Synergistic Chemotherapy Research Articles

Capturing Hydrophilic Chemotherapeutics Agents Into siRNA-Encapsulated Vesicle-Like Nanoparticles for Convenient ICB-Chemo Combination Therapy.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

An injectable dual-layer chitosan-alginate nano-hydrogel incorporated Cu(I)-isopolymolybdate-based metal-organic framework tailored for three-in-one anti-cancer nanotherapy

Designing potential agents and constructing hydrophilic nano-hydrogel platforms for biomedical and pharmaceutical applications, especially for polyoxometalate-based metal-organic frameworks (PMOF), present both great desirability and significant challenges. A unique open porous Cu(I)-isopolymolybdate-based metal-organic framework (CCUT) has been self-assembled through ionothermal processes for in vivo synergistic anti-cancer therapy. The periodicity of Drugs@CCUT-1 (nano-crystals of CCUT after cation exchange and anti-cancer drugs upload) has been investigated by synchrotron wide-angle X-ray scattering, confirming the lattice structure unchanged. To mitigate toxicity, enhance stimuli-responsive drug delivery, hydrophilicity, and biocompatibility, an injectable dual-layer chitosan//alginate-based nano-hydrogel is developed to incorporate Drugs@CCUT-1. Potential interactions between the chitosan layer and the surface of CCUT-1 have been analyzed by Density Functional Theory (DFT). Furthermore, the nanoparticles Drugs@CCUT-1@Gel exhibit efficient type I photodynamic therapy (PDT) and chemodynamic therapy (CDT) within the bio-window, effectively eradicating tumors in deep tissue. CCUT-1 generates a substantial amount of reactive oxygen species (ROS), stimulating the Keap1-Nrf2 signaling pathway and resulting in the expression of phase II enzymes, typically HO-1. CCUT-1@Gel not only demonstrates high capacity for anti-cancer drug upload and release, but also exhibits strong synergistic CDT/PDT in vivo anti-tumor efficacy. Hence, CCUT-1@Gel represents a promising in vivo nano-platform for synergistic chemotherapy (CT)/CDT/PDT three-in-one anti-cancer approach.

Synergistic effects of bloom helicase (BLM) inhibitor AO/854 with cisplatin in prostate cancer

To determine the synergistic effect and mechanism of AO/854, a new Bloom syndrome protein (BLM) helicase inhibitor, and cisplatin (CDDP), a DNA-crosslinking agent, cell viability assays, neutral comet assays, and Western blotting (WB) were performed on prostate cancer (PCa) cells. According to our findings, combining AO/854 and CDDP enhanced the antiproliferative capabilities of PC3 cell lines. As evidenced by the upregulation of γH2AX, cleaved caspase-3/caspase-3, and BAX/Bcl-2, AO/854 dramatically increased PC3 apoptosis and DNA damage induced by CDDP. Furthermore, combining AO/854 and CDDP synergistically inhibited PC3 cell migration and invasion. In addition, AO/854 inhibited CDDP-induced S-phase cell-cycle arrest in PC3 cells while enhancing G2/M-phase cell-cycle arrest. In vivo, the antitumor efficacy of the combination therapy group was greater than that of the groups treated with AO/854 or CDDP alone. Our findings indicate that synergistic chemotherapy with AO/854 and CDDP may be a novel anticancer strategy for PCa.

Targeted PHA Microsphere-Loaded Triple-Drug System with Sustained Drug Release for Synergistic Chemotherapy and Gene Therapy.

The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNAGEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNAGEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNAGEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNAGEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs.

Cell membrane camouflaged Cu-doped mesoporous polydopamine for combined CT/PTT/CDT synergistic treatment of breast cancer

Currently, traditional monotherapy for cancer often results in indiscriminate attacks on the body, leading to the emergence of new health problems. To confront these challenges, multimodal combination therapy has become necessary. However, how to develop new smart nanomaterials through green synthesis methods, delivering drugs while simultaneously synergizing multimodal combination therapies for tumor treatment, remains a topic of great significance. In this study, a biomimetic composite nanomaterial (RM-Cu/P) composed of mesoporous polydopamine (MPDA) as the core and red blood cell membranes (RBCMs) as the shell was synthesized as a drug carrier to deliver doxorubicin (DOX) while achieving synergistic chemotherapy, photothermal and chemodynamic therapy (CT/PTT/CDT). Herein, the nanoparticles were extensively characterized to examine their morphological characteristics, elemental composition, and drug-carrying capacity. Notably, the coating of RBCM reduced the toxicity of the RM-Cu/P@DOX nanoparticles, improved their targeting ability and prolonged their circulation time in vivo. The Cu-doped nanoparticles were capable of initiating a Fenton-like reaction to generate reactive oxygen species (ROS) for CDT, while the photothermal conversion efficiency (η) reached 45.20 % under NIR laser irradiation. Subsequently, the particles were examined by in vivo and in vitro experimental studies in cytotoxicity, cellular uptake, ROS levels, lysosomal escape, and mouse tumor model to evaluate their potential application in antitumor. Compared with monotherapy, the RM-Cu/P@DOX nanoparticles had multiple-stimulation response properties under redox, pH, and NIR, which exhibited the advantage of combined trimodal therapy, resulting in remarkable synergistic antitumor efficacy. In conclusion, this innovative platform exhibited promising applications in smart drug delivery and synergistic treatment of cancer.

Two-Dimensional Biodegradable l-Cysteine-Iodine Nanosheets for Computed Tomography-Guided Cancer Synergistic Sonodynamic Therapy and Chemotherapy.

Biodegradable versatile inorganic nanomaterials are highly desirable in the field of nanomedicine. Here, for the first time, we report a kind of novel two-dimensional biodegradable l-cysteine-iodine (l-Cys-I) nanosheet with high computed tomography (CT) imaging ability and sonosensitization efficacy. Such l-Cys-I nanosheets consist of iodine molecules and l-Cys, where the iodine molecules are coordinated and stabilized by l-Cys and cross-linked to form nanosheets through disulfide bonds. The large and convenient functional surface is further modified with targeting moieties DSPE-PEG-RGD and cancer drug doxorubicin (DOX) to construct a nanotheranostic nanoplatform (CIRD). Under ultrasound irradiation, the CIRD nanosheets assist in tremendous reactive oxygen species generation and controllable DOX release, leading to remarkable anticancer performance both in vitro and in vivo due to the synergistic sonodynamic therapy (SDT) and chemotherapy. Our results validate that the CIRD nanosheets enable effective body excretion and negligible systemic toxicity owing to the biodegradation properties. The CIRD nanosheets, with biodegradability, biocompatibility, and versatility, hold great promise in nanotheranostics.

Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu2+ depletes intracellular GSH and is reduced to Cu+ simultaneously, which reacts with local H2O2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

A “precision medicine” nanoplatform for synergistic photothermal therapy and chemotherapy in hepatocellular carcinoma

Targeted peptide-mediated photothermal therapy (PTT) in combination with chemotherapy has great potency in the field of “precision medicine” because of its ability to increase drug enrichment in the focal region, reduce systemic toxicity, and provide the advantages of superb spatial-temporal control and non-invasiveness. In this work, we developed a FoxM1c-targeted nanoplatform (GSDP) for synergistic PTT and chemotherapy for hepatocellular carcinoma (HCC). Under irradiation with an 808-nm laser, the enriched nanodrug in tumor sites could convert near-infrared (NIR) light into heat, causing tumor temperature to exceed the safety threshold, the high temperature triggers the release of Doxorubicin (DOX) correspondingly, which can achiev the synergistic PTT-chemotherapy treatment. More strikingly, the nanoplatform achieved "precision medicine" of tumors due to the modification of 9R-P201 peptide, ultimately achieved a tumor suppression rate of 84.6% in HCC. Hence, the design of this synergistic therapeutic platform offers a new perspective for improving the therapeutic efficacy of HCC.

From 2D to 3D In Vitro World: Sonodynamically-Induced Prooxidant Proapoptotic Effects of C60-Berberine Nanocomplex on Cancer Cells.

The primary objective of this research targeted the biochemical effects of SDT on human cervix carcinoma (HeLa) and mouse Lewis lung carcinoma (LLC) cells grown in 2D monolayer and 3D spheroid cell culture. HeLa and LLC monolayers and spheroids were treated with a 20 µM C60-Ber for 24 h, followed by irradiation with 1 MHz, 1 W/cm2 US. To evaluate the efficacy of the proposed treatment on cancer cells, assessments of cell viability, caspase 3/7 activity, ATP levels, and ROS levels were conducted. Our results revealed that US irradiation alone had negligible effects on LLC and HeLa cancer cells. However, both monolayers and spheroids irradiated with US in the presence of the C60-Ber exhibited a significant decrease in viability (32% and 37%) and ATP levels (42% and 64%), along with a notable increase in ROS levels (398% and 396%) and caspase 3/7 activity (437% and 246%), for HeLa monolayers and spheroids, respectively. Similar tendencies were observed with LLC cells. In addition, the anticancer effects of C60-Ber surpassed those of C60, Ber, or their mixture (C60 + Ber) in both cell lines. The detected intensified ROS generation and ATP level drop point to mitochondria dysfunction, while increased caspase 3/7 activity points on the apoptotic pathway induction. The combination of 1 W/cm2 US with C60-Ber showcased a promising platform for synergistic sonodynamic chemotherapy for cancer treatment.

In-situ nanoplatform with synergistic neutrophil intervention and chemotherapy to prevent postoperative tumor recurrence and metastasis

In addition to residual tumor cells, surgery-induced inflammation significantly contributes to tumor recurrence and metastasis by recruiting polymorphonuclear neutrophils (PMNs) and promoting their involvement in tumor cell proliferation, invasion and immune evasion. Efficiently eliminating residual tumor cells while concurrently intervening in PMN function represents a promising approach for enhanced postoperative cancer treatment. Here, a chitosan/polyethylene oxide electrospun fibrous scaffold co-delivering celecoxib (CEL) and doxorubicin-loaded tumor cell-derived microparticles (DOX-MPs) is developed for postoperative in-situ treatment in breast cancer. This implant (CEL/DOX-MPs@CP) ensures prolonged drug retention and sustained release within the surgical tumor cavity. The released DOX-MPs effectively eliminate residual tumor cells, while the released CEL inhibits the function of inflammatory PMNs, suppressing their promotion of residual tumor cell proliferation, migration and invasion, as well as remodeling the tumor immune microenvironment. Importantly, the strategy is closely associated with interference in neutrophil extracellular trap (NET) released from inflammatory PMNs, leading to a substantial reduction in postoperative tumor recurrence and metastasis. Our results demonstrate that CEL/DOX-MPs@CP holds great promise as an implant to enhance the prognosis of breast cancer patients following surgery.

Highly Efficient Synergistic Chemotherapy and Magnetic Resonance Imaging for Targeted Ovarian Cancer Therapy Using Hyaluronic Acid-Coated Coordination Polymer Nanoparticles.

The diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin-based chemotherapy is the first-line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt-COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt-COOH, and Gossypol from HA@PFG NPs. Pt-COOH with GSH consumption and cisplatin-basedchemotherapy plus Gossypol with pro-apoptotic effects displays asynergisticeffect forkillingtumorcells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. Inthe patient-derived tumor xenograft (PDX)model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL-6 signal pathways. This work combines MRI imaging with cisplatin-based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy.

Synergistic chemotherapy and photothermal therapy of lung cancer using MoS2 nanosheets co-loaded with silybin and doxorubicin

The active ingredient in traditional Chinese medicine, silybin (SBN), is known to inhibit the proliferation of cancer cells and synergistically enhance the anticancer effects of the chemotherapy drug doxorubicin (DOX). However, the combination of SBN and DOX faces challenges such as a lack of targeting, short half-lives, different administration routes, and pharmacokinetic processes, which prevent the drug combination from effectively targeting tumors and diminish their synergistic potential, thereby limiting their in vivo antitumor effects. In response, this study proposes the development of a novel nanocarrier system based on molybdenum disulfide (MoS₂) modified with polyethylene glycol (PEG) and sialic acid (SA) to co-deliver SBN and DOX. This system is designed to trigger the release of the drugs in response to dual stimuli of pH and near-infrared light, increasing the intracellular concentration of the drugs and enhancing their synergistic interaction. The MoS₂-LPN-SBN/DOX nanosystem circulates within the body and specifically accumulates at tumor sites due to the enhanced permeability and retention (EPR) effect and SA-mediated active targeting. Upon exposure to near-infrared light, the system provides combined chemo- and photothermal therapy, leading to significant tumor suppression. This research offers a new approach and strategy for the clinical treatment of lung cancer, suggesting a promising pathway for enhancing the efficacy of traditional therapies.

Nanocarrier-based drug delivery system with dual targeting and NIR/pH response for synergistic treatment of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

Multi-Sensitive Au NCs/5-FU@Carr-LA Composite Hydrogels for Targeted Multimodal Anti-Tumor Therapy.

Multifunctional targeted drug delivery systems have been explored as a novel cancer treatment strategy to overcome limitations of traditional chemotherapy. The combination of photodynamic therapy and chemotherapy has been shown to enhance efficacy, but the phototoxicity of traditional photosensitizers is a challenge. In this study, we prepared a multi-sensitive composite hydrogel containing gold nanoclusters (Au NCs) and the temperature-sensitive antitumor drug 5-fluorourac il (5-FU) using carboxymethyl cellulose (Carr) as a dual-functional template. Au NCs were synthesized using sodium borohydride as a reducing agent and potassium as a promoter. The resulting Au NCs were embedded in the Carr hydrogel, which was then conjugated with lactobionic acid (LA) as a targeting ligand. The resulting Au NCs/5-FU@Carr-LA composite hydrogel was used for synergistic photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy. Au NCs/5-FU@Carr-LA releases the drug faster at pH 5.0 due to the acid sensitivity of the Carr polymer chain. In addition, at 50 °C, the release rate of Au NCs/5-FU@Carr-LA is 78.2%, indicating that the higher temperature generated by the photothermal effect is conducive to the degradation of Carr polymer chains. The Carr hydrogel stabilized the Au NCs and acted as a matrix for drug loading, and the LA ligand facilitated targeted delivery to tumor cells. The composite hydrogel exhibited excellent biocompatibility and synergistic antitumor efficacy, as demonstrated by in vitro and in vivo experiments. In addition, the hydrogel had thermal imaging capabilities, making it a promising multifunctional platform for targeted cancer therapy.

A versatile nanoplatform carrying cascade Pt nanozymes remodeling tumor microenvironment for amplified sonodynamic/chemo therapy of thyroid cancer

Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (•OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.

Synergistic Photothermal Therapy and Chemotherapy Enabled by Tumor Microenvironment-Responsive Targeted SWCNT Delivery.

As a novel therapeutic approach, photothermal therapy (PTT) combined with chemotherapy can synergistically produce antitumor effects. Herein, dithiodipropionic acid (DTDP) was used as a donor of disulfide bonds sensitive to the tumor microenvironment for establishing chemical bonding between the photosensitizer indocyanine green amino (ICG-NH2) and acidified single-walled carbon nanotubes (CNTs). The CNT surface was then coated with conjugates (HD) formed by the targeted modifier hyaluronic acid (HA) and 1,2-tetragacylphosphatidyl ethanolamine (DMPE). After doxorubicin hydrochloride (DOX), used as the model drug, was loaded by CNT carriers, functional nano-delivery systems (HD/CNTs-SS-ICG@DOX) were developed. Nanosystems can effectively induce tumor cell (MCF-7) death in vitro by accelerating cell apoptosis, affecting cell cycle distribution and reactive oxygen species (ROS) production. The in vivo antitumor activity results in tumor-bearing model mice, further verifying that HD/CNTs-SS-ICG@DOX inhibited tumor growth most significantly by mediating a synergistic effect between chemotherapy and PTT, while various functional nanosystems have shown good biological tissue safety. In conclusion, the composite CNT delivery systems developed in this study possess the features of high biocompatibility, targeted delivery, and responsive drug release, and can achieve the efficient coordination of chemotherapy and PTT, with broad application prospects in cancer treatment.

Actively Targeting Redox-Responsive Multifunctional Micelles for Synergistic Chemotherapy of Cancer.

Stimuli-responsive polymeric micelles decorated with cancer biomarkers represent an optimal choice for drug delivery applications due to their ability to enhance therapeutic efficacy while mitigating adverse side effects. Accordingly, we synthesized a digoxin-modified novel multifunctional redox-responsive disulfide-linked poly(ethylene glycol-b-poly(lactic-co-glycolic acid) copolymer (Bi(Dig-PEG-PLGA)-S2) for the targeted and controlled release of doxorubicin (DOX) in cancer cells. Within the micellar aggregate, the disulfide bond confers redox responsiveness, while the presence of the digoxin moiety acts as a targeting agent and chemosensitizer for DOX. Upon self-assembly in aqueous solution, Bi(Dig-PEG-PLGA)-S2 formed uniformly distributed spherical micelles with a hydrodynamic diameter (D h ) of 58.36 ± 0.78 nm and a zeta potential of -24.71 ± 1.01 mV. The micelles exhibited desirable serum and colloidal stability with a substantial drug loading capacity (DLC) of 6.26% and an encapsulation efficiency (EE) of 83.23%. In addition, the release of DOX demonstrated the redox-responsive behavior of the micelles, with approximately 89.41 ± 6.09 and 79.64 ± 6.68% of DOX diffusing from DOX@Bi(Dig-PEG-PLGA)-S2 in the presence of 10 mM GSH and 0.1 mM H2O2, respectively, over 96 h. Therefore, in HeLa cell lines, DOX@Bi(Dig-PEG-PLGA)-S2 showed enhanced intracellular accumulation and subsequent apoptotic effects, attributed to the targeting ability and chemosensitization potential of digoxin. Hence, these findings underscore the promising characteristics of Bi(Dig-PEG-PLGA)-S2 as a multifunctional drug delivery vehicle for cancer treatment.

Sonoinduced Tumor Therapy and Metastasis Inhibition by a Ruthenium Complex with Dual Action: Superoxide Anion Sensitization and Ligand Fracture.

Photoresponsive ruthenium(II) complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology, as well as for antimicrobial applications. However, the limited penetration power of photons prevents the treatment of deep-seated lesions. In this study, we introduce a sonoresponsive ruthenium complex capable of generating superoxide anion (O2•-) via type I process and initiating a ligand fracture process upon ultrasound triggering. Attaching hydroxyflavone (HF) as an "electron reservoir" to the octahedral-polypyridyl-ruthenium complex resulted in decreased highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps and triplet-state metal to ligand charge transfer (3MLCT) state energy (0.89 eV). This modification enhanced the generation of O2•- under therapeutic ultrasound irradiation at a frequency of 1 MHz. The produced O2•- rapidly induced an intramolecular cascade reaction and HF ligand fracture. As a proof-of-concept, we engineered the Ru complex into a metallopolymer platform (PolyRuHF), which could be activated by low-power ultrasound (1.5 W cm-2, 1.0 MHz, 50% duty cycle) within a centimeter range of tissue. This activation led to O2•- generation and the release of cytotoxic ruthenium complexes. Consequently, PolyRuHF induced cellular apoptosis and ferroptosis by causing mitochondrial dysfunction and excessive toxic lipid peroxidation. Furthermore, PolyRuHF effectively inhibited subcutaneous and orthotopic breast tumors and prevented lung metastasis by downregulating metastasis-related proteins in mice. This study introduces the first sonoresponsive ruthenium complex for sonodynamic therapy/sonoactivated chemotherapy, offering new avenues for deep tumor treatment.

NIR-triggered arsenic-loaded layered double hydroxide-based films for localized thermal synergistic chemotherapy

Portal vein tumor thrombus (PVTT) formed by cancer cell invasion is a major cause of high mortality in hepatocellular carcinoma (HCC), and the formation of thrombus will be accelerated by bacterial colonization on the surface of the implant after surgery. In this work, Polypyrrole-coated arsenic-loaded layered double hydroxide films were in situ constructed on the nickel-titanium alloy for the efficient killing of tumour cells by thermo-therapeutic synergistic chemotherapy. The good near-infrared photothermal conversion ability of polypyrrole enables the sample surface temperature to be raised to about 51 °C at a low photothermal power (0.5 w/cm2), while the elevated temperature could further accelerate the release of drug arsenic. In addition, when NIR light is not applied, the polypyrrole coating also cleverly acts as a “barrier layer” to reduce the natural release of arsenic in normal tissues to avoid toxicity issues. In vivo and in vitro experiments have demonstrated that the platform exhibits excellent antitumor and antibacterial abilities. In contrast to the systemic toxicity issues associated with systemic circulation of nanotherapeutic drugs, this in situ functional film is expected to be used in localised interventions for precise drug delivery, and is also more suitable for surgical treatment scenarios in PVTT surgeries.

Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.