Explore the vast range of titles available.

ABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent structural insights, no anticancer drug bound to ABCG2 has been resolved, and the mechanisms of multidrug transport remain obscure. Such a gap of knowledge limits the development of novel compounds that block or evade this critical molecular pump. Here we present single-particle cryo-EM studies of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics. Without the binding of conformation-selective antibody fragments or inhibitors, the resting ABCG2 adopts a closed conformation. Our cryo-EM, biochemical, and functional analyses reveal the binding mode of three chemotherapeutic compounds, demonstrate how these molecules open the closed conformation of the transporter, and establish that imatinib is particularly effective in stabilizing the inward facing conformation of ABCG2. Together these studies reveal the previously unrecognized conformational cycle of ABCG2. ABCG2 is a human ABC transporter that actively extrudes a wide variety of compounds from cells but the mechanisms of multidrug transport remain obscure. Here authors present cryo-EM structures of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics and demonstrate how these molecules open the closed conformation of the transporter.

The blood-brain barrier (BBB) serves to protect and regulate the CNS microenvironment. The development of an in-vitro mimic of the BBB requires recapitulating the correct phenotype of the in-vivo BBB, particularly for drug permeation studies. However the majority of widely used BBB models demonstrate low transendothelial electrical resistance (TEER) and poor BBB phenotype. The application of shear stress is known to enhance tight junction formation and hence improve the barrier function. We utilised a high TEER primary porcine brain microvascular endothelial cell (PBMEC) culture to assess the impact of shear stress on barrier formation using the Kirkstall QuasiVivo 600 (QV600) multi-chamber perfusion system. The application of shear stress resulted in a reorientation and enhancement of tight junction formation on both coverslip and permeable inserts, in addition to enhancing and maintaining TEER for longer, when compared to static conditions. Furthermore, the functional consequences of this was demonstrated with the reduction in flux of mitoxantrone across PBMEC monolayers. The QV600 perfusion system may service as a viable tool to enhance and maintain the high TEER PBMEC system for use in in-vitro BBB models.

Ageing-associated cancers are characterised by the dual hallmarks of persistent DNA damage and the ability of tumour cells to escape senescence checkpoints, which drive genomic instability and uncontrolled proliferation. In this study, we identified crucial proteins with PDB IDs—2YEX (Chk1 kinase), 4HG7 (MDM2 E3 ubiquitin ligase), 4JSX (mTOR kinase domain), and 5DS3 (PARP-1 DNA repair enzyme)—involved in ageing-related cancers and performed docking studies with Extra Precision (XP) followed by MM-GBSA-based pose processing against the FDA-approved DrugBank library (LigPrep: 10907 compounds). The extensive docking computations identified many good candidates; however, Mitoxantrone emerges as the topmost candidate with docking scores of −6.23 to −16.044 Kcal/mol and MM-GBSA score of −49.19 to −85.14 Kcal/mol, which currently is being used to treat advanced prostate cancer and acute nonlymphocytic leukaemia (ANLL) and would be easier to repurpose to other ageing-related cancers. Mitoxantrone also emerges as a better candidate compared to the control drug Doxorubicin. Further, the complex of all 4 proteins with Mitoxantrone was taken for interaction fingerprints and found that the most interacting residues with counts were 6GLY, 6VAL, 5GLU, 5LEU, 4ALA, 3ASP, and 3TYR, among others. The pharmacokinetics and Density Functional Theory computations further support Mitoxantrone as a potential candidate. We also performed a 5-nanoseconds (ns) WaterMap for hydration site identification and the role of water in stabilisation of the complex, followed by a 100 ns MD Simulation that resulted in stable deviation and fluctuations mostly under <2Å and a web of simulation interactions making the complex stable. Furthermore, the same trajectories were used for the Binding Free and Total Complex Energies computations, revealing that the complexes were stable. All the studies, from protein energies to docking to simulation and binding free energy, supported the stable complexes; however, experimental studies are necessary before their use.

This study aimed to prepare mitoxantrone thermosensitive liposome (MTX-TSL) to enhance the targeting capability of liposomes and thus improve the therapeutic effect of the drug on prostate cancer. MTX-TSL were prepared using the thin-film hydration method. A single-factor experiment was conducted to optimize the formulation process, and the liposome quality was assessed alongside short-term stability testing. The in vitro efficacy of MTX-TSL was evaluated using RM-1 prostate cancer cell inhibition assays. In vivo experiments were conducted on BDF1 mice inoculated with RM-1 cells to assess the tissue distribution and anticancer activity of MTX-TSL. Quality assessments of MTX-TSL revealed a pH of 6.53 ± 0.02, osmotic pressure of 309 ± 3 mOsmol/Kg, particle size of 100.10 ± 1.50 nm, and encapsulation efficiency of 98.41% ± 0.23%. Stability tests showed no major quality changes for liposome suspensions stored at 2–8 °C for 2 months. In vitro release studies showed that MTX-TSL exhibited good thermosensitive properties. Experiments performed on BDF1 mice indicated that initiating hyperthermia before drug administration was beneficial for drug accumulation in tumor tissue and that MTX-TSL outperformed free drugs in suppressing tumor growth when combined with appropriate hyperthermia. MTX-TSL can effectively inhibit tumor growth while increasing the drug’s therapeutic index.

Background Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients’ quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. Results In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe 3 O 4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. Conclusions A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe 3 O 4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer. Graphical Abstract

The gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), and it is an important molecular target for cancer therapeutics. To develop a new class of drugs targeting OCC, we designed and synthesized Con-3 and Con-7 which are novel high-affinity GnRH-R agonists, covalently coupled through a disulfide bond to the DNA synthesis inhibitor mitoxantrone. We hypothesized that Con-3 and Con-7 binding to the GnRH-R of OCC would expose the conjugated mitoxantrone to the cellular thioredoxin, which reduces the disulfide bond of Con-3 and Con-7. The subsequent release of mitoxantrone leads to its intracellular accumulation, thus exerting its cytotoxic effects. To test this hypothesis, we determined the cytotoxic effects of Con-3 and Con-7 using the SKOV-3 human OCC. Treatment with Con-3 and Con-7, but not with their unconjugated GnRH counterparts, resulted in the accumulation of mitoxantrone within the SKOV-3 cells, increased their apoptosis, and reduced their proliferation, in a dose- and time-dependent manner, with half-maximal inhibitory concentrations of 0.6–0.9 µM. It is concluded that Con-3 and Con-7 act as cytotoxic “prodrugs” in which mitoxantrone is delivered in a GnRH-R-specific manner and constitute a new class of lead compounds for use as anticancer drugs targeting ovarian tumors.

The poor delivery and limited penetration of nanoparticles into breast cancer tumors remain essential challenges for effective anticancer therapy. This study aimed to design a promising nanoplatform with efficient tumor targeting and penetration capability for effective breast cancer therapy. A pH-sensitive mitoxantrone (MTO) and copper ion-loaded nanosystem functionalized with cyclic CRGDfK and r9 peptide (TPRN-CM) was rationally designed for chemo-chemodynamic combination therapy. TPRN-CM would be quiescent in blood circulation with the CRGDfK peptide on the surface of the nanoparticle to improve its targeting to the tumor. Then, the structure of TPRN-CM changes in the acidic tumor microenvironment, and the r9 peptide can be exposed to make a surface charge reversal to promote deep penetration in the tumor and facilitate their internalization by cancer cells, which was characterized using transmission electron microscopy, dynamic light scattering, flame atomic absorption, etc. The drug release behavior, anti-tumor effects in vivo and in vitro, and the biosafety of the nanoplatform were evaluated. TPRN-CM exhibited remarkable capability to load MTO and Cu with good stability in serum. It can achieve pH-responsive charge reversal, MTO, and Cu release, and can further generate toxic hydroxyl radicals in the presence of glutathione (GSH) and H O . In vitro experiments demonstrated that this nanoplatform significantly inhibited proliferation, migration, invasion activities and 3D-tumorsphere growth. In vivo experiments suggested that rationally designed TPRN-CM can be effectively delivered to breast cancer tumors with deep tumor penetration, thereby resulting in a notable reduction in tumor growth and suppression of lung metastasis without causing any apparent side effects. The constructed TPRN-CM nanoplatform integrated tumor targeting, tumor penetration, drug-responsive release, and chemo-chemodynamic combination therapy, thereby providing an intelligent drug delivery strategy to improve the efficacy of breast cancer treatment.

Mesoporous silica nanomaterials show great potential to deliver chemotherapeutics for cancer treatment. The key challenges in the development of injectable mesoporous silica formulations are colloidal instability, hemolysis and inefficient drug loading and release. In this study, we evaluated the effect of PEGylation of mesoporous silica nanorods (MSNR) on hemolysis, colloidal stability, mitoxantrone (MTX) loading, in vitro MTX release, and cellular MTX delivery under hypoxic conditions. We found that PEGylation prevented dose-dependent hemolysis in the concentrations studied (0–10 mg/ml) and improved colloidal stability of MSNR. A negative effect of PEGylation on MTX loading was observed but PEGylated MSNR (PMSNR) demonstrated increased MTX release compared to non-PEGylated particles. Under hypoxic conditions, a decrease in the IC50 of MTX and MTX-loaded MSNR was observed when compared to normoxic conditions. These results showed that MSNR could deliver the chemotherapeutic agent, MTX to tumor cells and induce effective cell killing. However, the effect of PEGylation needs to be carefully studied due to the observed adverse effect on drug loading.

Polymer nanoparticles are vehicles used for delivery of hydrophobic anti-cancer drugs, like doxorubicin, paclitaxel or chemopreventors like quercetin (Q). The present study deals with the synthesis and characterisation of nano formulations (NFs) from Q loaded PLGA (poly lactic-co-glycolic acid) nano particles (NPs) by surface modification. The surface of Q-loaded (NPs) is modified by coating with biopolymers like bovine serum albumin (BSA) or histones (His). Conventional chemotherapeutic drugs adriamycin (ADR) and mitoxantrone (MTX) are bound to BSA and His respectively before being coated on Q-loaded NPs to nano formulate NF1 and NF2 respectively. The sizes of these NFs are in the range 400-500 nm as ascertained by SEM and DLS measurements. Encapsulation of Q in polymer NPs is confirmed from shifts in FT-IR, TGA and DSC traces of Q-loaded NPs compared to native PLGA and Q. Surface modification in NFs is evidenced by three distinct regions in their TEM images; the core, polymer capsule and the coated surface. Negative zeta potential of Q-loaded NPs shifted to positive potential on surface modification in NF1 and NF2. In vitro release of Q from the NFs lasted up to twenty days with an early burst release. NF2 is better formulation than NF1 as loading of MTX is 85% compared to 23% loading of ADR. Such NFs are expected to overcome multi-drug resistance (MDR) by reaching and treating the target cancerous cells by virtue of size, charge and retention.