Tumor Microenvironment-Responsive Biodegradable Nanomedicine for Self-Enhanced Synergistic Chemo-, Photothermal, and Chemodynamic Therapy.

The nanoscale multidrug codelivery system for synergistic therapy is an effective strategy for tumor treatment. However, the low drug delivery efficiency and poor therapeutic effects limit its application. Here, based on the coordination effect of Artemisinin (Art), quercetin (Qc), and Fe3+, we had constructed a safe and efficient carrier-free hyaluronic acid (HA)-modified Art-Fe-Qc nanoparticles (AFQ@HA NPs) for enhanced chemotherapy/photothermal therapy (PTT)-chemodynamic therapy (CDT) synergistic therapy, which achieved an ultrahigh drug loading efficiency and a multifunction anticancer strategy. The results showed that high drug loading was achieved based on drug coordination self-assembly, with Art and Qc contents of 38.6 and 42.7%, respectively. At the same time, based on the Qc-Fe coordination molecular network, the system had excellent photothermal conversion performance with an efficiency of 57.3% and could effectively inhibit the expression of HSP70, achieving enhanced PTT. Further, under the stimulation of excessive H2O2 and glutathione (GSH) in the tumor microenvironment, the AFQ@HA NPs were continuously degraded, while releasing Art and Fe3+/Fe2+ to achieve iron ion-enhanced CDT. The results of in vitro and in vivo experiments showed that AFQ@HA NPs could achieve chemotherapy-PTT-CDT synergistic therapy in response to tumor microenvironment by passively targeting and actively targeting tumor cells with CD44, demonstrating its excellent targeted antitumor effects.

A combination of a TLR7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune.

BACKGROUND: Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor. METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining. RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model. CONCLUSION: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.

Functionalized Carbon Nanotubes for Delivery of Ferulic Acid and Diosgenin Anticancer Natural Agents.

It was investigated whether loading multi-wall carbon nanotubes (CNTs) with two natural anticancer agents: ferulic acid (FUA) and diosgenin (DGN), may enhance the anticancer effect of these drugs. The CNTs were functionalized with carboxylic acid (CNTCOOH) or amine (CNTNH2), loaded with the above pro-drugs, as well as both combined and coated with chitosan or chitosan-stearic acid. Following physicochemical characterization, the drug-loading properties and kinetics of the drug's release were investigated. Their effects on normal human skin fibroblasts and MCF-7 breast carcinoma cells, HepG2 hepatocellular carcinoma cells, and A549 non-small-cell lung cancer cells were evaluated in vitro. Their actions at the molecular level were evaluated by assessing the expression of lncRNAs (HULC, HOTAIR, CCAT-2, H19, and HOTTIP), microRNAs (mir-21, mir-92, mir-145, and mir-181a), and proteins (TGF-ß and E-cadherin) in HepG2 cells. The release of both pro-drugs depended on the glutathione concentration, coating, and functionalization. Release occurred in two stages: a no-burst/zero-order release followed by a sustained release best fitted to Korsmeyer-Peppas kinetics. The combined nanoformulation cancer inhibition effect on HepG2 cancer cells was more pronounced than for A549 and MCF7 cells. The combined nanoformulations had an additive impact followed by a synergistic effect, with antagonism demonstrated at high concentrations. The nanoformulation coated with chitosan and stearic acid was particularly successful in targeting HepG2 cells and inducing apoptosis. The CNT functionalized with carboxylic acid (CNTCOOH), loaded with both FUA and DGN, and coated with chitosan-stearic acid inhibited the expression of lncRNAs and modulated both microRNAs and proteins. Thus, nanoformulations composed of functionalized CNTs dual-loaded with FUA and DGN and coated with chitosan-stearic acid are a promising drug delivery system that enhances the activity of natural pro-drugs.

Mechanism underlying joint loading and controlled release of ß-carotene and curcumin by octenylsuccinated Gastrodia elata starch aggregates.

This study aimed to fabricate a novel codelivery system to simultaneously load ß-carotene and curcumin in a controlled and synergistic manner. We hypothesized that the aggregates of octenylsuccinated Gastrodia elata starch (OSGES) could efficiently load and control the release of ß-carotene and curcumin in combination. Mechanisms underlying the self-assembly of OSGES, coloading, and corelease of ß-carotene and curcumin by relevant aggregates were studied. The OSGES could form aggregates with a size of 120.2 nm containing hydrophobic domains surrounded by hydrophilic domains. For coloading, the increased solubilities were attributed to favorable interactions between ß-carotene and curcumin as well as interactions with octenyl and starch moieties via hydrophobic and hydrogen-bond interactions, respectively. The ß-carotene and curcumin molecules occupied the interior and periphery of hydrophobic domains of OSGES aggregates, respectively, and they did not exist in isolation but interacted with each other. The ß-carotene and curcumin combination-loaded OSGES aggregates with a size of 310.5 nm presented a more compact structure than ß-carotene-only and curcumin-only loaded OSGES aggregates with sizes of 463.5 and 202.9 nm respectively, suggesting that a transition from a loose cluster to a compact cluster was accompanied by coloading. During in vitro digestion, the joint effect of ß-carotene and curcumin prolonged their release and increased their bioaccessibility due to competition between favorable hydrophobic and hydrogen-bond interactions and the unfavorable structure erosion and relaxation of the loaded aggregates. Therefore, OSGES aggregates were designed for the codelivery of ß-carotene and curcumin, indicating their potential to be applied in functional foods and dietary supplements.

Targeted drug delivery systems for elemene in cancer therapy: The story thus far.

Elemene (ELE) is a group of broad-spectrum anticancer active ingredients with low toxicity extracted from traditional Chinese medicines (TCMs), such as Curcumae Rhizoma and Curcuma Radix, which can exert antitumour activities by regulating various signal pathways and targets. However, the strong hydrophobicity, short half-life, low bioavailability and weak in vivo targeting ability of ELE restrict its use. Targeted drug delivery systems based on nanomaterials are among the most viable methods to overcome these shortcomings. In this review, we first summarize recent studies on the clinical uses of ELE as an adjunct antitumour drug. ELE-based combination strategies have great promise for enhancing efficacy, reducing adverse reactions, and improving patients' quality of life and immune function. Second, we summarize recent studies on the antitumour mechanisms of ELE and ELE-based combination strategies. The potential mechanisms include inducing pyroptosis and ferroptosis, promoting senescence, regulating METTL3-mediated m6A modification, suppressing the Warburg effect, and inducing apoptosis and cell cycle arrest. Most importantly, we comprehensively summarize studies on the combination of targeted drug delivery systems with ELE, including passively and actively targeted drug delivery systems, stimuli-responsive drug delivery systems, and codelivery systems for ELE combined with other therapies, which have great promise in improving drug bioavailability, increasing drug targeting ability, controlling drug release, enhancing drug efficacy, reducing drug adverse effects and reversing MDR. Our summary will provide a reference for the combination of TCMs such as ELE with advanced targeted drug delivery systems in the future.

Doxorubicin-Loaded Polyelectrolyte Multilayer Capsules Modified with Antitumor DR5-Specific TRAIL Variant for Targeted Drug Delivery to Tumor Cells.

Recently, biodegradable polyelectrolyte multilayer capsules (PMC) have been proposed for anticancer drug delivery. In many cases, microencapsulation allows to concentrate the substance locally and prolong its flow to the cells. To reduce systemic toxicity when delivering highly toxic drugs, such as doxorubicin (DOX), the development of a combined delivery system is of paramount importance. Many efforts have been made to exploit the DR5-dependent apoptosis induction for cancer treatment. However, despite having a high antitumor efficacy of the targeted tumor-specific DR5-B ligand, a DR5-specific TRAIL variant, its fast elimination from a body limits its potential use in a clinic. A combination of an antitumor effect of the DR5-B protein with DOX loaded in the capsules could allow to design a novel targeted drug delivery system. The aim of the study was to fabricate PMC loaded with a subtoxic concentration of DOX and functionalized with the DR5-B ligand and to evaluate a combined antitumor effect of this targeted drug delivery system in vitro. In this study, the effects of PMC surface modification with the DR5-B ligand on cell uptake both in 2D (monolayer culture) and 3D (tumor spheroids) were studied by confocal microscopy, flow cytometry and fluorimetry. Cytotoxicity of the capsules was evaluated using an MTT test. The capsules loaded with DOX and modified with DR5-B demonstrated synergistically enhanced cytotoxicity in both in vitro models. Thus, the use of the DR5-B-modified capsules loaded with DOX at a subtoxic concentration could provide both targeted drug delivery and a synergistic antitumor effect.

A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer.

Lacking nano-systems for precisely codelivering the chemotherapeutics paclitaxel (PTX) and the natural P-glycoprotein (P-gp) inhibitor, quercetin (QU), into cancer cells and controlling their intracellular release extremely decreased the anticancer effects in multidrug resistant (MDR) tumors. To overcome this hurdle, we constructed hybrid polymeric nanoparticles (PNPs) which consist of redox-sensitive PTX/polyethyleneimine-tocopherol hydrogen succinate-dithioglycollic acid PNPs and pH-sensitive hyaluronic acid-QU conjugates. The obtained hybrid PNPs can be internalized into drug-resistant breast cancer cells by the hyaluronic acid/CD44-mediated endocytosis pathway and escape from the lysosome through the "proton sponge effect". Under the trigger of intracellular stimuli, the nanoplatform used the pH/glutathione dual-sensitive disassembly to release QU and PTX. The PTX diffused into microtubules to induce tumor cell apoptosis, while QU promoted PTX retention by down-regulating P-gp expression. Moreover, tocopherol hydrogen succinate and QU disturbed mitochondrial functions by generating excessive reactive oxygen species, decreasing the mitochondrial membrane potential, and releasing cytochrome c into the cytosol which consequently achieved intracellular multilevel chemotherapy amplification in MDR cancers. Importantly, the PNPs substantially suppressed tumors growth with an average volume 2.54-fold lower than that of the control group in the MCF-7/ADR tumor-bearing nude mice model. These presented PNPs would provide a valuable reference for the coadministration of natural compounds and anticarcinogens for satisfactory combination therapy in MDR cancers.

Hyaluronic Acid-Modified Nanoparticles Self-Assembled from Linoleic Acid-Conjugated Chitosan for the Codelivery of miR34a and Doxorubicin in Resistant Breast Cancer.

In this study, a chitosan-based, self-assembled nanosystem that codelivered microRNA34a (miR34a) and doxorubicin (Dox) with hyaluronic acid (HA) modification (named CCmDH NPs) was developed to reverse the resistance of breast cancer (BCa) cells to Dox. The CCmDH NPs had a diameter of 180 ± 8.3 nm and a ζ potential of 16.5 mV with a slow-release effect for 96 h. The codelivery system could protect miR34a from nuclease and serum degradation and transport miR34a and Dox into drug-resistant MCF-7/A cells. In addition, the CCmDH NPs could inhibit proliferation and promote apoptosis by regulating the protein expression of B-cell lymphoma-2 (Bcl-2) and poly(ADP-ribose) polymerase (PARP) and inhibit invasion, metastasis, and adhesion by regulating E-cadherin, N-cadherin, MMP2, CD44, and Snail molecules. The CCmDH NPs induced a 73.7% tumor reduction in xenograft tumor growth in nude mice in vivo. This study provides evidence for the anticancer activity of CCmDH NPs carrying Dox and miR34a in BCa, especially metastatic Dox-resistant BCa models.

Rational design and latest advances of codelivery systems for cancer therapy.

Current treatments have limited effectiveness in treating tumors. The combination of multiple drugs or treatment strategies is widely studied to improve therapeutic effect and reduce adverse effects of cancer therapy. The codelivery system is the key to realize combined therapies. It is necessary to design and construct different codelivery systems in accordance with the variable structures and properties of cargoes and vectors. This review presented the typical design considerations about codelivery vectors for cancer therapy and described the current state of codelivery systems from two aspects: different types of vectors and collaborative treatment strategies. The commonly used loading methods of cargoes into the vectors, including physical and chemical processes, are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of codelivery systems.

Hexahistidine-Metal Assemblies: A Facile and Effective Codelivery System of Subunit Vaccines for Potent Humoral and Cellular Immune Responses.

Fully effective vaccines must induce both potent humoral and cellular immunities. Nanoparticles coencapsulating antigens and adjuvants have shown promising advantages as subunit vaccines in many aspects. However, the low loading efficiency and complicated synthesis process of these nanomaterials need to be improved. Here, we utilized hexahistidine (His6)-metal assembly (HmA) particles as carriers to codeliver ovalbumin peptides and cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). We found that antigen/adjuvant-carrying HmA can efficiently enter into antigen-presenting cells and help the antigens escape from lysosomes to induce the maturation of these cells in vitro, characterized by increasing expression levels of costimulatory molecules and cytokines. More importantly, the vaccines with high biocompatibility can elicit strong humoral and cellular immunities by improving secretion of specific antibodies and cytokines, enhancing activation of DCs and T cells in vivo. Our results suggest that HmA provides a new approach for subunit vaccines by codelivery of antigens and adjuvants.

Targeting and Specific Activation of Antigen-Presenting Cells by Endogenous Antigen-Loaded Nanoparticles Elicits Tumor-Specific Immunity.

Immunotherapy has shown tremendous promise for improving cancer treatment. Unfortunately, antigen-presenting cells (APCs) in cancer patients cannot effectively recognize and process tumor antigens to activate host immune responses. In this study, an approach is developed to improve cancer immunotherapy that utilizes endogenous antigen-carrying nanoparticles (EAC-NPs), which encompasses a set of antigens isolated from solid tumors and adjuvants. The EAC-NPs specifically target APCs and subsequently result in enhanced T cell responses and improved antitumor efficacy. Mechanistic studies reveal that the EAC-NPs enhance and prolong the presence of immune compounds in APCs, which ensure persistent antigen loading and stimulation, induce a rapid proliferation of CD4+ and CD8+ T cells, and significantly increase the ratios of intratumoral CD4+ T/Treg and CD8+ T/Treg. The work using nanotechnology provides a promising strategy in improving antitumor immunity by enhancing the immunogenicity and presentation of tumor self-antigens for cancer immunotherapy.

Multifunctional Nanomodulators Regulate Multiple Pathways To Enhance Antitumor Immunity.

Immunosuppression is a key factor leading to a low therapeutic efficiency of the currently used immunotherapies. Monotherapies are unable to overcome immunosuppression because of the complex interplay of immune cells in tumors. Herein, we report a multifunctional nanomodulator (MFNM) as a carrier to deliver different types of immune modulators for comodulating multiple pathways. An MFNM has a core-shell structure, in which small-molecule drugs are encapsulated in a mesoporous silica nanoparticle (MSN) core with a pH-responsive polymer layer. Further, the polymeric shell provides active sites that are readily modifiable by multiple types of antibodies to regulate the immune-related processes. By codelivering cyclophosphamide (CTX), αPD-L1 (B7-H1), and α4-1BB (CD137L) monoclonal antibodies (mAbs) to tumors, an MFNM has been shown to regulate multiple immune pathways and enhance an antitumor immunity. As antibodies and small-molecule drugs loaded in an MFNM can be modified based on the tumor type, the MFNM provides a feasible platform for the development of advanced immunotherapies that require simultaneous modulation of multiple biological processes.

Nanoparticle-siRNA: a potential strategy for ovarian cancer therapy?

Ovarian cancer is one of the most common causes of mortality throughout the world. Unfortunately, chemotherapy has failed to cure advanced cancers developing multidrug resistance (MDR). Moreover, it has critical side effects because of nonspecific toxicity. Thanks to specific silencing of oncogenes and MDR-associated genes, nano-siRNA drugs can be a great help address the limitations of chemotherapy. Here, we review the current advances in nanoparticle-mediated siRNA delivery strategies such as polymeric- and lipid-based systems, rigid nanoparticles and nanoparticles coupled to specific ligand systems. Nanoparticle-based codelivery of anticancer drugs and siRNA targeting various mechanisms of MDR is a cutting-edge strategy for ovarian cancer therapy, which is completely discussed in this review.

Quick synthesis of a novel combinatorial delivery system of siRNA and doxorubicin for a synergistic anticancer effect.

Purpose: Combining siRNA and other chemotherapeutic agents into one nanocarrier can overcome the multidrug resistance (MDR) phenomenon by synergistically MDR relative genes silencing and elevated chemotherapeutic activity. Most of these systems are typically fabricated through complicated procedures, which involves materials preparation, drug loading and modifications. Herein, the purpose of this study is to develop a new and fast co-delivery system of siRNA and doxorubicin for potentially synergistic cancer treatment. Methods: The co-delivery system is constructed conveniently by a stable complex consisting of doxorubicin bound to siRNA via intercalation firstly, followed by interacting with (3-Aminopropyl)triethoxysilane (APTES) electrostatically and Tetraethyl orthosilicate (TEOS) co-condensed, and the characterizations of the resultant nanocarrier are also investigated. Furthermore, this study evaluates the synergistic anti-cancer efficacy in MCF-7/MDR cells after treatment of siRNA and doxorubicin 'two in one' nanocarriers. Results: We establish a new and fast method to craft a co-delivery system of siRNA and doxorubicin with controllable and nearly uniform size, and the entire fabrication process only costs in about 10 minutes. The resultant co-delivery system presents high loading capacities of siRNA and doxorubicin, and the encapsulated doxorubicin plays a pH-responsive control release. Further, biological functionality tests of the synthesized co-delivery nanocarriers show high inhibition of P-gp protein encoded by MDR-1 gene in MCF-7/MDR cells (a variant of human breast cancer cell line with drug resistance) after transfection of these nanocarriers carrying MDR-1 siRNA and doxorubicin simultaneously, which sensitize the MCF-7/MDR cells to doxorubicin, overall leading to improved cell suppression. Conclusion: Collectively, this co-delivery system not only serves as potent therapeutics for synergistic cancer therapy, it also may facilitate the bench-to-bedside translation of combinatorial delivery system as a robust drug nanocarrier by allowing for fabricating a simply and fast nanocarrier for co-delivery of siRNA and doxorubicin with predictable high production rate.

Preparation of a Codelivery System Based on Vancomycin/Silk Scaffold Containing Silk Nanoparticle Loaded VEGF.

One of the main challenges of using biomaterials for inducing bone regeneration is the bacterial resistance before complete bone repair. Biomaterials with both antibacterial and bone regeneration properties are more promising for bone repair. In the present study, vascular endothelial growth factor (VEGF) was loaded on silk fibroin nanoparticles (SFNPs) and then embedded in silk scaffold containing vancomycin to form a dual drug release system. The chemical and physical properties of the fabricated structure were confirmed by Fourier transform infrared, scanning electron microscopy, and ζ-potential analysis. The size of spherical SFNPs was ∼92 nm. The release kinetics of vancomycin and VEGF showed that ∼99.56% of vancomycin and ∼14% of VEGF were released during 21 and 28 days, respectively. The bioactivity of VEGF was ∼75%. Disk diffusion test confirmed the ability of this drug delivery system against methicillin-resistant Staphylococcus aureus (MRSA). Moreover, expression of the endothelial markers (FLK-1, vWF, and VE-cadherin), alkaline phosphatase, and matrix mineral production were higher in VEGF loaded groups. Taken together, the results indicated that the fabricated codelivery system was able to simultaneously deliver antibiotic and angiogenic factor, which can be considered as a potential candidate for the treatment of contaminated bone injuries.

Nanoparticle-mediated delivery of siRNA for effective lung cancer therapy.

Lung cancer is one of the most lethal diseases worldwide, and the survival rate is less than 15% even after the treatment. Unfortunately, chemotherapeutic treatments for lung cancer are accompanied by severe side effects, lack of selectivity and multidrug resistance. In order to overcome the limitations of conventional chemotherapy, nanoparticle-mediated RNA interference drugs represent a potential new approach due to selective silencing effect of oncogenes and multidrug resistance related genes. In this review, we provide recent advancements on nanoparticle-mediated siRNA delivery strategies including lipid system, polymeric system and rigid nanoparticles for lung cancer therapies. Importantly, codelivery of siRNA with conventional anticancer drugs and recent theranostic agents that offer great potential for lung cancer therapy is covered.