Drug Transport Research Articles

Interaction of the Atypical Tetracyclines Chelocardin and Amidochelocardin with Renal Drug Transporters.

Antimicrobial resistance is expected to increase mortality rates by up to several million deaths per year by 2050 without new treatment options at hand. Recently, we characterized the pharmacokinetic (PK) and pharmacodynamic properties of two atypical tetracyclines, chelocardin (CHD) and amidochelocardin (CDCHD) that exhibit no cross-resistance with clinically used antibacterials. Both compounds were preferentially renally cleared and demonstrated pronounced effects in an ascending urinary tract infection model against E. coli. Renal drug transporters are known to influence clearance into the urine. In particular, inhibition of apical transporters in renal tubular epithelial cells can lead to intracellular accumulation and potential cell toxicity, whereas inhibition of basolateral transporters can cause a higher systemic exposure. Here, selected murine and human organic cation (Oct), organic anion (Oat), and efflux transporters were studied to elucidate interactions with CHD and CDCHD underlying their PK behavior. CHD exhibited stronger inhibitory effects on mOat1 and mOat3 and their human homologues hOAT1 and hOAT3 compared to CDCHD. While CHD was a substrate of mOat3 and mOct1, CDCHD was not. By contrast, no inhibitory effect was observed on Octs. CDCHD rather appeared to foster enhanced substrate transport on mOct1. CHD and CDCHD inhibited the efflux transporter hMRP2 on the apical side. In summary, the substrate nature of CHD in conjunction with its autoinhibition toward mOat3 rationalizes the distinct urine concentration profile compared to CDCHD that was previously observed in vivo. Further studies are needed to investigate the accumulation in renal tubular cells and the nephrotoxicity risk.

Optimization of an in vitro method for assessing pulmonary permeability of inhaled drugs using alveolar epithelial cells

IntroductionInhalation of drugs for the treatment of pulmonary diseases has been used since a long time. Due to lungs' larger absorptive surface area, delivery of drugs to the lungs is the method of choice for different disorders. Here we present the establishment of a comprehensive permeability model using Type II alveolar epithelial cells and Beclomethasone Dipropionate (BDP) as a model drug delivered by pressurized metered dose inhaler (pMDI). MethodsUsing Type II alveolar epithelial cells, the method was standardized for parameters viz., cell density, viability, incubation period and membrane integrity. The delivery and deposition of drug were using the pMDI device with a Twin Stage Impinger (TSI) modified to accommodate cell culture insert having monolayer of cells. The analytical method for simultaneous estimation of BDP and Beclomathasone-17-Monopropionate (17-BMP) was validated as per the bioanalytical guidelines. The extent and rate of absorption of BDP was determined by quantifying the amount of drug permeated and the data represented by calculating its apparent permeability. ResultsType II alveolar epithelial cells cultured at 0.55 × 105 cells/cm2 for 8–12 days under air-liquid interface were optimized for conducting permeability studies. The data obtained for absorptive transport showed a linear increase in the drug permeated against time for both BDP and 17-BMP along with proportional permeability profile. DiscussionWe have developed a robust in vitro model to study absorptive rate of drug transport across alveolar layer. Such models would create potential value during formulation development for comparative studies and selection of clinical candidates.

Clinically important pharmacokinetic drug-drug interactions with antibacterial agents.

Antimicrobial agents are widely used, and drug interactions are challenging due to increased risk of adverse effects or reduced efficacy. Among the interactions, the most important are those affecting metabolism, although those involving drug transporters are becoming increasingly known. To make clinical decisions, it is key to know the intensity of the interaction, as well as its duration and time-dependent recovery after discontinuation of the causative agents. It is not only important to be aware of all patient treatments, but also of supplements and natural medications that may also interact. Although they can have serious consequences, most interactions can be adequately managed with a good understanding of them. Especially in patients with polipharmacy it is compulsory to check them with an electronic clinical decision support database. This article aims to conduct a narrative review focusing on the major clinically significant pharmacokinetic drug-drug interactions that can be seen in patients receiving treatment for bacterial infections.

Synthesis and Application of a pH-Responsive Functional Metal-Organic Framework: In Vitro Investigation for Delivery of Oridonin in Cancer Therapy.

Oridonin (Ori) is a naturally existing diterpenoid substance that mainly exists in the Chinese medicinal plant Rabdosia rubescens. It was previously found to possess intriguing biological properties; however, the quick clearance from plasma and limited solubility in water restricts its use as a drug. Several metal-organic frameworks (MOFs), having big surfaces and large pores, have recently been considered promising drug transporters. The zeolitic imidazolate framework-8 (ZIF-8), a form of MOF consisting of 2-methylimidazole with zinc ions, is structurally stable under physiologically neutral conditions, while it can degrade at low pH values such as in tumor cells. Herein, a nanosized drug delivery system, Ori@ZIF-8, was successfully designed for encapsulating and transporting oridonin to the tumor site. The drug loading of the prepared Ori@ZIF-8 was 26.78%, and the particles' mean size was 240.5 nm. In vitro, the release of Ori@ZIF-8 exhibited acid sensitivity, with a slow release under neutral conditions and rapid release of the drug under weakly acidic conditions. According to the in vitro anti-tumor experiments, Ori@ZIF-8 produced higher cytotoxicity than free Ori and induced apoptosis in A549 cancer cells. In conclusion, Ori@ZIF-8 could be a potential pH-responsive carrier to accurately release more oridonins at the tumor site.

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier.

The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism. A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included. During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects. Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.

Predicting particle deposition in an adult human lung using an oscillatory, lumped respiratory model

Inhalation has become widely accepted as the optimal drug delivery mechanism for respiratory diseases, which often requires targeting a particular region of the lung. Mathematical models are key to understanding the factors that influence drug transport and deposition in the lung. This study proposes a simple zero-dimensional typical path model that couples respiratory mechanics and particle deposition over multiple oscillatory breathing cycles. Respiration is modeled using an RLC (resistance–inductance–capacitance) circuit analog framework to capture airflows, lung pressures, and volumes. The model is validated against experimental deposition fractions reported in the literature. The model is used to explore the effects of oscillatory respiration and multiple breaths on particle deposition in different regions of the lung. The results indicate that oscillatory dynamics are important in compliant airways. Deposition increases over multiple breaths as the concentration of suspended particles increases in the respiratory airways.

Recent Advances in Biomedical Nanotechnology Related to Natural Products.

Natural product processing via nanotechnology has opened the door to innovative and significant applications in medical fields. On one hand, plants-derived bioactive ingredients such as phenols, pentacyclic triterpenes and flavonoids exhibit significant pharmacological activities, on another hand, most of them are hydrophobic in nature, posing challenges to their use. To overcome this issue, nanoencapsulation technology is employed to encapsulate these lipophilic compounds and enhance their bioavailability. In this regard, various nano-sized vehicles, including degradable functional polymer organic compounds, mesoporous silicon or carbon materials, offer superior stability and retention for bioactive ingredients against decomposition and loss during delivery as well as sustained release. On the other hand, some naturally occurring polymers, lipids and even microorganisms, which constitute a significant portion of Earth's biomass, show promising potential for biomedical applications as well. Through nano-processing, these natural products can be developed into nano-delivery systems with desirable characteristics for encapsulation a wide range of bioactive components and therapeutic agents, facilitating in vivo drug transport. Beyond the presentation of the most recent nanoencapsulation and nano-processing advancements with formulations mainly based on natural products, this review emphasizes the importance of their physicochemical properties at the nanoscale and their potential in disease therapy.

Utilising Endogenous Biomarkers in Drug Development to Streamline the Assessment of Drug-Drug Interactions Mediated by Renal Transporters: A Pharmaceutical Industry Perspective.

The renal secretion of many drugs is facilitated by membrane transporters, including organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K and organic anion transporters 1 and 3. Inhibition of these transporters can reduce renal excretion of drugs and thereby pose a safety risk. Assessing the risk of inhibition of these membrane transporters by investigational drugs remains a key focus in the evaluation of drug-drug interactions (DDIs). Current methods to predict DDI risk are based on generating in vitro data followed by a clinical assessment using a recommended exogenous probe substrate for the individual drug transporter. More recently, monitoring plasma-based and urine-based endogenous biomarkers to predict transporter-mediated DDIs in early phase I studies represents a promising approach to facilitate, improve and potentially avoid conventional clinical DDI studies. This perspective reviews the evidence for use of these endogenous biomarkers in the assessment of renal transporter-mediated DDI, evaluates how endogenous biomarkers may help to expand the DDI assessment toolkit and offers some potential knowledge gaps. A conceptual framework for assessment that may complement the current paradigm of predicting the potential for renal transporter-mediated DDIs is outlined.

Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.

e15006 Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased > 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.

Enhanced Brain Targeting Delivery of Salvianic Acid Using Borneol as a Promoter of Blood/Brain Transport and Regulator of P-gp.

Borneol can enhance the blood-brain barrier (BBB) permeability of some drugs and suppress the efflux transport of P-glycoprotein (P-gp), which will contribute to the brain delivery of salvianic acid A (SAA). The study aimed to develop an approach to improve the brain targeting delivery of SAA with the aid of borneol. "Borneol" was involved in SAA via esterified prodrug SAA borneol ester (SBE) and combined administration (SAA-borneol, SAA-B). Subsequently, the blood-brain transport of SAA through brain/blood distribution and P-gp regulation via expression and function assay were investigated in rats. The SBE and SAA-B-treated group received a three-fold brain concentration and longer t1/2 and retention period of active SAA than that of SAA alone (20.18/13.82 min vs. 6.48 min; 18.30/17.42 min vs. 11.46 min). In addition, blood to brain transport of active SAA in SBE was altered in comparison to that of SAA-B, ultimately resulting in a better drug targeting index (9.93 vs. 3.63). Further studies revealed that SBE-induced downregulation of P-gp expression occurred at the later stage of administration (60 min, P < 0.01), but SBE always showed a more powerful drug transport activity across BBB represented by Kp value of rhodamine 123 than SAA-B (30, 60 min, P < 0.05). The comparative results indicate that SBE exhibits prominent efficiency on SAA's targeting delivery through improved blood/brain metabolic properties and sustained inhibitory effect of "borneol" on P-gp efflux. Therefore, prodrug modification can be applied as a more effective approach for brain delivery of SAA.

Strategies of Pharmacological Repositioning for the Treatment of Medically Relevant Mycoses.

Fungal infections represent a worldwide concern for public health, due to their prevalence and significant increase in cases each year. Among the most frequent mycoses are those caused by members of the genera Candida, Cryptococcus, Aspergillus, Histoplasma, Pneumocystis, Mucor, and Sporothrix, which have been treated for years with conventional antifungal drugs, such as flucytosine, azoles, polyenes, and echinocandins. However, these microorganisms have acquired the ability to evade the mechanisms of action of these drugs, thus hindering their treatment. Among the most common evasion mechanisms are alterations in sterol biosynthesis, modifications of drug transport through the cell wall and membrane, alterations of drug targets, phenotypic plasticity, horizontal gene transfer, and chromosomal aneuploidies. Taking into account these problems, some research groups have sought new therapeutic alternatives based on drug repositioning. Through repositioning, it is possible to use existing pharmacological compounds for which their mechanism of action is already established for other diseases, and thus exploit their potential antifungal activity. The advantage offered by these drugs is that they may be less prone to resistance. In this article, a comprehensive review was carried out to highlight the most relevant repositioning drugs to treat fungal infections. These include antibiotics, antivirals, anthelmintics, statins, and anti-inflammatory drugs.

Laplace Transform Based Modeling of Drug Delivery with Reversible Drug Binding in a Multilayer Tissue.

Drug delivery from a drug-loaded device into an adjacent tissue is a complicated process involving drug transport through diffusion and advection, coupled with drug binding kinetics responsible for drug uptake in the tissue. This work presents a theoretical model to predict drug delivery from a device into a multilayer tissue, assuming linear reversible drug binding in the tissue layers. The governing mass conservation equations based on diffusion, advection and drug binding in a multilayer cylindrical geometry are written, and solved using Laplace transformation. The model is used to understand the impact of various non-dimensional parameters on the amounts of bound and unbound drug concentrations as functions of time. Good agreement for special cases considered in past work is demonstrated. The effect of forward and reverse binding reaction rates on the multilayer drug binding process is studied in detail. The effect of the nature of the external boundary condition on drug binding and drug loss is also studied. For typical parameter values, results indicate that only a small fraction of drug delivered binds in the tissue. Additionally, the amount of bound drug rises rapidly with time due to early dominance of the forward reaction, reaches a maxima and then decays due to the reverse reaction. The general model presented here can account for other possible effects such as drug absorption within the device. Besides generalizing past work on drug delivery modeling, this work also offers analytical tools to understand and optimize practical drug delivery devices.

Baicalein ameliorates lipid accumulation in HepG2 cells via the pregnane X receptor signaling pathway

The role of the pregnane X receptor (PXR) extended beyond regulating drug metabolism and transport, it also played a crucial part in lipid metabolism. Baicalein, a flavonoid derived from Scutellaria baicalensis, was demonstrated anti-inflammatory, anti-cancer, and anti-oxidative stress properties. Recent investigations reported its capacity to enhance lipid metabolism disorders. This study aimed to clarify the mechanism via which baicalein exerted its positive effects on lipid metabolism disorders by targeting PXR. The findings indicated that baicalein facilitated the nuclear translocation of PXR and controlled the expression of its target genes. In HepG2 cells with oleic acid and palmitic acid-induced lipid accumulation, baicalein treatment reduced the production of triglycerides, total cholesterol, and lipid droplets. In addition, it decreased the expression of sterol regulatory element-binding protein 1 (SREBP1), as well as lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1). The results of computer simulation indicated that baicalein was a natural ligand of PXR. In conclusion, baicalein might potentially alleviate lipid metabolism disorders by targeting the PXR pathway.

Chitosan Nanoparticles for Intranasal Drug Delivery.

This manuscript explores the use of nanostructured chitosan for intranasal drug delivery, targeting improved therapeutic outcomes in neurodegenerative diseases, psychiatric care, pain management, vaccination, and diabetes treatment. Chitosan nanoparticles are shown to enhance brain delivery, improve bioavailability, and minimize systemic side effects by facilitating drug transport across the blood-brain barrier. Despite substantial advancements in targeted delivery and vaccine efficacy, challenges remain in scalability, regulatory approval, and transitioning from preclinical studies to clinical applications. The future of chitosan-based nanomedicines hinges on advancing clinical trials, fostering interdisciplinary collaboration, and innovating in nanoparticle design to overcome these hurdles and realize their therapeutic potential.

Structural basis for antibiotic transport and inhibition in PepT2, the mammalian proton-coupled peptide transporter.

The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the mammalian proton-coupled peptide transporter, PepT2, in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of antibiotic recognition and the important role of protonation in drug binding and transport.

Efflux transporters in drug disposition during pregnancy.

Evidence-based dose selection of drugs in pregnant women has been lacking due to challenges in studying maternal-fetal pharmacokinetics. Hence, many drugs are administered off-label during pregnancy based on data obtained from non-pregnant women. During pregnancy, drug transporters play an important role in drug disposition along with known gestational age-dependent changes in physiology and drug-metabolizing enzymes. In this review, as Dr. Qingcheng Mao's former and current lab members, we summarize the collective contributions of Dr. Mao, who lost his life to cancer, focusing on the role of drug transporters in drug disposition during pregnancy. Dr. Mao and his team initiated their research by characterizing the structure of Breast Cancer Resistance Protein [BCRP, ATP-Binding Cassette (ABC) G2]. Subsequently, they have made significant contributions to the understanding of the role of BCRP and other transporters, particularly P-glycoprotein (P-gp/ABCB1), in the exposure of pregnant women and their fetuses to various drugs, including nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol, and their metabolites. This review also highlights the gestation- and pregnancy-dependent transporter expression at the blood-brain and blood-placenta barriers in mice. Significance Statement Dr. Qingcheng Mao and his team have made significant contributions to the investigation of the role of efflux transporters, especially P-glycoprotein and breast cancer resistance protein, in maternal-fetal exposure to many xenobiotics: nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol and their metabolites. Studies of individual compounds and the expression of transporters during gestation and pregnancy have improved the understanding of maternal-fetal pharmacokinetics.

Transporter Protein Expression of Corneal Epithelium in Rabbit and Porcine: Evaluation of Models for Ocular Drug Transport Study.

The transcorneal route is the main entry route for drugs to the intraocular parts, after topical administration. The outer surface, the corneal epithelium (CE), forms the rate-limiting barrier for drug permeability. Information about the role and protein expression of drug and amino acid transporter proteins in the CE is sparse and lacking. The aim of our study was to characterize transporter protein expression in rabbit and porcine CE to better understand potential drug and nutrient absorption after topical administration. Proteins, mainly Abc and Slc transporters, were characterized with quantitative targeted absolute proteomics and global untargeted proteomics methods. In the rabbit CE, 24 of 48 proteins were detected in the targeted approach, and 21 of these were quantified. In the porcine CE, 26 of 58 proteins were detected in the targeted approach, and 20 of these were quantified. Among these, 15 proteins were quantified in both animals: 4f2hc (Slc3a2), Aqp0, Asct1 (Slc1a4), Asct2 (Slc1a5), Glut1 (Slc2a1), Hmit (Slc2a13), Insr, Lat1 (Slc7a5), Mct1 (Slc16a1), Mct2 (Slc16a7), Mct4 (Slc16a3), Mrp 4 (Abcc4), Na+/K+-ATPase, Oatp3a1 (Slco3a1), and Snat2 (Slc38a2). Overall, the global proteomics results supported the targeted proteomics results. Organic anion transporting polypeptide Oatp3a1 was detected and quantified for the first time in both rabbit (1.4 ± 0.4 fmol/cm2) and porcine (11.1 ± 5.3 fmol/cm2) CE. High expression levels were observed for L-type amino acid transporter, Lat1, which was quantified with newly selected extracellular domain peptides in rabbit (48.9 ± 11.8 fmol/cm2) and porcine (37.6 ± 11.5 fmol/cm2) CE. The knowledge of transporter protein expression in ocular barriers is a key factor in the successful design of new ocular drugs, pharmacokinetic modeling, understanding ocular diseases, and the translation to human.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response

Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation invitro and invivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Characterization and efficacy of C60 nano-photosensitive drugs in colorectal cancer treatment

BackgroundFullerenes C60 shows great potential for drug transport. C60 generates large amounts of singlet oxygen upon photoexcitation, which has a significant inhibitory effect on tumor cells, so the photosensitive properties of C60 were exploited for photodynamic therapy of tumors by laser irradiation. MethodsIn this study, C60-NH2 was functionalized by introducing amino acids on the surface of C60, coupled with 5-FU to obtain C60 amino acid-derived drugs (C60AF, C60GF, C60LF), and activated photosensitive drugs (C60AFL, C60GFL, C60LFL) were obtained by laser irradiation. The C60 nano-photosensitive drugs were characterized in various ways, and the efficacy and safety of C60 nano-photosensitive drugs were verified by cellular experiments and animal experiments. Bioinformatics methods and cellular experiments were used to confirm the photosensitive drug targets and verify the therapeutic targets with C60AF. ResultsPhotosensitised tumor-targeted drug delivery effectively crosses cell membranes, leads to more apoptotic cell death, and provides higher anti-tumor efficacy and safety in vitro and in vivo colorectal cancer pharmacodynamic assays compared to free 5-FU.C60 photosensitized drug promotes tumor killing by inhibiting the colorectal cancer FLOR1 tumor protein target, with no significant toxic effects on normal organs. ConclusionC60 photosensitized drug delivery systems are expected to improve efficacy and reduce side effects in the future treatment of colorectal cancer. Further and better development and design of drugs and vectors for colorectal cancer therapy.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer.

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might encourage tumor progression. The reprogramming of lipid metabolism is pivotal in promoting tumorigenesis and cancer progression, with tumors often displaying significant changes in lipid profiles. This review concentrates on the essential factors that drive lipid metabolic reprogramming, which contributes to the advancement and drug resistance in melanoma. Moreover, we discuss recent advances and current therapeutic strategies that employ small-molecule inhibitors to target lipid metabolism in skin cancers, particularly those associated with inflammation and melanoma.