlich tumor-bearing mice.

BACKGROUND: Photodynamic therapy (PDT) is a targeted treatment option for cancers that are non-responding to ordinary anticancer therapies. It involves activating a photosensitizer with a light source of a specific wavelength to destroy targeted cells and their surrounding vasculature. Aluminum phthalocyanine tetra sulfonate (AlPcS4) has gained attention as a second-generation photosensitizer for its strong absorption in the red-light region. AlPcS4 can be conjugated to magnetic iron oxide nanoparticles (IONs) to provide targeted drug delivery to the tumor cells while reducing its undesired effect on healthy tissues in other body parts. METHODS: Magnetic glutamine functionalized iron oxide nanocomposites loaded with AlPcS4 (IONs-NH2-AlPcS4) were synthesized via the co-precipitation method. The conjugate (IONs-NH2-AlPcS4) was characterized by TEM, Zeta potential, DLS, FTIR, and UV-VIS absorption spectroscopy. Furthermore, its photodynamic activity was investigated using albino mice with induced Ehrlich solid tumors. RESULTS: AlPcS4 was successfully conjugated to IONs-NH2 with a high loading efficiency of 54±2%. The synthesized conjugate exhibited a spherical shape, with 7±2 nm particle size. The In vivo experiment revealed that the albino mice with induced Ehrlich solid tumor that were treated by combined PDT and magnetic targeting conjugate exhibited significant tumor regression and notably higher levels of necrotic tissue compared to the animals in other groups. CONCLUSION: PDT mediated by magnetic targeting significantly inhibited tumor growth with minimal adverse effects, indicating its great potential as a promising strategy for solid cancer treatment.

Nanocarriers for targeted drug delivery in the vascular system: focus on endothelium.

Endothelial cells (ECs) are pivotal in maintaining vascular health, regulating hemodynamics, and modulating inflammatory responses. Nanocarriers hold transformative potential for precise drug delivery within the vascular system, particularly targeting ECs for therapeutic purposes. However, the complex interactions between vascular ECs and nanocarriers present significant challenges for the development and clinical translation of nanotherapeutics. This review assesses recent advancements and key strategies in employing nanocarriers for drug delivery to vascular ECs. It suggested that through precise physicochemical design and surface modifications, nanocarriers can enhance targeting specificity and improve drug internalization efficiency in ECs. Additionally, we elaborated on the applications of nanocarriers specifically designed for targeting ECs in the treatment of cardiovascular diseases, cancer metastasis, and inflammatory disorders. Despite these advancements, safety concerns, the complexity of in vivo processes, and the challenge of achieving subcellular drug delivery remain significant obstacles to the effective targeting of ECs with nanocarriers. A comprehensive understanding of endothelial cell biology and its interaction with nanocarriers is crucial for realizing the full potential of targeted drug delivery systems.

A pH-Responsive Drug-Delivery System Based on Apatinib-Loaded Metal-Organic Frameworks for Ferroptosis-Targeted Synergistic Anti-Tumor Therapy.

Purpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.

State-dependent inhibition of Nav1.8 channels by VX-150 and VX-548.

Nav1.8 channels are an attractive therapeutic target for pain because they are prominent in primary pain-sensing neurons with little expression in most other kinds of neurons. Recently, two Nav1.8-targeted compounds, VX-150 and VX-548, have shown efficacy in clinical trials for reducing pain. We examined the characteristics of Nav1.8 inhibition by these compounds. The active metabolite form of VX-150 (VX-150m) inhibited human Nav1.8 channels with an IC50 of 15 nM. VX-548 (suzetrigine) was even more potent (IC50 0.27 nM). Both VX-150m and VX-548 had the unusual property of "reverse use-dependence", whereby inhibition could be relieved by repetitive depolarizations, a property seen before with another Nav1.8 inhibitor, A-887826. The relief of VX-548 inhibition by large depolarizations occurred with a time constant of ~40 ms that was not concentration-dependent. Re-inhibition at negative voltages occurred with a rate that was nearly proportional to drug concentration, consistent with the idea that relief of inhibition reflects dissociation of drug from the channel and re-inhibition reflects re-binding. The relief of inhibition by depolarization suggests a remarkably strong and unusual state-dependence for both VX-150m and VX-548, with very weak binding to channels with fully activated voltage sensors despite very tight binding to channels with voltage sensors in the resting state. Significance Statement The Nav1.8 sodium channel is a current target for new drugs for pain. This work describes the potency, selectivity, and state-dependent characteristics of inhibition of Nav1.8 channels by VX-150 and VX-548, compounds that have recently shown efficacy for relief of pain in clinical trials but whose mechanism of interaction with channels has not been described. The results show that the compounds share an unusual property whereby inhibition is relieved by depolarization, demonstrating a state-dependence different than most sodium channel inhibitors.

Probing the Chemical Space of Guanidino-Carboxylic Acids to Identify the First Blockers of the Creatine-Transporter-1.

The creatine transporter-1 (CRT-1/SLC6A8) maintains the uphill transport of creatine into cells against a steep concentration gradient. Cellular creatine accumulation is required to support the ATP-buffering by phosphocreatine. More than 60 compounds have been explored in the past for their ability to inhibit cellular creatine uptake, but the number of active compounds is very limited. Here, we show that all currently known inhibitors are full alternative substrates. We analyzed their structure-activity relation for inhibition of CRT-1 to guide a rational approach to the synthesis of novel creatine transporter ligands. Measurements of both, inhibition of [3H]creatine uptake and transport associated currents, allowed for differentiating between full and partial substrates and true inhibitors. This combined approach led to a refined understanding of the structural requirements for binding to CRT-1, which translated into the identification of three novel compounds - i.e. compound 1 (2-(N-benzylcarbamimidamido)acetic acid), and MIPA572 (=carbamimidoylphenylalanine) and MIPA573 (=carbamimidoyltryptophane) that blocked CRT-1 transport, albeit with low affinity. In addition, we found two new alternative full substrates, namely MIP574 (carbamimidoylalanine) and GiDi1257 (1-carbamimidoylazetidine-3-carboxylic acid), which was superior in affinity to all known CTR-1 ligands, and one partial substrate, namely GiDi1254 (1-carbamimidoylpiperidine-4-carboxylic acid). Significance Statement The creatine transporter-1 (CRT-1) is required to maintain intracellular creatine levels. Inhibition of CRT-1 has been recently proposed as a therapeutic strategy for cancer, but pharmacological tools are scarce. In fact, all available inhibitors are alternative substrates. We tested existing and newly synthesized guanidinocarboxylic acids for CRT-1 inhibition and identified three blockers, one partial and two full substrates of CRT-1. Our results support a refined structural understanding of ligand binding to CRT-1 and provide a proof-of-principle for blockage of CRT-1.

Elevated Cellular Uptake of Succinimide- and Glucose-Modified Liposomes for Blood-Brain Barrier Transfer and Glioblastoma Therapy.

The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. Three of the formulations had an additional PEG chain (nominally 5000 Da, conjugated to DSPE) with either succinimide (NHS), glucose (PEG-bound at C-6), or 4-aminophenyl ß-D-glucopyranoside (bound at C-1) as ligands at the distal end. Measuring the uptake kinetics at 1 h and 3 h for liposomal incubation concentrations of 100 µM, 500 µM, and 1000 µM, we calculated the liposomal uptake saturation S and the saturation half-time t1/2. We show that only succinimide has an elevated uptake in bEnd.3 cells, which makes it a very promising and so far largely unexplored candidate for BBB transfer and brain cancer therapies. Half-times are uniform at low concentrations but diversify for high concentrations for bEnd.3 cells. Contrary, U-87 MG cells show almost identical saturations for all three ligands, making a uniform uptake mechanism likely. Only mPEG liposomes stay at 60% of the saturation for ligand-coated liposomes. Half-times are diverse at low concentrations but unify at high concentrations for U-87 MG cells.

Ephrin receptor type-A2 (EphA2) targeting in cancer: a patent review (2018-present).

INTRODUCTION: EphA2 is a tyrosine kinase receptor and is considered a promising target in cancer. Different approaches are used to target EphA2 receptor, and a lot of preclinical data demonstrate the potential exploitation of this receptor in clinical oncology for diagnosis and cancer therapy, including immunotherapy. AREAS COVERED: In this review, we have summarized the recent patents involving the EphA2 targeting in cancer. For this aim, we used the patent database Patentscope covering the time period of 2018-present. Preclinical and clinical data of the inventions were considered when published on peer reviewed journals. Moreover, the clinicalTrial.gov identifiers (NCT numbers) were included when available. For an easier and more immediate reading, we classify the patents in different categories, considering the nature (aptamers, small molecules, antibodies, peptides, antigens and chimeric antigen receptors) of the inventions exploiting EphA2 in clinical oncology. EXPERT OPINION: Despite the availability of a plethora of chemically diverse agents, there are no approved anticancer drugs targeting EphA2 yet. However, these intellectual properties, some of which supported by strong preclinical evidence, keep the hope that, after more than 30 years from its discovery, we will finally see the first EphA2 targeting agent approved in clinical oncology.

Exploring the Insights on Exosomes and their Utility in Treating Ophthalmic Disease: Delving into the Clinical Approval and Present Trials.

Ophthalmic diseases include a wide array of conditions, each requiring individualized treatment approaches. In ophthalmic research and as therapeutics against potential pharmacological indications, several subtypes of exosomes (EVs) have been reconnoitered, mainly for their regenerative, neuroprotective, and anti-inflammatory characteristics. EVs are recently gaining wider attention as promising vehicles for therapies because of their natural participation in communication between cells and targeted delivery. These small vesicles, derived from cells, transport numerous molecules between cells, thus contributing advantages like low immunogenicity, stability, and the ability to target cells specifically. These inherent advantages of carrying the therapeutic cargo and enabling intercellular signaling make them a captivating avenue for progressing ophthalmic disease treatment options. While research is ongoing, and clinical applications are still emerging, several EV subtypes have shown promise for possible applications in addressing several ophthalmic diseases, such as glaucoma, age-related macular degenerative disorders, retinal degenerative disorders, and ocular inflammatory conditions.

Enhancing capture efficiency of drug-carrier particles in the carotid sinus by utilizing a combination of magnetic fields: A numerical approach.

Magnetic drug targeting is a relatively new method to treat vascular occlusion in different body parts. However, the effectiveness of this method can be affected due to the severity and location of the occlusion. This can lead to the injection of high dosages of drugs, which can cause serious side effects due to the deposition of drugs in unwanted parts. To mitigate these effects, this study investigates the potential of a guiding magnetic field in enhancing drug absorption for vascular occlusion treatment. The method relies on guiding magnetic nanoparticles (NPs) loaded with drugs toward the occlusion site using two external magnetic fields. Blood flow was modeled as non-Newtonian, considering shear-rate-dependent viscosity and unsteady at the inlet. To test this idea, a computational fluid dynamic (CFD) coupled with a discrete phase model (DPM) approach has been employed to simulate drug delivery in three-vessel structures with varying degrees of occlusion (45 %, 60 %, and 90 %). To avoid the escape of drug carriers, a secondary magnetic field was applied at the bifurcation point to direct the NPs to the site of blockage where the primary magnetic field acts. Then, the states with or without a guiding source at the bifurcation site are compared based on the capture efficiency of each structure. The simulation demonstrated a significant increase in NP capture at the target site, ranging from 2 % to 15 %, depending on the NP size. However, the severity of occlusion substantially impacted the secondary magnetic field's effectiveness. In the 90 % occlusion scenario, the method's efficiency decreased significantly from 26 % to 16 % for NP sizes exceeding 1.5µm. This study highlights the potential of guiding magnetic fields in improving drug delivery to target sites in vascular occlusion.

Emerging Pharmacotherapies for Obesity: A Systematic Review.

The history of anti-obesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging anti-obesity drugs or combinations thereof and four withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4-24.2%. Almost half of the drugs undergoing phase 2 trials were incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on under-represented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. Significance Statement Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium. However, emerging alternatives of novel agents and combinations populate the obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

Optimization of polymer coating thickness and strut width in drug Eluting stents using Magnetic field.

The transport of drug/magnetic particle (MP) conjugates in the presence of a Magnetic Field (MF) in Drug Eluting Stents (DESs) is modeled numerically using the Finite Volume Method (FVM). The effects of physiological conditions corresponding to different degrees of calcification, drug particles sizes and hematocrit level, were analyzed by investigating the roles of the tissue permeability, its anisotropy and the plasma viscosity. It was found that both in the absence and presence of the MF, as the tissue permeability decreases or the plasma viscosity increases, the free-phase drug and Extracellular Matrix (ECM)-bound phase contents increase. Stronger tissue anisotropy leads to a decrease of the free-phase drug content and an increase of the ECM-bound phase content. Within the explored ranges, the Specific Receptor (SR)-bound phase of the drug was found to be insensitive to the tissue permeability and plasma viscosity, and to be larger in anisotropic tissues. The activation of the MF leads systematically to larger free-phase drug contents, with the increases most prominent at smaller tissue permeability, anisotropy and plasma viscosity. On the other hand, the effects on the ECM-bound phase content are found to be stronger at larger permeability, smaller plasma viscosity and lower tissue anisotropy. For an isotropic tissue, the MF induces a decrease of the ECM-bound phase content at early times, followed by an increase at later times. For the considered ranges of permeability and viscosity, the MF does not seem to have any noticeable effects on the SR-bound phase. However, this phase of the drug tends to increase with the activation of the MF in isotropic tissues and is unchanged in anisotropic ones. These reported effects of the MF hold promise for alleviating two factors contributing to In-Stent Restenosis, namely the polymer coating width and thickness. The study reveals that a narrower or thinner polymer layer, in combination with the MF, can mimic the drug release dynamics of a wider or thicker polymer layer in the absence of the MF. The corresponding width and thickness of the magnetized stents, that we referred to as the equivalent polymer width (EPW) and equivalent polymer thickness (EPT) were determined and their dependence on the tissue permeability, isotropy and the plasma viscosity, was investigated. The study shows that it is possible to achieve the same drug delivery with polymer coating of half the width or half the thickness of the non-magnetized stent when an electric intensity of 3A is used.

Modification of the Biorelevant Release Testing of Esophageal Applied Mucoadhesive Films and Development of Formulation Strategies to Increase the Mucosal Contact Time.

The increasing prevalence of esophageal disease highlights the clinical relevance of novel, long-lasting mucoadhesive oral dosage forms. The EsoCap device enables targeted local application of films in the esophagus. Biorelevant test systems such as EsoPeriDiss are essential for early formulation development. To this end, the developed and already described release model for simulating the esophagus is being further developed for its potential for biorelevant mapping of the application site through complete tempering and investigation of biorelevant release media. Particularly viscous saliva formulations led to an extension of the retention time. In addition, possible formulation strategies for increasing the retention time of esophageal applied films are being evaluated, such as different film thicknesses, polymer grades and the influence of different active ingredient properties on the retention time. For highly soluble active ingredients, the film thickness represents an option for extending the retention time, while for less soluble substances, the choice of polymer grade may be of particular interest.

3D printing chronicles in medical devices and pharmaceuticals: tracing the evolution and historical milestones.

The objective of this study is to collect the significant advancements of 3D printed medical devices in the biomedical area in recent years. Especially related to a range of diseases and the polymers employed in drug administration. To address the existing limitations and constraints associated with the method used for producing 3D printed medical devices, in order to optimize their suitability for degradation. The compilation and use of research papers, reports, and patents that are relevant to the key keywords are employed to improve comprehension. According to this thorough investigation, it can be inferred that the 3D Printing method, specifically Fuse Deposition Modeling (FDM), is the most suitable and convenient approach for preparing medical devices. This study provides an analysis and summary of the development trend of 3D printed implantable medical devices, focusing on the production process, materials specially the polymers, and typical items associated with 3D printing technology. This study offers a comprehensive examination of nanocarrier research and its corresponding discoveries. The FDM method, which is already facing significant challenges in terms of achieving optimal performance and cost reduction, will experience remarkable advantages from this highly valuable technology. The objective of this analysis is to showcase the efficacy and limitations of 3D-printing applications in medical devices through thorough research, highlighting the significant technological advancements it offers. This article provides a comprehensive overview of the most recent research and discoveries on 3D-printed medical devices, offering significant insights into their study.

Potential of Pullulan-Based Polymeric Nanoparticles for Improving Drug Physicochemical Properties and Effectiveness.

Pullulan, a natural polysaccharide with unique biocompatibility and biodegradability, has gained prominence in nanomedicine. Its application in nanoparticle drug delivery systems showcases its potential for precision medicine. AIM OF STUDY: This scientific review aims to comprehensively discuss and summarize recent advancements in pullulan-based polymeric nanoparticles, focusing on their formulation, characterization, evaluation, and efficacy. METHODOLOGY: A search on Scopus, PubMed, and Google Scholar, using "Pullulan and Nanoparticle" as keywords, identified relevant articles in recent years. RESULTS: The literature search highlighted a diverse range of studies on the pullulan-based polymeric nanoparticles, including the success of high-selectivity hybrid pullulan-based nanoparticles for efficient boron delivery in colon cancer as the active targeting nanoparticle, the specific and high-efficiency release profile of the development of hyalgan-coated pullulan-based nanoparticles, and the design of multifunctional microneedle patches that incorporated pullulan-collagen-based nanoparticle-loaded antimicrobials to accelerate wound healing. These studies collectively underscore the versatility and transformative potential of pullulan-based polymeric nanoparticles in addressing biomedical challenges. CONCLUSION: Pullulan-based polymeric nanoparticles are promising candidates for innovative drug delivery systems, with the potential to overcome the limitations associated with traditional delivery methods.

The Bright Side of Curcumin: A Narrative Review of Its Therapeutic Potential in Cancer Management.

Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant therapeutic potential in cancer management. This review explores curcumin's mechanisms of action, the challenges related to its bioavailability, and its enhancement through modern technology and approaches. Curcumin demonstrates strong antioxidant and anti-inflammatory properties, contributing to its ability to neutralize free radicals and inhibit inflammatory mediators. Its anticancer effects are mediated by inducing apoptosis, inhibiting cell proliferation, and interfering with tumor growth pathways in various colon, pancreatic, and breast cancers. However, its clinical application is limited by its poor bioavailability due to its rapid metabolism and low absorption. Novel delivery systems, such as curcumin-loaded hydrogels and nanoparticles, have shown promise in improving curcumin bioavailability and therapeutic efficacy. Additionally, photodynamic therapy has emerged as a complementary approach, where light exposure enhances curcumin's anticancer effects by modulating molecular pathways crucial for tumor cell growth and survival. Studies highlight that combining low concentrations of curcumin with visible light irradiation significantly boosts its antitumor efficacy compared to curcumin alone. The interaction of curcumin with cytochromes or drug transporters may play a crucial role in altering the pharmacokinetics of conventional medications, which necessitates careful consideration in clinical settings. Future research should focus on optimizing delivery mechanisms and understanding curcumin's pharmacokinetics to fully harness its therapeutic potential in cancer treatment.

Demystifying the potential of lipid-based nanocarriers in targeting brain malignancies.

Drug targeting for brain malignancies is restricted due to the presence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), which act as barriers between the blood and brain parenchyma. Certainly, the limited therapeutic options for brain malignancies have made notable progress with enhanced biological understanding and innovative approaches, such as targeted therapies and immunotherapies. These advancements significantly contribute to improving patient prognoses and represent a promising shift in the landscape of brain malignancy treatments. A more comprehensive understanding of the histology and pathogenesis of brain malignancies is urgently needed. Continued research focused on unraveling the intricacies of brain malignancy biology holds the key to developing innovative and tailored therapies that can improve patient outcomes. Lipid nanocarriers are highly effective drug delivery systems that significantly improve their solubility, bioavailability, and stability while also minimizing unwanted side effects. Surface-modified lipid nanocarriers (liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, lipid nanocapsules, lipid-polymer hybrid nanocarriers, lipoproteins, and lipoplexes) are employed to improve BBB penetration and uptake through various mechanisms. This systematic review illuminates and covers various topics related to brain malignancies. It explores the different methods of drug delivery used in treating brain malignancies and delves into the benefits, limitations, and types of brain-targeted lipid-based nanocarriers. Additionally, this review discusses ongoing clinical trials and patents related to brain malignancy therapies and provides a glance into future perspectives for treating this condition.

PSMA-targeted combination brusatol and docetaxel nanotherapeutics for the treatment of prostate cancer.

Active targeting to cancer involves exploiting specific interactions between receptors on the surface of cancer cells and targeting moieties conjugated to the surface of vectors such that site-specific delivery is achieved. Prostate specific membrane antigen (PSMA) has proved to be an excellent target for active targeting to prostate cancer. We report the synthesis and use of a PSMA-specific ligand (Glu-NH-CO-NH-Lys) for the site-specific delivery of brusatol- and docetaxel-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles to prostate cancer. The PSMA targeting ligand covalently linked to PLGA-PEG3400 was blended with methoxyPEG-PLGA to prepare brusatol- and docetaxel-loaded nanoparticles with different surface densities of the targeting ligand. Flow cytometry was used to evaluate the impact of different surface densities of the PSMA targeting ligand in LNCaP prostate cancer cells at 15 min and 2 h. Cytotoxicity evaluations of the targeted nanoparticles reveal differences based on PSMA expression in PC-3 and LNCaP cells. In addition, levels of reactive oxygen species (ROS) were measured using the fluorescent indicator, H2DCFDA, by flow cytometry. PSMA-targeted nanoparticles loaded with docetaxel and brusatol showed increased ROS generation in LNCaP cells compared to PC-3 at different time points. Furthermore, the targeted nanoparticles were evaluated in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors. Evaluation of the percent relative tumor volume show that brusatol-containing nanoparticles show great promise in inhibiting tumor growth. Our data also suggest that the dual drug-loaded targeted nanoparticle platform improves the efficacy of docetaxel in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors.

Thymoquinone, artemisinin, and thymol attenuate proliferation of lung cancer cells as Sphingosine kinase 1 inhibitors.

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non-small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.