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To reveal the relationship between metallodrugs and cancer malignancy, molecular networks of anti-cancer drugs were analyzed. Molecular networks in several types of cancers were analyzed in Ingenuity Pathway Analysis (IPA). Analysis of carboplatin revealed the causal network in diffuse large B-cell lymphoma. Analysis of 12 analyses of cisplatin treatment identified causal networks including camptothecin and NUPR1. The causal network of camptothecin, which includes PTEN, FAS, and IRF1, was inactivated in diffuse-type GC and activated in intestinal-type GC. Upstream regulator analysis of cisplatin revealed an increase in FAS, BTG2, SESN1 and CDKN1A, and the involvement of the tumor microenvironment pathway. Upstream regulators of cisplatin-treated lung adenocarcinoma included a histone deacetylase inhibitor, trichostatin A (TSA). Causal network of arsenic was inactivated in diffuse-type GC and activated in intestinal-type GC, and included ERK, EGFR, SRC, IKK and TP53. Prediction of RNA-RNA interactions with the causal network of arsenic identified 10 microRNAs including mir-101, mir-103, and mir-22. The results revealed the involvement of EMT in arsenic treatment. Analysis of oxaliplatin, a platinum drug, revealed that the SPINK1 pancreatic cancer pathway is inactivated in ischemic cardiomyopathy. The study showed the importance of the relationship between platinum drugs or arsenic trioxide and the tumor microenvironment in the treatment of resistant cancer in humans.

Tumor resistance and recurrence have been associated with the presence of cancer stem cells (CSCs) in tumors. The functions and survival of the CSCs have been associated with several intracellular and extracellular features. Particularly, the abnormal glycosylation of these signaling pathways and markers of CSCs have been correlated with maintaining survival, self-renewal and extravasation properties. Here, we highlight the importance of glycosylation in promoting the stemness character of CSCs and the current strategies for targeting abnormal glycosylation toward generating effective therapies against the CSC population.

Glioblastoma (GBM) is resistant to immune checkpoint inhibition due to its low mutation rate, phosphatase and tensin homologue (PTEN)-deficient immunosuppressive microenvironment, and high fraction of cancer stem-like cells (CSCs). Nanomedicines fostering immunoactivating intratumoral signals could reverse GBM resistance to immune checkpoint inhibitors (ICIs) for promoting curative responses. Here, we applied pH-sensitive epirubicin-loaded micellar nanomedicines, which are under clinical evaluation, to synergize the efficacy of anti-PD1antibodies (aPD1) against PTEN-positive and PTEN-negative orthotopic GBM, the latter with a large subpopulation of CSCs. The combination of epirubicin-loaded micelles (Epi/m) with aPD1 overcame GBM resistance to ICIs by transforming cold GBM into hot tumors with high infiltration of antitumor immune cells through the induction of immunogenic cell death (ICD), elimination of immunosuppressive myeloid-derived suppressor cells (MSDCs), and reduction of PD-L1 expression on tumor cells. Thus, Epi/m plus aPD1 eradicated both PTEN-positive and PTEN-negative orthotopic GBM and provided long-term immune memory effects. Our results indicate the high translatable potential of Epi/m plus aPD1 for the treatment of GBM.

Delivering therapeutic antibodies into the brain across the blood-brain barrier at a therapeutic level is a promising while challenging approach in the treatment of neurological disorders. Here, we present a polymeric nanomicelle (PM) system capable of delivering therapeutically effective levels of 3D6 antibody fragments (3D6-Fab) into the brain parenchyma for inhibiting Aβ aggregation. PM assembly was achieved by charge-converting 3D6-Fab through pH-sensitive citraconylation to allow complexation with reductive-sensitive cationic polymers. Brain targeting was achieved by functionalizing the PM surface with glucose molecules to allow interaction with recycling glucose transporter (Glut)-1 proteins. Consequently, 41-fold enhanced 3D6-Fab accumulation in the brain was achieved by using the PM system compared to free 3D6-Fab. Furthermore, therapeutic benefits were obtained by successfully inhibiting Aβ1-42 aggregation in Alzheimer's disease mice systemically treated with 3D6-Fab-loaded glucosylated PM. Hence, this nanocarrier system represents a promising method for effectively delivering functional antibody agents into the brain and treating neurological diseases.

Simple Summary The epithelial-mesenchymal transition (EMT) is an important hallmark in drug resistance and cancer malignancy in cancer stem cells (CSCs). In this study, gene expression in diffuse- and intestinal-type gastric cancer (GC) was investigated to reveal the precise mechanism of EMT. The pathways of cell cycle regulation and DNA damage response were found to be altered in diffuse- and intestinal-type GC. The findings of this study may provide broader insights into CSCs, with new possibilities of the involvement of the cell cycle in EMT. Abstract Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G1/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G1/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G1/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT.

Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G1/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G1/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G1/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT.

CNS tumors remain among the deadliest forms of cancer, resisting conventional and new treatment approaches, with mortality rates staying practically unchanged over the past 30 years. One of the primary hurdles for treating these cancers is delivering drugs to the brain tumor site in therapeutic concentration, evading the blood-brain (tumor) barrier (BBB/BBTB). Supramolecular nanomedicines (NMs) are increasingly demonstrating noteworthy prospects for addressing these challenges utilizing their unique characteristics, such as improving the bioavailability of the payloadsviacontrolled pharmacokinetics and pharmacodynamics, BBB/BBTB crossing functions, superior distribution in the brain tumor site, and tumor-specific drug activation profiles. Here, we review NM-based brain tumor targeting approaches to demonstrate their applicability and translation potential from different perspectives. To this end, we provide a general overview of brain tumor and their treatments, the incidence of the BBB and BBTB, and their role on NM targeting, as well as the potential of NMs for promoting superior therapeutic effects. Additionally, we discuss critical issues of NMs and their clinical trials, aiming to bolster the potential clinical applications of NMs in treating these life-threatening diseases.

Effective inhibition of the protein derived from cellular myelocytomatosis oncogene (c-Myc) is one of the most sought-after goals in cancer therapy. While several c-Myc inhibitors have demonstrated therapeutic potential, inhibiting c-Myc has proven challenging, since c-Myc is essential for normal tissues and tumors may present heterogeneous c-Myc levels demanding contrasting therapeutic strategies. Herein, we developed tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action. These nanomedicines loaded homologues of the bromodomain and extraterminal (BET) motif inhibitor JQ1 as epigenetic c-Myc inhibitors through pH-cleavable bonds engineered for fast or slow drug release at intratumoral pH. In tumors with high c-Myc expression, the fast-releasing (FR) nanomedicines suppressed tumor growth more effectively than the slow-releasing (SR) ones, whereas, in the low c-Myc tumors, the efficacy of the nanomedicines was the opposite. By studying the tumor distribution and intratumoral activation of the nanomedicines, we found that, despite SR nanomedicines achieved higher accumulation than the FR counterparts in both c-Myc high and low tumors, the antitumor activity profiles corresponded with the availability of activated drugs inside the tumors. These results indicate the potential of engineered nanomedicines for c-Myc inhibition and spur the idea of precision pH-sensitive nanomedicine based on cancer biomarker levels.

Molecular network activation states alter dynamically in biology and diseases. In cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) networks play an important role to acquisition of the drug resistance and cancer malignant feature. To reveal the network pathways in EMT and CSCs, gene expression in diffuse- and intestinal-type gastric cancer (GC) have been analyzed. The several canonical pathways have been found to be altered in diffuse- and intestinal-type GC. Canonical pathway on Cell Cycle: G1/S Checkpoint Regulation was activated in diffuse-type GC, and Cyclins and Cell Cycle Regulation was activated in intestinal-type GC. In Cell Cycle: G1/S Checkpoint Regulation, DNA damage induces p53, which was predicted to be activated in diffuse-type GC. Canonical pathway related to Role of BRCA1 in DNA Damage Response was activated in intestinal-type GC, where BRCA1 which is related to G1/S phase transition was up-regulated. Cell cycle regulation may be altered in EMT condition in diffuse-type GC.

Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism, catalyzing the first step to fatty acid oxidation (FAO). Inhibiting CPT1A, especially in the brain, can have several pharmacological benefits, such as in treating obesity and brain cancer. C75-CoA is a strong competitive inhibitor of CPT1A. However, due to its negatively charged nature, it has low cellular permeability. Herein, we report the use of poly-ion complex (PIC) micelles to deliver the specific CPT1A inhibitors (±)-, (+)-, and (-)-C75-CoA into U87MG glioma cells and GT1-7 neurons. PIC micelles were formed through charge-neutralization of the cargo with the cationic side chain of PEG-poly{N-[N'-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-PAsp(DET)), forming particles with 55 to 65 nm diameter. Upon short-term incubation with cells, the micelle-encapsulated CPT1A inhibitors resulted in up to 5-fold reduction of ATP synthesis compared to the free drug, without an apparent decline in cell viability. Micelle treatment showed a discernible decrease in 14C-palmitate oxidation into CO2 and acid-soluble metabolites, confirming that the substantial lowering of ATP production has resulted from FAO inhibition. Micelle treatment also diminished IC50 by 2 to 4-fold over the free drug-treated U87MG after long-term incubation. To measure the cellular uptake of these CoA-adduct loaded PIC micelles, we synthesized a fluorescent CoA derivative and prepared Fluor-CoA micelles which showed efficient internalization in the cell lines, both in 2D and 3D culture models, especially in neurons where uptake reached up to 3-fold over the free dye. Our results starkly demonstrate that the PIC micelles are a promising delivery platform for anionic inhibitors of CPT1A in glioma cells and neurons, laying the groundwork for future research or clinical applications.

The mechanism of epithelial-mesenchymal transition (EMT) consists of the cellular phenotypic transition from epithelial to mesenchymal status. The cells exhibiting EMT exist in cancer stem cell (CSC) population, which is involved in drug resistance. CSCs demonstrating EMT feature remain after cancer treatment, which leads to drug resistance, recurrence, metastasis and malignancy of cancer. In this context, the recent advance of nanotechnology in the medical application has ascended the possibility to target CSCs using nanomedicines. In this review article, we focused on the mechanism of CSCs and EMT, especially into the signaling pathways in EMT, regulation of EMT and CSCs by microRNAs and nanomedicine-based approaches to target CSCs.

The crucial balance of stability in blood-circulation and tumor-specific delivery has been suggested as one of the challenges for effective bench-to-bedside translation of nanomedicines (NMs). Herein, we developed a supramolecularly enabled tumor-extracellular (Tex) pH-triggered NM that can maintain the micellar structure with the entrapped-drug during systemic circulation and progressively release drug in the tumor by rightly sensing heterogeneous tumor-pH. Desacetylvinblastine hydrazide (DAVBNH), a derivative of potent anticancer drug vinblastine, was conjugated to an aliphatic ketone-functionalized poly(ethylene glycol)-b-poly(amino acid) copolymer and the hydrolytic stability of the derived hydrazone bond was efficiently tailored by exploiting the compartmentalized structure of polymer micelle. We confirmed an effective and safe therapeutic application of Tex pH-sensitive DAVBNH-loaded micelle (Tex-micelle) in orthotopic glioblastoma (GBM) models, extending median survival to 1.4 times in GBM xenograft and 2.6 times in GBM syngeneic model, compared to that of the free DAVBNH. The work presented here offers novel chemical insights into the molecular design of smart NMs correctly sensing Tex-pH via programmed functionalities. The practical engineering strategy based on a clinically relevant NM platform, and the encouraging therapeutic application of Tex-micelle in GBM, one of the most lethal human cancers, thus suggests the potential clinical translation of this system against other types of common cancers, including GBM.

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with potential to cross the blood-brain-barrier, however, the concentrations necessary for a cytotoxic effect against cancer cells exceeds the concentration achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the 3D models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain-barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration, however, if transport across the blood-brain-barrier is sufficient to reach therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

Unlike the related aminoglycoside neomycin B, N-protected tobramycin can be selectively esterified at its sole, primary hydroxyl group under Mitsunobu conditions. However, depending on the reaction conditions, the reaction can take a different course with intramolecular cyclization of an N-Boc amine leading to formation of an unusual tobramycin pyrrolidine derivative as the major reaction product.

The aminoglycoside antibiotic neomycin B has been converted into several novel building blocks that can be used for the specific modification of three of the four ring systems. Under carefully controlled conditions, the Mitsunobu reaction can be used to selectively dehydrate the ido ring to give the talo epoxide. Subsequently however, under more forcing conditions, the 2-deoxy streptamine ring undergoes Mitsunobu dehydration to give an aziridine. An unusual remote neighboring group effect was observed. When the primary hydroxyl of the ribose ring was blocked, aziridine formation on the deoxystreptamine ring did not occur. Both the epoxide and epoxide-aziridine neomycin building blocks can be ring-opened with azide and subjected to "click" type chemistry with terminal alkynes to generate a series of new neomycin analogues. These reactions can all be carried out without recourse to O-protecting groups. A detailed conformational analysis by NMR revealed some unexpected conformer preferences in these systems.

In the structure of the title steroid, C23H34O3, the molecules are linked in infinite chains through intermolecular C11(n) O-H...O hydrogen bonds between the hydroxy proton and the ester carbonyl O atom.

Reaction of N-Boc neomycin with triphenylphosphine and diissopropyl azodicarboxylate in either toluene or THF results in an epoxide in ring IV, not an aziridine or azetidine as previously reported.

Reaction of hexa-N-Boc neomycin B with TPP and DIAD in toluene results in the formation of an epoxide in ring IV, not an aziridine or azetidine as previously reported.

The crystal structure of the title compound, C27H45N3, has been determined as part of our investigation into the hydrophobic modification of aminoglycoside antibiotics. The isopropyl group showed disorder for the tertiary carbon (equal occupancies), with high thermal motion for the peripheral atoms of the isopropyl and azide groups also apparent in the structure. The axial disposition of the azide group is consistent with the clean inversion of stereochemistry at C-3 under Mitsunobu conditions.