Systemic Toxicity Research Articles

Paclitaxel Prodrug Enables Glutathione Depletion to Boost Cancer Treatment.

Herein, we constructed a paclitaxel (PTX) prodrug (PA) by conjugating PTX with acrylic acid as a cysteine-depleting agent. The as-synthesized PA can assemble with diacylphosphatidylethanolamine-PEG2000 to form stable nanoparticles (PA NPs). After endocytosis into cells, PA NPs can specifically react with cysteine and trigger release of PTX for chemotherapy. On the other hand, the depletion of cysteine can greatly downregulate the intracellular content of glutathione and lead to oxidative stress outburst-provoking ferroptosis. The released PTX can elicit antitumor immune response by inducing immunogenic cell death, thus promoting dendritic cells maturation and cascaded cytotoxic T lymphocytes activation, which not only produces a robust immunotherapy effect but also synergizes the ferroptosis therapy by inhibiting cysteine transport via the release of interferon-γ in the activated immune system. As a result, PA NPs exhibit favorable in vitro and in vivo antitumor performance with reduced systemic toxicity. Our work highlights the potential of simple molecular design of prodrugs for enhancing the therapeutic efficacy toward malignant cancer.

A multifunctional self-reinforced injectable hydrogel for enhancing repair of infected bone defects by simultaneously targeting macrophages, bacteria, and bone marrow stromal cells

Injectable hydrogels (IHs) have demonstrated huge potential in promoting repair of infected bone defects (IBDs), but how to endow them with desired anti-bacterial, immunoregulatory, and osteo-inductive properties as well as avoid mechanical failure during their manipulation are challenging. In this regard, we developed a multifunctional AOHA-RA/Lap nanocomposite IH for IBDs repair, which was constructed mainly through two kinds of reversible cross-links: (i) the laponite (Lap) crystals mediated electrostatic interactions; (ii) the phenylboronic acid easter bonds between the 4-aminobenzeneboronic acid grafted oxidized hyaluronic acid (AOHA) and rosmarinic acid (RA). Due to the specific structural composition, the AOHA-RA/Lap IH demonstrated superior injectability, self-recoverability, spatial adaptation, and self-reinforced mechanical properties after being injected to the bone defect site. In addition, the RA molecules could be locally released from the hydrogel following a Weibull model for over 10 days. Systematic in vitro/vivo assays proved the strong anti-bacterial activity of the hydrogel against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Moreover, its capability of inducing M2 polarization of macrophages (Mφ) and osteogenic differentiation of bone marrow stromal cells (BMSCs) was verified either, and the mechanism of the former was identified to be related to the JAK1-STAT1 and PI3K-AKT signaling pathways and that of the latter was identified to be related to the calcium signaling pathway, extracellular matrix (ECM) receptor interaction and TGF-β signaling pathway. After being implanted to a S. aureus infected rat skull defect model, the AOHA-RA/Lap IH significantly accelerated repair of IBDs without causing significant systemic toxicity. Statement of significanceRosmarinic acid and laponite were utilized to develop an injectable hydrogel, promising for accelerating repair of infected bone defects in clinic. The gelation of the hydrogel was completely driven by two kinds of reversible cross-links, which endow the hydrogel superior spatial adaption, self-recoverability, and structural stability. The as-prepared hydrogel demonstrated superior anti-bacterial/anti-biofilm activity and could induce M2 polarization of macrophages and osteogenic differentiation of BMSCs. The mechanism behind macrophages polarization was identified to be related to the JAK1-STAT1 and PI3K-AKT signaling pathways. The mechanism behind osteogenic differentiation of BMSCs was identified to be related to the ECM receptor interaction and calcium signaling/TGF-β signaling pathways.

Utility of iron concentration two to four hours post ingestion in predicting toxicity

IntroductionIron products are widely available over the counter and have the potential to cause serious toxicity. Iron concentrations can be used to prognosticate and guide treatment during acute ingestions. Traditionally, a concentration of 350 μg/dL with symptoms, or 500 μg/dL without symptoms, is considered toxic and will likely need treatment to prevent decompensation. It is generally recommended that an iron concentration is obtained at least 4 h after exposure to provide adequate absorption time and avoid falsely low iron concentrations. Despite this, many iron overdoses have concentrations drawn immediately upon patient presentation. The utility of an iron concentration drawn before 4 h in assessing exposure risk is not clear. The purpose of this study is to determine if patients' symptoms and iron concentrations obtained between 2 and 4 h can predict the development of iron concentrations after 4 h. MethodsThis is a single-center, retrospective study of patient cases with a primary ingestion of oral iron reported to a Regional Poison Center from January 1, 2015 to January 1, 2020. The primary outcome is the incidence of an iron concentration of 350 μg/dL or greater at or beyond 4 h. Secondary outcomes include the incidence of antidotal deferoxamine administration, incidence of iron concentration > 500 μg/dL, incidence of positive findings on abdominal radiography, and time to highest reported iron concentration. ResultA total of 75 patients were included in this study. No patients who developed at most minor symptoms (abdominal discomfort, nausea, vomiting, or diarrhea without evidence of systemic toxicity) and had a 2-to-4-h concentration ≤ 300 μg/dL symptoms had a subsequent concentration > 350 μg/dL (negative predictive value [NPV] 100 %). Deferoxamine was used to treat five patients, all reached concentrations of >300 μg/dL 2–4-h post-ingestion. ConclusionPatients with only minor GI symptoms and an iron concentration of ≤300 μg/dL between 2 and 4-h post ingestion are unlikely to develop further toxicity. In this case series, a concentration of 300 μg/dL or less between 2 and 4 h was the ideal cutoff to predicting subsequent potentially toxic concentrations, with a sensitivity of 100 % and a specificity of 54 %.

MicroRNAs in Anticancer Drugs Hepatotoxicity: From Pathogenic Mechanism and Early Diagnosis to Therapeutic Targeting by Natural Products.

Patients receiving cancer therapies experience severe adverse effects, including hepatotoxicity, even at therapeutic doses. Consequently, monitoring patients on cancer therapy for hepatic functioning is necessary to avoid permanent liver damage. Several pathways of anticancer drug-induced hepatotoxicity involve microRNAs (miRNAs) via targeting mRNAs. These short and non-coding RNAs undergo rapid modulation in non-targeted organs due to cancer therapy insults. Recently, there has been an interest for miRNAs as useful and promising biomarkers for monitoring toxicity since they have conserved sequences across species and are cellular-specific, stable, released during injury, and simple to analyze. Herein, we tried to review the literature handling miRNAs as mediators and biomarkers of anticancer drug-induced hepatotoxicity. Natural products and phytochemicals are suggested as safe and effective candidates in treating cancer. There is also an attempt to combine anticancer drugs with natural compounds to enhance their efficiencies and reduce systemic toxicities. We also discussed natural products protecting against chemotherapy hepatotoxicity via modulating miRNAs, given that miRNAs have pathogenic and diagnostic roles in chemotherapy-induced hepatotoxicity and that many natural products can potentially regulate their expression. Future studies should integrate these findings into clinical trials by formulating suitable therapeutic dosages of natural products to target miRNAs involved in anticancer drug hepatotoxicity.

High-temperature emulsification coupled with low-temperature gelation for fabrication of agarose microsphere implants with well-controlled size for skin tissue enhancement.

Soft tissue deficiencies profoundly impact the daily lives, and mental well-being of patients. Microspheres facilitate collagen synthesis by establishing a conducive environment for fibroblast growth. Existing synthetic polymer microspheres are typically prepared through emulsification and cross-linking at normal temperatures. However, residues of cross-linking agents can adversely affect biocompatibility, thereby limiting their biomedical applications. Agarose has garnered significant attention owing to its biodegradability and excellent biocompatibility. We have for the first time developed high-temperature emulsification coupled with low-temperature gelation for fabrication of agarose microsphere implants with well-controlled size for skin tissue enhancement. The agarose microspheres exhibited favorable sphericity and dispersion, possessing a uniform particle size with an average diameter of 37.24 μm. Furthermore, the microspheres demonstrated commendable injectability and biodegradability. Additionally, the implants displayed remarkable biocompatibility, effectively promoting the proliferation of human foreskin fibroblast-1 (HFF-1) cells. The microspheres exhibited no systemic toxicity and induced no hemolytic or thermogenic reactions. In photoaged mice skin models, the agarose microspheres augmented dermal density, and enhanced skin elasticity. The microspheres showed the capacity to stimulate the regeneration of collagen fibers. The agarose microspheres offer a novel avenue for soft tissue filling and hold significance in the field of tissue engineering and skin regeneration.

Albumin-binding toll-like receptor 7 agonist nanocomplexes elicit antitumor immunity for cancer immunotherapy

Toll-like receptor agonists have been extensively applied as immunostimulatory adjuvants because of their well-defined pharmacological mechanisms, while systemic administration of Toll-like receptor agonists have shown limited efficacy due to their unfavorable pharmacokinetic properties. Here we constructed an albumin-binding Toll-like receptor 7 agonist (Ab1V209) by conjugating the Toll-like receptor 7 agonist 1V209 with truncated Evans Blue for binding to endogenous albumin. The resulting Ab1V209 has the ability to hijack albumin and is retained in tumor tissuesfor a higher accumulation than 1V209. As monotherapy, the systemic administration of Ab1V209 alters the function of tumor-associated macrophages towards anti-tumor phenotype, and increases the infiltration of CD8+ T cells, leading to controlled tumor growth with minimal systemic toxicity. When used in combination with an mRNA cancer vaccine, the combination therapy activated dendritic cells to provide antigen presentation molecule and co-stimulatory molecule, resulting in a strong T cell activation and expansion. This study presents a strategy for the rational engineering of albumin-binding adjuvants to enhance cancer immunotherapy.

Cisplatin-based Liposomal Nanocarriers for Drug Delivery in Lung Cancer Therapy: Recent Progress and Future Outlooks.

In order to improve the treatment of lung cancer, this paper looks at the development of cisplatinbased liposomal nanocarriers. It focuses on addressing the drawbacks of conventional cisplatin therapy, including systemic toxicity, inadequate tumor targeting, and drug resistance. Liposomes, or spherical lipid vesicles, offer a potentially effective way to encapsulate cisplatin, enhancing its transport and minimizing harmful effects on healthy tissues. The article discusses many liposomal cisplatin formulations, including pH-sensitive liposomes, sterically stabilized liposomes, and liposomes coupled with specific ligands like EGFR antibodies. These novel formulations show promise in reducing cisplatin resistance, optimizing pharmacokinetics, and boosting therapeutic results in the two in vitro and in vivo models. They also take advantage of the Enhanced Permeability and Retention (EPR) effect in the direction of improved tumor accumulation. The study highlights the need for more investigation to move these liposomal formulations from experimental to clinical settings, highlighting their potential to offer less harmful and more effective cancer therapy alternatives.

Development and characterization of formulations based on combinatorial potential of antivirals against genital herpes.

Herpes simplex virus type 2 (HSV-2) treatment faces challenges due to antiviral resistance and systemic side effects of oral therapies. Local delivery of antiviral agents, such as tenofovir (TDF) and zinc acetate dihydrate (ZAD), may offer improved efficacy and reduced systemic toxicity. This study's objective is to develop and evaluate local unit dose formulations of TDF and ZAD combination for local treatment of HSV-2 infection and exploring their individual and combinatory effects in vitro. The study involved the development of immediate-release film and pessary formulations containing TDF and ZAD. These formulations were characterized for physicochemical properties and in vitro drug release profiles. Cytotoxicity and antiviral activity assays were conducted to evaluate the individual and combinatory effects of TDF and ZAD. Film formulations released over 90% of the drugs within 1h, and pessary formulations within 90min, ensuring effective local drug delivery. ZAD showed moderate antiviral activity while TDF exhibited significant antiviral activity at non-cytotoxic concentrations. The combination of TDF and ZAD demonstrated synergistic effects in co-infection treatments, reducing the concentration required for 50% inhibition of HSV-2. Developed film and pessary formulations offer consistent and predictable local drug delivery, enhancing antiviral efficacy while minimizing systemic side effects. The combination of TDF and ZAD showed potential synergy against HSV-2, particularly in co-infection treatments. Further preclinical studies on pharmacokinetics, safety, and efficacy are necessary to advance these formulations toward clinical application.

A metal-organic nanoframework for efficient colorectal cancer immunotherapy by the cGAS-STING pathway activation and immune checkpoint blockade

Immunotherapy has shown marked progress in promoting systemic anti-colorectal cancer (CRC) clinical effects. For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS). In this nanoframework, CS endows CS/NPs with specific tumor-targeting activity and reduced systemic toxicity. Of note, the coordinated Zn2+ disrupts glycolytic processes and downregulates the expression of glucose transporter type 1 (GLUT1), thus depriving the cancer cells of their energy. Zn2+ further initiates the adenosine 5’-monophosphate activated protein kinase (AMPK) pathway, which leads to PD-L1 protein degradation and sensitizes CRC cells to immunotherapy. Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.Graphical

A Customizable Platform to Integrate CAR and Conditional Expression of Immunotherapeutics in T Cells.

The potential of chimeric antigen receptor (CAR)-based immunotherapy as a promising therapeutic approach is often hindered by the presence of highly immunosuppressive tumor microenvironments (TME). Combination therapies with either co-administration or built-in expression of additional TME-modulating therapeutic molecules to potentiate the functions of CAR-T cells can cause systemic toxicities due to the lack of control over the delivery of biologics. Here, we present a proof-of-concept engineered platform in human Jurkat T cells that combines CAR with a therapeutic gene circuit capable of sensing β-galactosidase (a reported cancer-associated signal) and subsequently activate the production of customized therapeutic gene products. We have demonstrated the integration of the chemically induced proximity (CIP) and associated signal sensing technologies with CAR in this study. A β-galactosidase-activatable prodrug was designed by conjugating a galactose moiety with a CIP inducer abscisic acid (ABA). We showed that Jurkat T cells engineered with CAR and the ABA-inducible genetic circuits can respond to recombinant β-galactosidase to drive the production and secretion of various immunotherapeutics including an anti-cancer agent, an immunomodulatory cytokine, and immune checkpoint inhibitors. Our design is highly modular and could be adapted to sense different cancer-related signals to locally produce antitumor therapeutics that can potentially boost CAR-T efficacy and persistence.

The antimicrobial peptide Microcin C7 inhibits the growth of Porphyromonas gingivalis and improves the perodontal status in a rat model.

This study aimed to investigate the antibacterial and anti-inflammatory effects of the antimicrobial peptide Microcin C7 for Porphyromonas gingivalis-associated diseases. Reverse-phase high-performance liquid chromatography revealed that Microcin C7 could remain 25.5% at 12 hours in saliva. At a concentration of <10mg mL-1, Microcin C7 showed better cytocompatibility, as revealed by hemolysis test and subchronic systemic toxicity test. Moreover, the minimum inhibitory concentration and minimum bactericidal concentration of Microcin C7 were analyzed using a broth microdilution method, bacterial growth curve, scanning electron microscopy, and confocal laser microscopy and determined to be 0.16mg mL-1 and 5mg mL-1, respectively. Finally, in a rat model, 5mg mL-1 Microcin C7 showed better performance in decreasing the expression of inflammatory factors (IL-1β, IL-6, IL-8, and TNF-α) and alveolar bone resorption than other concentrations. Microcin C7 demonstrated favorable biocompatibility, antibacterial activity, anti-inflammatory effect, and could decrease the alveolar bone resorption in a rat model, indicating the promising potential for clincal translation and application on P. gingivalis-associated diseases.

Exploring the therapeutic potential of lipid-based nanoparticles in the management of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a highly malignant and invasive tumor with significant mortality and morbidity. Current treatment modalities such as surgery, radiotherapy, and chemotherapy encounter significant limitations, such as poor targeting, systemic toxicity, and drug resistance. There is an urgent need for novel therapeutic strategies that offer targeted delivery, enhanced efficacy, and reduced side effects. The advent of lipid-based nanoparticles (LNPs) offers a promising tool for OSCC therapy, potentially overcoming the limitations of current therapeutic approaches. LNPs are composed of biodegradable and biocompatible lipids, which minimize the risk of toxicity and adverse effects. LNPs can encapsulate hydrophobic drugs, improving their solubility and stability in the biological environment, thereby enhancing their bioavailability. LNPs demonstrate significantly higher ability to encapsulate lipophilic drugs than other nanoparticle types. LNPs offer excellent storage stability, minimal drug leakage, and controlled drug release, making them highly effective nanoplatforms for the delivery of chemotherapeutic agents. Additionally, LNPs can be modified by complexing them with specific target ligands on their surface. This surface modification allows the active targeting of LNPs to the tumors in addition to the passive targeting mechanism. Furthermore, the PEGylation of LNPs improves their hydrophilicity and enhances their biological half-life by reducing clearance by the reticuloendothelial system. This review aims to discuss current treatment approaches and their limitations, as well as recent advancements in LNPs for better management of OSCC.

Polyphenol-Based Self-Assembled Nanomedicine for a Three-Pronged Approach to Reversing Tumor Immunosuppression.

The challenges of multi-pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid-responsive PD-L1 antibody (αPD-L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa-B (NF-κB) signaling pathway, to regulate pro-tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD-L1 and NF-κB blocking/ICD inducing three-pronged strategy, thereby effectively combating tumor growth and metastasis.

Lignocaine in Migraine Treatment: A Comprehensive Review

Introduction: Migraine is a prevalent and debilitating neurological disorder characterized by recurrent headaches and associated symptoms such as nausea, photophobia, and phonophobia. While conventional treatments exist, a significant subset of patients suffers from refractory migraines, prompting the exploration of alternative therapies like lignocaine. Purpose of the work: This review examines the mechanisms by which lignocaine modulatespain and underscores the potential of lignocaine as a therapeutic option for refractory migraines, while also highlighting the need for continued research to refine its clinical application. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: chronic migraine / lignocaine migraine / migraine treatment/ migraine pain mechanism / migraine chronic pain mechanism / lignocaine and ketamine migraine / lignocaine adverse effects / lignocaine safety / refractory migraine. Results: Lignocainehas shown promise in alleviating both acute and chronic migraine pain. However, its use requires careful patient selection and monitoring due to potential side effects, such as cardiac and central nervous system toxicity. Despite these risks, the favorable safety profile and efficacy of lignocaine make it a valuable option in migraine management. Future research should focus on optimizing dosing protocols, evaluating long-term outcomes, and identifying biomarkers to guide patient selection.

Hyaluronic acid-zein shell-core biopolymer nanoparticles enhance hepatocellular carcinoma therapy of celastrol via CD44-mediated cellular uptake

Low concentrations or limited residence times in tumor tissues, making celastrol (Cel) difficult to exert significant therapeutic effects. Thus, we developed Zein/hyaluronic acid core-shell nanoparticles (Cel/Zein@HA NPs) for active targeted delivery of Cel via CD44 receptor over-expression on cancer cells, which may strengthen the therapeutic efficacy of Cel and improve delivery targeting. Cel-loaded Zein nanoparticles (core), are elegantly enveloped by a hydrophilic HA coating that forms the shell, resulting in significantly improved encapsulation efficiency and ensured good stability. The cellular uptake of Cel/Zein@HA NPs in HepG2 cells was 1.57-fold higher than nontargeting Cel/Zein NPs. Near-infrared fluorescence imaging confirmed the accumulation of Cel/Zein@HA NPs in H22 liver cancer tumors in mice, resulting in effective antitumor effects and good biosafety. Besides, in vitro and in vivo experiments showed that compared with Cel/Zein NPs, Cel/Zein@HA NPs had more efficient inhibitory effect on tumor proliferation and lower systemic toxicity. Further studies revealed that Cel/Zein@HA NPs induced apoptosis in hepatocellular carcinoma cells by modulating Bax and Bcl-2 expression, while also inhibiting tumor angiogenesis by decreasing CD31 and VEGF levels. Overall, this study presents a promising strategy for enhancing targeted liver cancer therapy through the utilization of biopolymer nanoparticle-based nano-pharmaceuticals that facilitate CD44-mediated cellular uptake.

Ethosomes-mediated tryptanthrin delivery as efficient anti-psoriatic nanotherapy by enhancing topical drug absorption and lipid homeostasis

Psoriasis is a chronic, relapsing, and refractory immune-mediated skin disease with the etiology and pharmaceutical targets remaining unsatisfactorily addressed. Topical herbal-derived compounds, such as tryptanthrin (Tryp), have been considered as an alternative therapy for psoriasis due to their lower costs and fewer side effects compared to other therapies. However, the effectiveness of topically administered drugs is substantially limited by the thickened pathological skin barrier and the low bioavailability of drugs in the deeper layers of the lesion. Ethosomes, being a novel phospholipid-based vesicle system with high content of ethanol, have been implicated in enhancing topical drug absorption and restoring psoriatic lesions. In this study, taking advantages of ethosomes as a soft and malleable drug carrier, we constructed the Tryp-loaded ethosome (Tryp-ES) through a one-step microfluidics-based technique. The optimal formulation of Tryp-ES was achieved by adding amino-acid-derived surfactant sodium lauroyl glutamate, and Tryp-ES exhibited homogeneous particle size and favorable stability at room temperature. In vitro evaluations showed that Tryp of Tryp-ES could be easily internalized into cells and accumulated in cell nuclei, hence inhibited the abnormally proliferated keratinocytes by inducing apoptosis. In vivo and in vitro assessment using psoritic skin of mice revealed that Tryp-ES had preferred skin retention and permeation of loaded drugs within the initial 1 h of topical administration, which could be attributed to transient disintegrations of cell membranes by ethosomes, thus improved cellular fluidity and permeability. Notably, a synergistic effect of ethosomes and Tryp was found in psoriatic mice. Tryp-ES-treated mice showed substantially ameliorated symptoms of psoriasis and reduced pathological alterations due to hyperplasia, inflammation and angiogenesis, without detectable local or systemic toxicities. Interestingly, lipidomics analysis confirmed that the supplementation of phospholipids, as in the form of ethosome vehicles, was an alterantive strategy to relieve psoriatic pathologies. Taken together, this study provides a novel impact for ethosomal topical delivery of Tryp and underlines their potential as an effective therapy for the management of psoriasis.

Theranostic Approaches for Gastric Cancer: An Overview of In Vitro and In Vivo Investigations

Gastric cancer (GC) is the second most common cause of cancer-related death worldwide and a serious public health concern. This high death rate is mostly caused by late-stage diagnoses, which lead to poor treatment outcomes. Radiation immunotherapy and targeted therapies are becoming increasingly popular in GC treatment, in addition to surgery and systemic chemotherapy. In this review, we have focused on both in vitro and in vivo research, which presents a summary of recent developments in targeted therapies for gastric cancer. We explore targeted therapy approaches, including integrin receptors, HER2, Claudin 18, and glutathione-responsive systems. For instance, therapies targeting the integrin receptors such as the αvβ3 and αvβ5 integrins have shown promise in enhancing diagnostic precision and treatment efficacy. Furthermore, nanotechnology provides novel approaches to targeted drug delivery and imaging. These include glutathione-responsive nanoplatforms and cyclic RGD peptide-conjugated nanoparticles. These novel strategies seek to reduce systemic toxicity while increasing specificity and efficacy. To sum up, the review addresses the significance of personalized medicine and advancements in gastric cancer-targeted therapies. It explores potential methods for enhancing gastric cancer prognosis and treatment in the future.

Non-clinical evaluation of pmIL12 gene therapy for approval of the phase I clinical study

Immunotherapeutic drugs are promising medicines for cancer treatment. A potential candidate for immunotherapy is interleukin-12 (IL-12), a cytokine well known for its ability to mediate antitumor activity. We developed a plasmid encoding human IL-12 devoid of an antibiotic resistance gene (phIL12). For the approval of phase I clinical trials in basal cell carcinoma (BCC), the regulatory agency requires non-clinical in vivo testing of the pharmacodynamic, pharmacokinetic and toxicological properties of the plasmid. As human IL-12 is not biologically active in mice, a mouse ortholog of the plasmid phIL12 (pmIL12) was evaluated. The evaluation demonstrated the antitumor effectiveness of the protein accompanied by immune cell infiltration. The plasmid was distributed throughout the body, and the amount of plasmid diminished over time in all organs except the skin around the tumor. The therapy did not cause any detectable systemic toxicity. The results of the non-clinical evaluation demonstrated the safety and efficacy of the pmIL12/phIL12 GET, and on the basis of these results, approval was obtained for the initiation of a phase I clinical study in BCC.

A pH-modulated polymeric drug-release system simultaneously combats biofilms and planktonic bacteria to eliminate bacterial biofilm

Bacterial infection, leading to biofilm formation, raises grave concerns. With the aim of eliminating both integrity of biofilms and individual bacterial cells, it is desirable to develop bacterial biofilm-eliminating material to be combined with dispersal and anti-microbial agents. Herein, a biofilm-eliminating enzyme (α amylase) was incorporated in novel pH-sensitive polymer hydrogel, Poly (methacrylic acid-co-2-(dimethylamino)ethyl methacrylate), which encapsulates drug-loaded porous Zeolitic Imidazolate Framework-8 (ZIF-8). At body temperature (37 °C) the maximum swelling of the hydrogel was observed at pH 8.5, which assisted in rupturing biofilm by releasing α amylase. Amylase, encapsulated in polymer matrix reached 90% release after 6 days at 8.5, while CIP was released 96% on day 23 at pH 8.5. The antibiofilm activity of drug-releasing system was assessed against E. coli and S. aureus. The overall bacterial viability of biofilms showed significant time-dependent declines, when exposed to drug-loaded hydrogel. Importantly, cytotoxicity experiments showed excellent biocompatibility of hydrogel. In the in vivo deep wound infection model, drug-loaded hydrogel treatment showed complete wound closure with proper tissue regeneration. No inflammatory, or systemic toxicity of hydrogel was observed. The drug release from hydrogel is initiated only upon receiving physiological cue arising due to biofilm formation. Therefore, this hydrogel serves as reservoir for antibacterial drug, which release it only in presence of biofilm and thus work for sustained release for long period, compared to conventional drug loaded films or coatings. A powerful modality for management of biofilm-associated infections can be provided by the proposed synergistic strategy for complete elimination of biofilms.

Novel Carbohydrate Polymer-Based Systems for Precise Drug Delivery in Colon Cancer: Improving Treatment Effectiveness With Intelligent Biodegradable Materials.

Due to their biocompatibility, biodegradability, and controlled release, carbohydrates polymers are crucial to targeted drug delivery systems, notably for colon cancer treatment. This article examines how carbohydrate polymers like chitosan, pectin, guar gum, alginate, hyaluronic acid, dextran, and chondroitin sulfate are used in improved drug delivery. Modifying these polymers improves drug loading, stability, and release patterns, enhancing chemotherapeutic drugs' therapeutic index. Chitosan nanoparticles are pH-responsive, making them perfect for cancer treatment. Pectin's resistance to gastric enzymes and colonic bacteria makes it a promising colon-specific medication delivery agent. The combination of these polymers with nanotechnology, 3D printing, and AI allows the creation of stimuli-responsive systems that release drugs precisely in response to environmental signals like pH, redox potential, or colon enzymatic activity. The review highlights intelligent delivery system design advances that reduce systemic toxicity, improve treatment efficacy, and improve patient adherence. Carbohydrate polymers will revolutionize colon cancer treatment with personalized and accurate alternatives.