Anticancer Research Articles

In Vitro Apoptotic and Antiproliferative Activity of Hypericum Perforatum Extract on Human Osteosarcoma Cell Line.

Hypericum perforatum (HP) has been widely used as an alternative medicine due to its active pharmacological properties. While the antiproliferative effects of components such as hypericin and hyperforin have been demonstrated in malignant cell lines, most studies have focused on the pharmacological properties of the HP extract itself. Recent research has indicated that HP and its active substances possess anticancer activities; however, there is a lack of studies examining its effects on osteosarcoma. In addition, HP has demonstrated the ability to mitigate the toxicity of several drugs, including chemotherapeutic agents. Hence, the primary objective of this study was to explore the potential anticancer properties of HP in relation to osteosarcoma cells. MG-63 human osteosarcoma cells were cultured and treated with HP extract. Apoptotic factors were analyzed using ELISA, while cell viability was assessed using the MTT test. The results revealed a significant increase in the activities of proapoptotic proteins GRP78, Wee1, apoptosis-inducing factor (AIF), GADD153, Bax, and cleaved caspase-3 in MG-63 osteosarcoma cells after 48 hours of treatment with HP at a concentration of 0.8%. Conversely, the activity of Bcl-2, an antiapoptotic protein, significantly decreased. Moreover, HP extract demonstrated a dose-dependent reduction in cell viability in MG-63 cells. In conclusion, HP extract induces apoptosis in MG-63 osteosarcoma cells by upregulating the expressions of proapoptotic proteins GRP78, Wee1, AIF, GADD153, Bax, and cleaved caspase-3. This study will assist researchers in understanding the importance of alternative treatments using HP in the context of human osteosarcoma therapy, which many researchers are currently unaware of.

Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism

AbstractDysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and expression of indoleamine 2,3‐dioxygenase 1 (IDO1), a rate‐limiting enzyme in tryptophan metabolism. Lacidipine activates effector T cells and incapacitates regulatory T cells (Tregs) to augment the anti‐tumor effect of chemotherapeutic agents in breast cancer by converting immunologically “cold” into “hot” tumors. Mechanistically, lacidipine targets calcium channels (CaV1.2/1.3) to inhibit Pyk2‐JAK1‐calmodulin complex‐mediated IDO1 transcription suppression, which suppresses the kynurenine pathway and maintains the total nicotinamide adenine dinucleotide (NAD) pool by regulating NAD biosynthesis. These results reveal a new function of calcium channels in IDO1‐mediated tryptophan metabolism in tumor immunity and warrant further development of lacidipine for the metabolic immunotherapy in breast cancer.

Doxorubicin-loaded core@shell cobalt ferrite-barium titanate magnetoelectric nanofibers for improved anticancer activity.

Conventional drug delivery systems often suffer from non-specific distribution and limited therapeutic efficacy, leading to significant side effects. To address these challenges, we developed magnetoelectric, cobalt ferrite@barium titanate (CFO@BTO) nanofibers, with a core-shell structure for targeted anticancer drug delivery. The electrospinning method was employed to synthesize polymeric nanofibers based on magnetoelectric core-shell nanostructures. The Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), X-ray diffraction (XRD) and Vibrating sample magnetometer (VSM) analysis confirmed the successful loading of nanostructures on polymeric nanofiber, the core-shell morphology and magnetoelectric phase of cobalt ferrite@barium titanate CFO@BTO, respectively. To verify the drug attachment, the optimization of drug release in an applied external magnetic field, and the time required for control drug release, UV-Vis spectroscopy was used. The effectiveness of magnetic field-assisted controlled drug release was demonstrated by achieving a 95 ± 1.03% drug release from magnetoelectric nanofibers (MENFs) within 30 minutes under a magnetic field of 4mT. In vitro cytotoxicity assay on human skin cancer (SK-MEL-28) cell lines exhibited a maximum 90 ± 2% cytotoxicity with 2±0.03 cm of drug loaded MENFs. Furthermore, the Hemolysis assay was carried out to affirm the biocompatibility and non-toxicity of drug loaded MENFs, which is suitable for anticancer therapy.

Molecular Docking: Study of Chalcone Derivatives from Boesenbergia pandurata Targeting Estrogen Receptor Alpha (ER–a) for Breast Cancer

The increasing number of cancer patients and the challenge of multidrug resistance (MDR) demand more effective drugs, which can be developed by modifying compounds derived from natural resources, such as the flavonoid-rich temu kunci rhizome (Boesenbergia pandurata (Roxb.) Schlecht.). This study aims to predict the cytotoxicity and toxicity of 20 Pinostrobin derivatives and 19 Chalcone derivatives as potential anticancer candidates. Estrogen receptor alpha (ER-α), a validated cancer therapy target, was used for molecular docking in in silico tests using Molecular Graphics Laboratory (MGL) Tools (including, AutoDock Vina, AutoDock Tools 4.1, and Python 2.5.2) and PyRx Program. Toxicity was predicted using the pkCSM program and Protox online tool. The docking process involved binding the compounds to ER-α (PDB IDs 6CHZ and 3ERT), with the binding energy indicating activity; lower binding energy values suggest greater cytotoxic potential and stronger ligand-receptor interactions. The results showed that Chalcone derivatives from temu kunci exhibited lower toxicity and higher cytotoxic activity compared to Pinostrobin derivatives and the reference compound, Tamoxifen (TAM). Notably, Bis-3-chlorobenzyloxychalcone and Bis-2-chlorobenzyloxychalcone demonstrated the highest predicted cytotoxic activity. In conclusion, Chalcone derivatives are promising candidates for further development as more effective anticancer drugs, especially those that outperform Tamoxifen. These findings highlight the potential of natural compounds, particularly Chalcone derivatives, in combating cancer while addressing the growing challenge of MDR in clinical treatments.

Clinical efficacy observation of heat-sensitive moxibustion combined with intrapleural perfusion of cisplatin in treatment of malignant pleural effusion

To investigate the clinical efficacy of heat-sensitive moxibustion combined with intrapleural perfusion of cisplatin in comparison with simple intrapleural perfusion of cisplatin on malignant pleural effusion (MPE). Forty patients with MPE, in compliance with the inclusion criteria, were randomly divided into an observation group (20 cases) and a control group (20 cases). In the control group, cisplatin solution (60 mg/m2) was injected into the thoracic cavity after pleural drainage under B-ultrasound positioning, once a week for 4 weeks. In the observation group, based on the intervention as the control group, the heat-sensitive moxibustion was delivered at the back and lumbar region (where Feishu ［BL13］, Pishu ［BL20］ and Shenshu ［BL23］ are located) and the chest-abdomen region (where Danzhong ［CV17］, Guanyuan ［CV4］ and Shuidao ［ST28］ are located), for 30 min to 90 min, once daily (the treatment was discontinued on Saturday and Sunday) and for 4 weeks. Before and after treatment, in the two groups, the pleural effusion volume was detected using B ultrasound, the activity of daily living was evaluated with Karnofsky performance statue (KPS) scale and TCM symptoms with TCM syndrome grading scale. The clinical therapeutic effect was evaluated in the two groups. According to the classification criteria table for acute and subacute toxicity of anticancer drugs made by WHO, the toxic and side reaction was judged. After treatment, the pleural effusion volume was reduced in comparison with that before treatment in the two groups (P<0.01, P<0.001), and the volume in the observation group was lower than that of the control group (P<0.05). KPS score was increased in the two groups after treatment compared with that before treatment (P<0.001), and the score in the observation group was higher than that of the control group (P<0.05). After treatment, the total score of TCM syndromes and the scores for dyspnea, cough and chest pain were lower than those before treatment in the two groups (P<0.001), and the scores in the observation group were lower than those of the control group (P<0.001, P<0.05). The scores for anorexia and lassitude were reduced in comparison with those before treatment in the observation group (P<0.001)；and the scores in the observation group were lower than those in the control group after treatment (P<0.001, P<0.01). After treatment, the effective rate of the observation group was 65.0%(13/20), which was higher than that of the control group (30.0%, 6/20, P<0.05). The incidence of bone marrow suppression in the observation group was 15.0%(3/20), lower than that in the control group (55.0%, 11/20, P<0.05). The incidence of gastrointestinal reactions in the observation group was 30.0%, lower than that in the control group (65.0%, 13/20, P<0.05). Heat-sensitive moxibustion combined with intrapleural infusion of cisplatin is superior to intrapleural infusion of cisplatin in the aspects of the amelioration of pleural effusion, daily-living activity and TCM syndromes in patients with MPE. This combined therapy presents the synergism by cooperating with chemotherapeutics and reduces the incidence of toxic and side effects implicated in chemotherapy so as to attenuate the toxicity of chemotherapeutics.

Breast Cancer Treatment: The Potential of Organic and Inorganic Nanocarriers in Targeted Drug Delivery

Breast cancer (BC) is the most prevalent form of malignancy among women on a global scale, ranking alongside lung cancer. Presently, conventional approaches to cancer treatment include surgical procedures followed by chemotherapy or radiotherapy. Nonetheless, the efficacy of these treatments in battling BC is often compromised due to the adverse effects they inflict on healthy tissues and organs. In recent times, a range of nanoparticles (NPs) has emerged, exhibiting the potential to specifically target malignant cells while sparing normal cells and organs from harm. This has paved the way for the development of nanoparticle-mediated targeted drug delivery systems, holding great promise as a technique for addressing BC. To increase the efficacy of this new method, several nanocarriers including inorganic NPs (such as magnetic NPs, silica NPs, etc.) and organic NPs (e.g., dendrimers, liposomes, micelles, and polymeric NPs) have been used. Herein, we discuss the mechanism of NP-targeted drug delivery and the recent advancement of therapeutic strategies of organic and inorganic nanocarriers for anticancer drug delivery in BC. We also discuss the future prospects and challenges of nanoparticle-based therapies for BC.

Synthesis, characterization, antioxidant activity, docking and simulation of potential anticancer agents of azo dye for pyridyl and its palladium(II) complex

Synthesis, characterization, antioxidant activity, docking and simulation of potential anticancer agents of azo dye for pyridyl and its palladium(II) complex

Overview of lysosome-mediated chemoresistance mechanisms in breast cancer: A mini review

It is widely acknowledged that chemoresistance is one of the major consequences that leads to chemotherapeutic treatment failure and cancer-related death. In recent studies, lots of attempts have been made to clarify the mechanisms that cancer cells utilize and/or modify to become resistant to chemotherapeutic drugs. Among these, lysosomes, also called ‘‘drug-safe house’’, have emerged as one of the crucial drivers of chemoresistance through trapping passively the chemotherapeutics, thereby preventing them from reaching their intracellular targets. Notably, lysosomes take part in regulating cellular metabolism, tumor growth and metastasis. Besides, lysosomes are a platform for inter- and intracellular communication among cellular organelles and/or cell surfaces and/or between tumor cells and extracellular microenvironment. In breast cancer (BCa), the mechanisms underlying chemotherapeutic resistance are perplexing and have not been fully understood. Therefore, in this review, we briefly highlight some aspects that describe lysosome-mediated regulation of chemoresistance in BCa.

Importance of the CuAAC Reaction in the Synthesis of Platinum Complexes with 1,4-Disubstituted-1H-1,2,3-triazoles: A Review of Their Anticancer Activity

Despite multiple advances in treatment and prevention, cancer remains one of the leading causes of death worldwide. Chemotherapy remains the most effective method for cancer treatment. However, commercial chemotherapeutic drugs have limited efficacy, severe side effects, and acquired resistance. Therefore, the scientific community has devoted a great effort to designing new, more effective, and cheaper drugs. In this sense, copper-catalyzed azide-alkyne cycloaddition reactions (CuAAC) provide 1,4-disubstituted 1H-1,2,3-triazoles in high yields without forming by-products. This reaction allows the easy, efficient, functional, ordered, rapid, selective, and specific joining of small molecules, giving rise to more complex molecules. The CuACC reaction simplifies the synthesis processes, accelerating the discovery of new chemotherapeutic agents by allowing the joining of commercial platinum drugs, slightly altering their structure, or creating new molecules with improved properties. This work shows the importance of CuAAC reactions in the search for new metallodrugs with possible anticancer activity.

Cisplatin caused highly delayed cytotoxicity in the immortalized cells derived from S3 segment of mouse kidney proximal tubules

Anti-cancer drug cisplatin (CDDP) causes severe acute kidney injury (AKI). CDDP-induced AKI does not occur immediately after administration, but rather 6 to 10 days after administration. However, the mechanism underling the delayed renal injury by CDDP is not well understood. In a previous investigation using immortalized cells derived from the S1, S2, and S3 segments of the proximal tubules, we found that S3 cells were more sensitive to CDDP than S1 and S2 cells. In this study, we examined whether S1, S2, and S3 cells would be useful in elucidating the mechanism of CDDP-induced delayed renal injury and whether the high sensitivity of S3 cells contributes to CDDP-induced delayed renal injury. Measurement of platinum (Pt) content by ICP-MS showed that Pt accumulation peaked at 15 min after CDDP exposure in each cell type. Even when the medium was replaced with CDDP-free medium after the 15-min CDDP exposure and the cells were further incubated, delayed cytotoxicity was still observed. The S3 cells exhibited greater sensitivity to CCDP than the S1 and S2 cells at all time points after the medium change. To investigate the mechanism of the CDDP-induced delayed cytotoxicity, we examined the cell cycle distribution of cells after CDDP exposure. The results showed that CDDP-induced perturbation of cell cycle was greater in S3 than in S1 and S2 cells. These results suggest that perturbation of the cell cycle in S3 cells due to enhanced CDDP–DNA adduct formation contributes to the high susceptibility of S3 cells to CDDP-induced delayed cytotoxicity.

Synthesis of novel estradiol bisselenocyanate with unique 2-selenocyano-17-selenocyanoesteryl structure and evaluation of antitumor activity.

Cancer is one of the most significant diseases that afflict human beings. The pursuit of high efficacy and low-toxicity anticancer drugs has always been a paramount research objective for scientists. In the present study, we incorporated two selenocyano pharmacophores into the 2-site and 17-branch chain of the steroid nucleus in various manners, utilizing estradiol as the fundamental framework. Consequently, several estradiol bisselenocyanate compounds with a 2-selenocyano-17-selenocyanoester structure were synthesized. When compared to the positive control steroidal anti-tumor drug 2-methoxyestradiol, certain derivatives exhibited superior inhibitory activity against tumor cells in vitro, surpassing their monoselenocyanate precursors. The representative compound 4b induced programmed apoptosis in HeLa cells in a concentration-dependent manner during apoptosis and cell cycle experiments, while causing G2 phase arrest predominantly in the cell cycle. Moreover, compound 4b exhibited significant inhibitory effects on cell migration and demonstrated remarkable inhibitory activity against HeLa xenograft tumors in zebrafish models. These findings suggest that these compounds hold potential as promising candidates for anti-tumor drugs and warrant further investigation.

Curcuma Longa Phytocompounds: An in Silico Analysis Aimed at Targeting the EGFR Protein as a Potential Anti-cancer Agent

&gt;Background: Curcumin, a well-known phytocompound in turmeric, has demonstrated anti-cancer properties. However, its therapeutic efficacy is often limited. Additionally, Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in various cancers, making it a promising target for novel drug development. This study aims to utilise in silico analysis to identify potential anti-cancer agents within the phytocompounds of Curcuma longa (turmeric) that target the EGFR protein. The objective of this research is to investigate the binding interactions between curcumin and other Curcuma longa phytocompounds with the EGFR protein through computational modelling. Methods: Curcumin and paclitaxel (standard drug) were chosen as ligands and retrieved from PubChem. The researchers obtained the 3D structure of the EGFR protein from the Protein Data Bank (PDB) and prepared it for docking simulations. To assess curcumin’s drug-likeness and potential safety profile, online tools were utilised: SWISSADME analysed its ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, and ProTox-II evaluated its predicted toxicity. Finally, molecular docking simulations using Pyrx software were performed to predict how curcumin interacts with the EGFR protein. This computational approach helps predict how well a small molecule (ligand) like curcumin binds to a larger molecule (protein) like the EGFR receptor. Results: In silico analysis predicted favourable drug-like properties and a potentially safer profile for curcumin compared to paclitaxel. Curcumin exhibited high gastrointestinal absorption, adhered to Lipinski’s rule, and lacked predicted hepatotoxicity or carcinogenicity. The molecular docking binding energy for curcumin was –5.64 as compared to –3.85 for paclitaxel. Conclusion: This in silico investigation identified the potential for curcumin to target the EGFR protein, a promising strategy for cancer treatment. Curcumin displayed favourable drug-like properties and a potentially safer profile compared to the reference drug paclitaxel. However, in-vitro and in-vivo experiments are crucial to validate these findings and assess curcumin’s efficacy as a potential anti-cancer agent.

New pyrano-pyridine conjugates as potential anticancer agents: design, synthesis and computational studies.

New pyrano[3,2-c]pyridine 4a-h, 5-8 and pyrano[2,3-d]pyrimidin 9a,b series were designed and chemically synthesized. Using the standard drug doxorubicin, the novel chemical entities have been assessed in vitro as potential anticancer prospects on cell lines from liver, breast, colon, and lung cancer along with examining their inhibitory behaviors upon both EGFR and VEGFR-2 kinases. Compared to erlotinib (IC50 = 0.18 µM), compounds 8a and 8b demonstrated the highest anticancer activity with IC50 Values 0.23 and 0.15 µM, respectively). Further, derivative 8a illustrated encouraging inhibitory characteristics against EGFR and VEGFR-2 (IC50 = 1.21 and 2.65 μM, respectively). A computational study was used to estimate the physicochemical and pharmacokinetic properties to afford insightful information about the newly synthesized agents.

Harnessing the Engineered Probiotic-Nanosystem to Remodulate Tumor Extracellular Matrix and Regulate Tumor-Colonizing Bacteria for Improving Pancreatic Cancer Chemo-Immunotherapy.

Poor chemotherapy efficacy in pancreatic cancer is attributed to limited drug permeation caused by the dense extracellular matrix (ECM) and drug degradation induced by tumor-colonizing bacteria. Here, a tumor-targeting probiotic-nanosystem is elaborately designed to remodulate ECM and selectively regulate tumor-colonizing bacteria for improving chemo-immunotherapy against pancreatic cancer. Specifically, drug-loaded liposomes are conjugated with Clostridium Butyricum (CB) via matrix metalloproteinase-2 (MMP-2)-responsive peptide to construct a probiotic-nanosystem. Particularly, vactosertib (VAC, a transforming growth factor-β1 receptor inhibitor) is delivered by probiotic-nanosystem to silence the active pancreatic stellate cells (PSCs) for inhibiting the development of ECM, resulting in a loosened ECM and providing a golden opportunity for the deep penetration of chemotherapy drugs and immune cells. Subsequently, gemcitabine (GEM) is efficiently delivered into the core of tumors via probiotic-nanosystem, achieving an enhanced chemotherapy efficacy. Noteworthily, CB can alleviate γ-proteobacteria-mediated GEM degradation through competitively reducing the contents of γ-proteobacteria and promoting the amounts of tumor-inhibiting bacteria, thereby significantly potentiating the therapeutic effect of GEM. The engineered probiotic-nanosystem can not only enhance the GEM-induced immunogenic cell death (ICD) of a pancreatic tumor to activate antitumor immune responses but also markedly increase the tumor-infiltration of effector immune cells to heighten tumoricidal immunity, offering a promising strategy for chemo-immunotherapy of pancreatic cancer.

Identification of a novel prognostic signature for breast cancer derived from post-translational ubiquitin and ubiquitin-like modification-related genes.

Ubiquitin and ubiquitin-like (UUL) modifications play pleiotropic functions and are subject to fine regulatory mechanisms frequently altered in cancer. However, the comprehensive impact of UUL modification on breast cancer remains unclear. Transcriptomic and clinical data of breast cancer were downloaded from TCGA and GEO databases. Molecular subtyping of breast cancer was conducted using the NMF and CIBERSORT algorithms. Prognostic genes were identified via univariate, lasso and multivariate Cox regression analyses. Clinical pathological features, immune cell infiltration, immune therapeutic response and chemotherapy drug sensitivity were compared between groups using the Wilcoxon test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. A total of 63 UUL modification-related genes were differentially expressed, with 29 up-regulated and 34 down-regulated genes. These genes were used to generate two UUL modification patterns that exhibited significant differences in prognostic features and immune cell infiltration. The UUL modification patterns were associated with 2038 differentially expressed genes that were significantly enriched in nuclear division, chromosome segregation, neuroactive ligand-receptor interaction, cell cycle, and other biological processes. Of these genes, 425 were associated with breast cancer prognosis, which enabled the classification of breast cancer into two clusters with significantly distinct prognoses. We developed a prognostic model, UULscore, which comprised nine genes and showed a significant correlation with partial immune cell infiltration. Furthermore, UULscore demonstrated potential predictive value in breast cancer overall survival prediction, immune therapeutic response, and chemotherapy drug sensitivity. UULscore, stage, radiotherapy, and chemotherapy were identified as independent prognostic factors for breast cancer. Based on these factors, a nomogram model was constructed, which demonstrated exceptional prognostic predictive performance. The present study identified two UUL modification-derived molecular subtypes in breast cancer, and have successfully constructed a risk-scoring model that holds potential value in prognosis, immune infiltration, immune therapeutic response, and chemotherapy sensitivity.

Engineered cell membrane-cloaked metal-organic framework nanocrystals for intracellular cargo delivery

This investigation demonstrates the development and functionality of cell membrane-cloaked UiO-67 nanosized metal–organic frameworks (NMOFs), which are engineered for precise intracellular delivery of encapsulated cargoes. Utilizing the robust and porous nature of UiO-67, we enveloped these NMOFs with fusogenic cell membrane-derived nanovesicles (FCSMs) sourced from adenocarcinomic human alveolar basal epithelial (A549) cells. This biomimetic coating enhances biocompatibility and leverages the homotypic targeting capabilities of the cell-derived coatings, facilitating direct cytoplasmic delivery and avoiding endolysosomal entrapment. Our nanoplatform exhibited high efficiency in loading and releasing two model cargoes: cresyl violet (CV), a staining agent, and carboplatin (CbPt), a chemotherapeutic agent. This approach demonstrated substantial potential in drug delivery in both 2D cell cultures and 3D spheroids. This study underscores the enhanced cellular uptake facilitated by the engineered biomimetic shell and highlights the system’s capacity for sustained release, offering a promising strategy for targeted drug delivery.

Protective Effects of L-Cysteine Against Cisplatin-Induced Oxidative Stress-Mediated Reproductive Damage

Cisplatin (CIS) is a widely used chemotherapeutic agent, but its side effects, such as oxidative stress, inflammation, and apoptosis, often lead to male reproductive damage. Oxidative stress, primarily caused by the excessive generation of reactive oxygen species (ROS), plays a critical role in disrupting testicular homeostasis, resulting in spermatogenic impairment and tissue injury. L-cysteine (CYS), a semi-essential amino acid with potent antioxidant and anti-inflammatory properties, may offer protection against CIS-induced oxidative damage. This study aimed to assess the protective potential of CYS against CIS-induced male reproductive toxicity using in vivo and in vitro models. In vitro, treatment of TM3 (Leydig) and TM4 (Sertoli) cells with CIS led to increased ROS levels, reduced cell viability, and elevated apoptosis and inflammation, all of which were significantly ameliorated by subsequent CYS exposure. In vivo, CIS-treated male rats displayed heightened oxidative stress, impaired spermatogenesis, and histopathological damage in reproductive organs. However, CYS administration for 21 days significantly reduced oxidative stress, improved sperm viability, and protected testicular tissues from damage. These findings suggest that CYS has a protective effect against CIS-induced oxidative stress and male reproductive damage, making it a promising therapeutic agent for mitigating CIS-induced reproductive toxicity.

Using Poly(amidoamine) PAMAM-βCD Dendrimer for Controlled and Prolonged Delivery of Doxorubicin as Alternative System for Cancer Treatment

Background/Objectives: Doxorubicin (Dox) is an anticancer drug used in the treatment of a wide range of solid tumors; however, Dox causes systemic toxicity and irreversible cardiotoxicity. The design of a new nanosystem that allows for the control of Dox loading and delivery results is a powerful tool to control Dox release only in cancer cells. For this reason, supramolecular self-assembly was performed between a poly(amidoamine) (PAMAM) dendrimer decorated with four β-cyclodextrin (βCD) units (PAMAM-βCD) and an adamantane–hydrazone–doxorubicin (Ad-h-Dox) prodrug. Methods: The formation of inclusion complexes (ICs) between the prodrug and all the βCD cavities present on the surface of the PAMAM-βCD dendrimer was followed by 1H-NMR titration and corroborated by 2D NOESY experiments. A full characterization of the supramolecular assembly was performed in the solid state by thermal analysis (DSC/TGA) and scanning electron microscopy (SEM) and in solution by the DOSY NMR technique in D2O. Furthermore, the Dox release profiles from the PAMAM-βCD/Ad-h-Dox assembly at different pH values was studied by comparing the efficiency against a native βCD/Ad-h-Dox IC. Additionally, in vitro cytotoxic activity assays were performed for the nanocarrier alone and the two supramolecular assemblies in different carcinogenic cell lines. Results: The PAMAM-βCD/Ad-h-Dox assembly was adequately characterized, and the cytotoxic activity results demonstrate that the nanocarrier alone and its hydrolysis product are innocuous compared to the PAMAM-βCD/Ad-h-Dox nanocarrier that showed cytotoxicity equivalent to free Dox in the tested cancer cell lines. The in vitro drug release assays for the PAMAM-βCD/Ad-h-Dox system showed an acidic pH-dependent behavior and a prolonged profile of up to more than 72 h. Conclusions: The design of PAMAM-βCD/Ad-h-Dox consists of a new controlled and prolonged Dox release system for potential use in cancer treatment.

Fluorous-tagged bortezomib supramolecular nanomedicine for cancer therapy

Lipidation is a well-established post-translational modification strategy to modulate the structure and function of proteins and peptides. Lipids can improve the overall or local hydrophobicity of the biomolecule, boosting its affinity with the cell membranes. Lipidation, despite its great potential, remains an underutilized technique for translating bioactive molecules into the clinic. Herein, we have optimized the lipidation strategy by involving the fluorous lipidation combined with supramolecular engineering, which can be facilely achieved by grafting an anticancer peptide drug (bortezomib, BTZ) with a series of fluorous lipids bearing a catechol moiety via the dynamic catechol-boronate ester bond. Compared with BTZ, the fluorous-tagged BTZ nanomedicine exhibited an on-demand and traceless release behavior, and enhanced therapeutic effect and biocompatibility. More importantly, the fluorous tag could improve the serum stability of the supramolecular nanomedicine, which allowed efficient in vivo utilization of BTZ to kill cancer cells. This work introduces a novel lipidation strategy for bioactive peptides via the integration of fluorination chemistry and supramolecular engineering strategies.

MTOR inhibitors as potential therapeutics for endometriosis: A narrative review.

Mammalian target of rapamycin (mTOR) inhibitors have been used clinically as anticancer and immunosuppressive agents for over 20 years, demonstrating their safety after long-term administration. These inhibitors exhibit various effects, including inhibition of cell proliferation, interaction with the oestrogen and progesterone pathways, immunosuppression, regulation of angiogenesis, and control of autophagy. We evaluated the potential of mTOR inhibitors as therapeutic agents for endometriosis, examined the secondary benefits related to reproductive function, and assessed how their side effects can be managed. We conducted a thorough review of publications on the role of the mTOR pathway and the effectiveness of mTOR inhibitors in endometriosis patients. These results indicate that the mTOR pathway is activated in endometriosis. Additionally, mTOR inhibitors have shown efficacy as monotherapies for endometriosis. They may alleviate resistance to hormonal therapy in endometriosis, suggesting a potential synergistic effect when used in combination with hormonal therapy. The potential reproductive benefits of mTOR inhibitors include decreased miscarriage rates, improved implantation, and prevention of age-related follicular loss and ovarian hyperstimulation syndrome. Activation of the mTOR pathway has also been implicated in the malignant transformation of endometriosis. Preclinical studies suggest that the dosage of mTOR inhibitors needed for treating endometriosis may be lower than that required for anticancer or immunosuppressive therapy, potentially reducing dosage-dependent side effects. In conclusion, while mTOR inhibitors, which allow for pregnancy during oral administration, show potential for clinical use in all stages of endometriosis, current evidence is limited to preclinical studies, and further research is needed to confirm clinical effectiveness.