Drug DOX Research Articles

Dual responsive drug-loaded nanomotor based on zwitterionic materials for the treatment of peritoneal metastatic cancer

Innovative treatments for peritoneal metastatic cancer have attracted widespread attention from researchers. Here, we propose a drug-loaded nanomotor (PSBMA/l-Arg/DOX, PLD) based on zwitterionic materials for the treatment of peritoneal metastatic cancer through intraperitoneal injection. Zwitterionic polymer nanocarriers (PSBMA NPs) are obtained by radical polymerization with zwitterionic SBMA as the polymerization monomer and N,N’-Bis(acryloyl)cystamine (BAC) as the cross-linking agent. The zwitterionic substrate of this nanomotor has the ability to resist non-specific protein adsorption in ascites. The loaded l-arginine enables the nanomotor to have the ability to chemotaxis towards high concentrations of ROS/iNOS in tumors and be catalyzed to produce NO, achieving deep penetration into tumor tissue. Furthermore, the disulfide bond (SS) carried by the crosslinking agent used in the preparation of the nanomotor can respond to the high expression of reducing glutathione in the tumor microenvironment and undergo degradation, releasing a large amount of loaded drug DOX. Cell and animal disease model experiments confirme the good therapeutic effect of this drug-loaded nanomotor, providing new therapeutic concepts and strategies for the treatment of peritoneal metastatic cancer.

Ferroptosis-inducing nanomedicine and targeted short peptide for synergistic treatment of hepatocellular carcinoma

The poor prognosis of hepatocellular carcinoma (HCC) is still an urgent challenge to be solved worldwide. Hence, assembling drugs and targeted short peptides together to construct a novel medicine delivery strategy is crucial for targeted and synergy therapy of HCC. Herein, a high-efficiency nanomedicine delivery strategy has been constructed by combining graphdiyne oxide (GDYO) as a drug-loaded platform, specific peptide (SP94-PEG) as a spear to target HCC cells, sorafenib, doxorubicin-Fe2+ (DOX-Fe2+), and siRNA (SLC7A11-i) as weapons to exert a three-path synergistic attack against HCC cells. In this work, SP94-PEG and GDYO form nanosheets with HCC-targeting properties, the chemotherapeutic drug DOX linked to ferrous ions increases the free iron pool in HCC cells and synergizes with sorafenib to induce cell ferroptosis. As a key gene of ferroptosis, interference with the expression of SLC7A11 makes the ferroptosis effect in HCC cells easier, stronger, and more durable. Through gene interference, drug synergy, and short peptide targeting, the toxic side effects of chemotherapy drugs are reduced. The multifunctional nanomedicine GDYO@SP94/DOX-Fe2+/sorafenib/SLC7A11-i (MNMG) possesses the advantages of strong targeting, good stability, the ability to continuously induce tumor cell ferroptosis and has potential clinical application value, which is different from traditional drugs.

Dual pH and Ca2+-Responsive PEG-Modified Pillar[5]arene-Based Supramolecular Nanodrug Delivery System: Excellent Cargo Encapsulation and Minimal Drug Toxicity.

Chemotherapy is one of the most employed strategies in clinical treatment of cancer. However, reducing medication adverse effects and improving the biological activity remains a significant issue for chemotherapy. We developed a pH and Ca2+-responsive pillar[5]arene-based supramolecular nanodrug delivery system (NDDS) WP5⊃EV@DOX to address the aforementioned challenges. The formation of this NDDS began with the spontaneous formation of supramolecular nanodrug carrier WP5⊃EV in water from PEG-modified pillar[5]arene and the bipyridilium salt derivative EV through simple host-guest interaction. Then the antitumor drug doxorubicin DOX was efficiently loaded with a high encapsulation rate of 84.6 %. Cytotoxicity results indicated that the constructed nanoplatform not only reduced DOX toxicity and side effects on normal cell (293T), but also significantly enhanced the antitumor activity on cancer cell (HepG2). Moreover, in vivo experiments showed that WP5⊃EV@DOX had a longer half-life and higher bioavailability in the blood of mice compared to the nake drug DOX, with increases to 212 % and 179 %, respectively. Therefore, WP5⊃EV@DOX has great potential in tumor therapy and provides a new idea for host-guest drug delivery system.

Development of Bivalent Aptamer-DNA Carrier-Doxorubicin Conjugates for Targeted Killing of Esophageal Squamous Cell Carcinoma Cells.

Esophageal cancer ranks the seventh in cancer incidence and the sixth in cancer death. Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of the total cases of esophageal cancer. Chemotherapy is the most effective drug-based method for treatment of esophageal cancer. However, severe side effects of traditional chemotherapy limit its treatment efficacy. Targeted chemotherapy can deliver chemotherapeutic drugs to cancer cells and specifically kill these cells with reduced side effects. In the work, the bivalent aptamer-DNA carrier (BAD) was designed by using an ESCC cell-specific aptamer as the recognition molecule and a GC base-rich DNA sequence as the drug carrier. With doxorubicin (Dox) as chemotherapeutic drugs, the bivalent aptamer-DNA-Dox conjugate (BADD) was constructed for targeted killing of ESCC cells. Firstly, the truncated A2(35) aptamer with a retained binding ability was obtained through optimization of an intact A2(80) aptamer and was used to fuse with DNA carrier sequences for constructing the BAD through simple DNA hybridization. The results of gel electrophoresis and flow cytometry analysis showed that the BAD was successfully constructed and had a stronger binding affinity than monovalent A2(35). Then, the BAD was loaded with Dox drugs to construct the BADD through noncovalent intercalation. The results of fluorescence spectra and flow cytometry assays showed that the BADD was successfully constructed and can bind to target cells strongly. Confocal imaging further displayed that the BADD can be specifically internalized into target cells and release Dox. The results of CCK-8 assays, Calcein AM/PI staining, and wound healing assays demonstrated that the BADD can specifically kill target cells, but not control cells. Our results demonstrate that the developed BADD can specifically deliver doxorubicin to target ESCC cells and selectively kill these cells, offering a potentially effective strategy for targeted chemotherapy of ESCC.

Shifting from sustained to delayed drug delivery systems: Encapsulated mesoporous silica-chitosan grafted polylactic acid-based composite approach

The current study demonstrates a desired drug delivery-controlled system with a wide range of release parameters. It illustrates the feasibility of carriers in the systems for extended and short drug release. Herein, mesoporous silica nanoparticles (MSNs) coated with chitosan (Cs) grafted polylactic acid (PLA) composite were fabricated by a sol-gel method in the form of micrometric porous particles (∼270 nm) with ζ-potential of −17.7 ± 1.7 mV and a specific surface area and total pore volume of 122700 cm2/g and 0.057 cm3/g, respectively. The prepared template of polymer-silica composite pores proved to be essential in the incorporation of Doxorubicin (Dox) drug molecules with adsorption capacity of 83.33 mg/g and encapsulation efficiency of 88 %. Dox was incorporated via the solvent diffusion method into the polymer-silica composites at suitable pH and concentration, resulting in solid drug dispersions. The silica-Cs-g-PLA composites showed greater effectiveness in the delayed release of the Dox with complete release after 10 days as compared to pristine MSNs and silica-Cs, which were completed after 12 h and 24 h, respectively. The drug release profiles were studied at different pH (2, 7, and 8), with maximum results obtained at pH 2. Both pristine MSNs and silica-Cs suffered from the burst effect, which was overcome by the grafting of PLA. The functionalized silica-Cs with PLA shows a significant change in the drug release properties from a sustained release process for pristine MSNs and silica-Cs to an enhanced delayed process for the silica-Cs-g-PLA composite, which makes this composite attractive for oral multi-particulate formulations of modified release.

Human Serum Albumin Mediated Controllable Synthesis of Defect-Rich Copper Hydroxide Nanowire for Cuproptosis-Based Anti-Tumor Therapy.

Cuproptosis, as a newly identified form of programmed cell death, shows great promise in cancer treatment. Efficient Cu+ delivery while avoiding systemic toxicity and elimination of the resistance from over-expressed intracellular copper chelator glutathione (GSH) are critical for cuproptosis. Herein, this work innovatively constructs a biocompatible and defect-rich copper hydroxide nanowire (HCu nanowire) through a human serum albumin (HSA) mediated biomineralization method. This work finds that the morphology and size of HCu nanowires can be controlled adjusted by the feed ratio of HSA and Cu2+. Remarkably, except for outstanding biocompatibility, HSA coordination endows HCu nanowires abundant oxygen vacancies (OVs), and the defect-rich HCu nanowire possesses excellent GSH consumption efficiency. Density functional theory studies indicate that OVs change GSH absorption energy on defective HCu nanowires. In cancer cells, HCu nanowires deplete GSH and simultaneously produce sufficient free Cu+ for enhanced cuproptosis. Meanwhile, Cu+ can catalyze endogenous H2O2 into hydroxyl radicals (·OH) via a Fenton-like reaction. Thus, synergetic cuproptosis and ROS mediated apoptosis against tumor are achieved. The experimental results show that HCu nanowires have a better performance in both antitumor efficiency and safety compared with chemotherapeutic drug Dox at the same dose, demonstrating its great potential in clinical applications.

Expression of Concern: pH-Responsive Anticancer Drug Delivery Systems: Insights into the Enhanced Adsorption and Release of DOX Drugs using Graphene Oxide as a Nanocarrier

Expression of Concern: pH-Responsive Anticancer Drug Delivery Systems: Insights into the Enhanced Adsorption and Release of DOX Drugs using Graphene Oxide as a Nanocarrier

A Silver Nanoparticle‐Embedded Tamarind Kernel Gum/Poly (Sodium Acrylate) Nanocomposite for Sustainable Release of Doxycycline

AbstractThe current work describes an eco‐friendly novel synthesis of silver (Ag) nanoparticles (NPs)/Tamarind kernel gum (TKG)/Poly (sodium acrylate) (PSA) nanocomposite without the use of any toxic materials. It is a one‐step route synthesis of silver nanocomposite hydrogel in which TKG and PSA are cross‐linked using methylene bisacrylamide (MBA) cross‐linker. The developed hydrogels were characterized using XRD, FTIR, UV‐visible, FE‐SEM, and TEM techniques. Doxycycline (dox) was chosen as a model drug for release studies using TKG/PSA and Ag/TKG/PSA nanocomposite. The observation is that Ag NP/TKG/PSA nanocomposite showed a pH‐dependent swelling which is higher at pH 7.4 than at pH 1.2. Similarly, the cumulative drug release percentage (CDR %) using silver nanocomposite is higher at pH 7.4 than at pH 1.2. Also, the presence of Ag NPs decreased the swelling ratio (SR) of TKG/PSA hydrogel, which controls the rate of release of the dox drug. In addition, the dox release kinetics were studied using the Korsmeyer‐Peppas and Higuchi model. It has been found that drug release data was fitted in the Korsmeyer‐Peppas model with a higher value of regression coefficient (R2). Thus, Ag/TKG/PSA nanocomposite showed satisfactory results for sustainable release of doxycycline drug.

A Microfluidics-Assisted Double-Barreled Nanobioconjugate Synthesis Introducing Aprotinin as a New Moonlight Nanocarrier Protein: Tested toward Physiologically Relevant 3D-Spheroid Models.

Proteins are promising substances for introducing new drug carriers with efficient blood circulation due to low possibilities of clearance by macrophages. However, such natural biopolymers have highly sophisticated molecular structures, preventing them from being assembled into nanoplatforms with manipulable payload release profiles. Here, we report a novel anticancer nanodrug carrier moonlighting protein, Aprotinin, to be used as a newly identified carrier for cytotoxic drugs. The Aprotinin-Doxorubicin (Apr-Dox) nanobioconjugate was prepared via a single-step microfluidics coflow mixing technique, a feasible and simple way to synthesize a carrier-based drug design with a double-barreled approach that can release and actuate two therapeutic agents simultaneously, i.e., Apr-Dox in 1:11 ratio (the antimetastatic carrier drug aprotinin and the chemotherapeutic drug DOX). With a significant stimuli-sensitive (i.e., pH) drug release ability, this nanobioconjugate achieves superior bioperformances, including high cellular uptake, efficient tumor penetration, and accumulation into the acidic tumor microenvironment, besides inhibiting further tumor growth by halting the urokinase plasminogen activator (uPA) involved in metastasis and tumor progression. Distinctly, in healthy human umbilical vein endothelial (HUVEC) cells, drastically lower cellular uptake of nanobioconjugates has been observed and validated compared to the anticancer agent Dox. Our findings demonstrate an enhanced cellular internalization of nanobioconjugates toward breast cancer, prostate cancer, and lung cancer both in vitro and in physiologically relevant biological 3D-spheroid models. Consequently, the designed nanobioconjugate shows a high potential for targeted drug delivery via a natural and biocompatible moonlighting protein, thus opening a new avenue for proving aprotinin in cancer therapy as both an antimetastatic and a drug-carrying agent.

Studying the Effects and Competitive Mechanisms of YOYO-1 on the Binding Characteristics of DOX and DNA Molecules Based on Surface-Enhanced Raman Spectroscopy and Molecular Docking Techniques.

Revealing the interaction mechanisms between anticancer drugs and target DNA molecules at the single-molecule level is a hot research topic in the interdisciplinary fields of biophysical chemistry and pharmaceutical engineering. When fluorescence imaging technology is employed to carry out this kind of research, a knotty problem due to fluorescent dye molecules and drug molecules acting on a DNA molecule simultaneously is encountered. In this paper, based on self-made novel solid active substrates NpAA/(ZnO-ZnCl2)/AuNPs, we use a surface-enhanced Raman spectroscopy method, inverted fluorescence microscope technology, and a molecular docking method to investigate the action of the fluorescent dye YOYO-1 and the drug DOX on calf thymus DNA (ctDNA) molecules and the influencing effects and competitive relationships of YOYO-1 on the binding properties of the ctDNA-DOX complex. The interaction sites and modes of action between the YOYO-1 and the ctDNA-DOX complex are systematically examined, and the DOX with the ctDNA-YOYO-1 are compared, and the impact of YOYO-1 on the stability of the ctDNA-DOX complex and the competitive mechanism between DOX and YOYO-1 acting with DNA molecules are elucidated. This study has helpful experimental guidance and a theoretical foundation to expound the mechanism of interaction between drugs and biomolecules at the single-molecule level.

PH/GSH-responsive diselenide-containing micelle via backbone ketoxime cross-links for efficient drug delivery and controlled release

Stimulus-responsive polymers are promising drug delivery systems for cancer therapy. However, low drug loading and drug leakage of polymeric carriers remain challenges. Here, a crosslinked diselenide-containing micelle was developed with pH/GSH dual responsiveness. Polyesters with multiple diselenide bonds and pendant ketone groups were synthesized by the ring-opening copolymerization of three cyclic monomers (diselenide-containing macrocyclic carbonate, 2-oxepane-1,5-dione, and 1,3-dioxan-2-one). The crosslinked polyester was obtained by the oxime click reaction of pendant ketone groups with hydroxylamine and then self-assembled into crosslinked micelle. This crosslinked micelle remained stable for 14 days, and responded to disassembly under the condition of pH = 5.0 and 10 mM glutathione (GSH). When the crosslinked micelle was loaded with the chemotherapeutic drug DOX, which possessed an active ketone group, the encapsulation efficiency of the crosslinked micelle increased to 91.36 %. The cumulative DOX release reached approximately 45 % under pH = 5.0 and 10 mM GSH. Importantly, the crosslinked diselenide-containing micelle could be taken up in MCF-7 breast cancer cells, responding to the tumor microenvironment and releasing encapsulated DOX. This crosslinked diselenide-containing micelle with pH/GSH dual responsiveness was proven to be a stable and efficient carrier with a promising application.

Zirconium-containing nanoscale coordination polymers for positron emission tomography and fluorescence-guided cargo delivery to triple-negative breast tumors

Nanoscale coordination polymer (NCP) is a class of hybrid materials formed by self-assembly of metal ions and organic ligands through coordination. The applications of NCP in biomedicine are quite extensive due to the diversity choice of metal ions and organic ligands. Here we designed Zr-P1 NCP based on Zr4+ selected as metal ion nodes and tetrakis(4-carboxyphenyl) ethylene as bridging ligands. Zr-P1 NCP was modified with functionalized pyrene derived polyethylene glycol (Py-PAA-PEG-Mal) on the surface and further conjugated with cRGD for active targeting of integrin αvβ3 overexpressed in triple-negative breast cancer. Doxorubicin was loaded on Zr-P1 NCP with encapsulation efficiency up to 22 % for the treatment of triple negative breast cancer. 89Zr-P1 NCP can be used for in vivo tumor imaging due to the fluorescence properties resulting from the enhanced aggregation-induced Emission (AIE) behavior of P1 ligands and its positron emission tomography (PET) capability. Cellular evaluation indicated that the functionalized Zr-P1@PEG-RGD presented a good function for tumor cell targeting imaging and doxorubicin could be targeted to triple negative breast cancer when it was loaded onto Zr-P1@PEG-RGD, which corroborated with the in vivo results. In summary, 89Zr-P1@PEG-RGD can serve as a biocompatible nanoplatform for fluorescence and PET image-guided cargo delivery. Statement of SignificanceNanoscale coordination polymer (NCP) is a class of hybrid materials formed by self-assembly of metal ions and organic ligands through coordination. The diversity of available metals and ligand structures upon NCP synthesis plays an advantage in establishing multimodal imaging platforms. Here we designed 89Zr-P1@PEG-RGD NCP based on Zr4+ selected as metal ion nodes and tetrakis(4-carboxyphenyl) ethylene as bridging ligands. 89Zr-P1@PEG-RGD nanomaterials have positron emission tomography (PET) capability due to the incorporation of zirconium-89, which can be used for in vivo tumor imaging with high sensitivity. The chemotherapeutic drug DOX was loaded on Zr-P1 NCP for the treatment of triple-negative breast cancer, and dual modality imaging can provide visual guidance for drug delivery.

Fe3O4@TiO2 Microspheres: Harnessing O2 Release and ROS Generation for Combination CDT/PDT/PTT/Chemotherapy in Tumours.

In the treatment of various cancers, photodynamic therapy (PDT) has been extensively studied as an effective therapeutic modality. As a potential alternative to conventional chemotherapy, PDT has been limited due to the low Reactive Oxygen Species (ROS) yield of photosensitisers. Herein, a nanoplatform containing mesoporous Fe3O4@TiO2 microspheres was developed for near-infrared (NIR)-light-enhanced chemodynamical therapy (CDT) and PDT. Titanium dioxide (TiO2) has been shown to be a very effective PDT agent; however, the hypoxic tumour microenvironment partly affects its in vivo PDT efficacy. A peroxidase-like enzyme, Fe3O4, catalyses the decomposition of H2O2 in the cytoplasm to produce O2, helping overcome tumour hypoxia and increase ROS production in response to PDT. Moreover, Fe2+ in Fe3O4 could catalyse H2O2 decomposition to produce cytotoxic hydroxyl radicals within tumour cells, which would result in tumour CDT. The photonic hyperthermia of Fe3O4@TiO2 could not only directly damage the tumour but also improve the efficiency of CDT from Fe3O4. Cancer-killing effectiveness has been maximised by successfully loading the chemotherapeutic drug DOX, which can be released efficiently using NIR excitation and slight acidification. Moreover, the nanoplatform has high saturation magnetisation (20 emu/g), making it suitable for magnetic targeting. The in vitro results show that the Fe3O4@TiO2/DOX nanoplatforms exhibited good biocompatibility as well as synergetic effects against tumours in combination with CDT/PDT/PTT/chemotherapy.

Polydopamine nanoplatform with near infrared light and pH dual stimuli-responsive for chemo-photothermal cancer therapy.

Photothermal agent accompanying with thermally responsive materials, displays well controlled drug release property, which is well-received as an outstanding design strategy for simultaneous photothermal/chemotherapy in cancer. Cyanine dye, as the prestigious photothermal agent has shown great potential due to its preeminent near-infrared absorbance and excellent thermal conversion efficiency. However, their inherent defect such as inferior photothermal stability, high leakage risk and poor therapy efficacy limit their further application in cancer therapy. Hence, a facile and universal strategy to make up these deficiencies is developed. Chemotherapeutic drug DOX and cyanine dye were loaded into polydopamine (PDA) nanoparticles. The PDA encapsulation dramatically improved the photothermal stability of cyanine dye. Attributed by the PDA structure feature, the thermo-sensitive small molecule glyamine (Gla) is introduced into the PDA surface to lessen leakage. The Gla can form a dense encapsulation layer on the dopamine surface through hydrogen bond. This newly fabricated Cyanine/DOX@PDA-Gla nanopaltform is characterized with NIR light/pH dual-responsive property, high NIR photothermal conversion performance and fluorescence guided chemo-photothermal therapy.

Engineered triphenylphosphonium-based, mitochondrial-targeted liposomal drug delivery system facilitates cancer cell killing actions of chemotherapeutics.

In addition to their classical role in ATP generation, mitochondria also contribute to Ca2+ buffering, free radical production, and initiation of programmed cell death. Mitochondrial dysfunction has been linked to several leading causes of morbidity and mortality worldwide including neurodegenerative, metabolic, and cardiovascular diseases as well as several cancer subtypes. Thus, there is growing interest in developing drug-delivery vehicles capable of shuttling therapeutics directly to the mitochondria. Here, we functionalized the conventional 10,12-pentacosadiynoic acid/1,2-dimyristoyl-sn-glycero-3-phosphocholine (PCDA/DMPC)-based liposome with a mitochondria-targeting triphenylphosphonium (TPP) cationic group. A fluorescent dansyl dye (DAN) group was also included for tracking mitochondrial drug uptake. The resultant PCDA-TPP and PCDA-DAN conjugates were incorporated into a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based lipid bilayer, and these modified liposomes (Lip-DT) were studied for their cellular toxicity, mitochondrial targeting ability, and efficacy in delivering the drug Doxorubicin (Dox) to human colorectal carcinoma (HCT116) and human breast (MCF7) cancer cells in vitro. This Lip-DT-Dox exhibited the ability to shuttle the encapsulated drug to the mitochondria of cancer cells and triggered oxidative stress, mitochondrial dysfunction, and apoptosis. The ability of Lip-DT-Dox to trigger cellular toxicity in both HCT116 and MCF7 cancer cells was comparable to the known cell-killing actions of the unencapsulated drug (Dox). The findings in this study reveal a promising approach where conventional liposome-based drug delivery systems can be rendered mitochondria-specific by incorporating well-known mitochondriotropic moieties onto the surface of the liposome.

Synthesis, characterization and biological research of novel 2-(quinoline-4-carbonyl)hydrazide-acrylamide hybrids as potential anticancer agents on MCF-7 breast carcinoma cells by targeting EGFR-TK.

Novel derivatives of the 2-(quinoline-4-carbonyl)hydrazide scaffold carrying the acrylamide moiety were synthesized and tested for their cytotoxic efficacy against the breast carcinoma MCF-7 cell line. The most active members 6a, 6b and 6h revealed significant antiproliferative action with an IC50 value of 3.39, 5.94 and 2.71 μM, respectively, which were more potent than the reference drug Dox (IC50 = 6.18 μM). Aiming to enlighten the antiproliferative activity, compounds 6a and 6h were examined for their inhibitory potential against EGFR kinase. The results demonstrated that compound 6h displayed potent inhibitory activity, as concluded from the IC50 value (IC50 = 0.22 μM) compared to the standard drug Lapatinib (IC50 value of 0.18 μM). Compound 6h was found to induce significant cellular cycle arrest at the G1 phase and provoke apoptosis. Besides, compound 6h triggered apoptosis via upregulating p53 and initiator caspase 9 by 7.4- and 8.7-fold, respectively, compared to DMSO controls.

PH Sensitive Peptide Hydrogel Encapsulating Anti-angiogenesis Drug Conbercept and Chemotherapy Drug DOX for the Combined Treatment of Retinoblastoma

Retinoblastoma(RB) is a malignant tumor originating from retina. Radiotherapy, chemotherapy, photodynamic therapy, cryotherapy and surgery are commonly used in clinical RB treatment, but the overall efficacy is poor and often...

A biomimetic cuproptosis amplifier for targeted NIR-II fluorescence/photoacoustic imaging-guided synergistic NIR-II photothermal immunotherapy

The therapeutic efficacy of cuproptosis combined with phototheranostics is still hindered by easy copper efflux, nonspecific accumulation and limited light penetration depth. Here, a high-performance NIR-II semiconductor polymer was first synthesized through dual-donor engineering. Then a biomimetic cuproptosis amplifier (PCD@CM) was prepared by Cu(II)-mediated coordinative self-assembly of NIR-II ultrasmall polymer dots and the chemotherapeutic drug DOX, followed by camouflaging of tumor cell membranes. After homologous targeting delivery to tumor cells, overexpressed GSH in the tumor microenvironment (TME) triggers the disassembly of the amplifier and the release of therapeutic components through the reduction of Cu(II) to Cu(I), which enable NIR-II fluorescence/photoacoustic imaging-guided NIR-II photothermal therapy (PTT) and chemotherapy. The released Cu(I) induces the aggregation of lipoylated mitochondrial proteins accompanied by the loss of iron-sulfur proteins, leading to severe proteotoxic stress and eventually cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis sensitization provokes significant immune surveillance, triggering the immunogenic cell death (ICD) to promote cytotoxic T lymphocyte infiltration together with aPD-L1-mediated immune checkpoint blockade. This work proposes a new strategy to develop cuproptosis sensitization systems enhanced by NIR-II phototheranostics with homologous targeting and anti-tumor immune response capabilities.

Molecular structure, spectroscopy, molecular docking, and molecular dynamic studies of tetrahydroneoprzewaquinone as potent cervical cancer agent

Abstract Cervical cancer is one of the most prevalent cancer-related diseases, causing accelerated morbidity and mortality rates in low-income countries and African states. This study explores the potential of (3R,3′R)-2,2′,3,3′-tetrahydroneoprzewaquinone (TDN) as a treatment for cervical cancer by investigating its structural and molecular properties using molecular modelling technique, which include; DFT, molecular docking, molecular dynamic simulation. The results are promising, with TDN demonstrating exceptional stability in the energy gap (E g) as well as through natural bond order analysis (NBO). π → σ* electronic transitions were found to contribute mainly to the molecule’s stability, with an outstanding total stabilization energy (E (2)). Docking exercises showed that TDN binds more favorably to the pro-apoptotic receptor 4s0o with a stronger H-bond compared to the conventional DOX drug, which interacted less effectively with TDN and more strongly with the anti-apoptotic protein, forming an outstanding strong H-bond. Molecular dynamics simulations also revealed that TDNʼs interaction with the pro-apoptotic protein (TDN_4S0o) was more stable than the standard DOX drug (DOX_4s0o). The H-bond plot indicated that TDN could effectively interact with both anti and pro-apoptotic receptors, forming approximately 1 to 4 hydrogen bonds between TDN_1g5M with respect to each picosecond (ps) ranging from 0 to 1000 ps. In contrast, the number of hydrogen bonds fluctuated when DOX interacted with the anti-apoptotic protein (1g5M), ranging from 1 to 5 H-bonds. Overall, these results suggest that TDN may be a promising drug candidate for cervical cancer treatment.

Multi-Stimuli-Responsive and Cell Membrane Camouflaged Aggregation-Induced Emission Nanogels for Precise Chemo-photothermal Synergistic Therapy of Tumors.

Targeted and controllable drug release at lesion sites with the aid of visual navigation in real-time is of great significance for precise theranostics of cancers. Benefiting from the marvelous features (e.g., bright emission and phototheranostic effects in aggregates) of aggregation-induced emission (AIE) materials, constructing AIE-based multifunctional nanocarriers that act as all-arounders to integrate multimodalities for precise theranostics is highly desirable. Here, an intelligent nanoplatform (P-TN-Dox@CM) with homologous targeting, controllable drug release, and in vivo dual-modal imaging for precise chemo-photothermal synergistic therapy is proposed. AIE photothermic agent (TN) and anticancer drug (Dox) are encapsulated in thermo-/pH-responsive nanogels (PNA), and the tumor cell membranes are camouflaged onto the surface of nanogels. Active targeting can be realized through homologous effects derived from source tumor cell membranes, which advantageously elevates the specific drug delivery to tumor sites. After being engulfed into tumor cells, the nanogels exhibit a burst drug release at low pH. The near-infrared (NIR) photoinduced local hyperthermia can activate severe cytotoxicity and further accelerate drug release, thus generating enhanced synergistic chemo-photothermal therapy to thoroughly eradicate tumors. Moreover, P-TN-Dox@CM nanogels could achieve NIR-fluorescence/photothermal dual-modal imaging to monitor the dynamic distribution of therapeutics in real-time. This work highlights the great potential of smart P-TN-Dox@CM nanogels as a versatile nanoplatform to integrate multimodalities for precise chemo-photothermal synergistic therapy in combating cancers.