ABSTRACT
The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANPMTO/ALCD) and a deformable nanoadjuvant (PPER848). The ANPMTO/ALCD composite consisted of ß-cyclodextrin-decorated alginate (Alg-g-CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANPMTO) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPER848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.
Subject(s)
Adjuvants, Immunologic , Cancer Vaccines , Immunotherapy , Nanoparticles , Cancer Vaccines/chemistry , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Animals , Mice , Immunotherapy/methods , Nanoparticles/chemistry , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , Adjuvants, Immunologic/pharmacology , Hydrogels/chemistry , Humans , Cell Line, Tumor , Dendritic Cells/immunology , beta-Cyclodextrins/chemistry , Neoplasms/therapy , Neoplasms/immunology , Alginates/chemistry , Adamantane/chemistry , Adamantane/therapeutic useABSTRACT
Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development. However, it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors (TFs) except for the nuclear receptor family of TFs. Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma (GEA) or the therapeutic effects of targeting TF and transcription cofactor complexes. In this study, we found that ETS homologous factor (EHF) expression is promoted by a core transcriptional regulatory circuitry (CRC), specifically ELF3-KLF5-GATA6, and interference with its expression suppressed the malignant biological behavior of GEA cells. Importantly, we identified Ajuba LIM protein (AJUBA) as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA. Furthermore, we identified KRAS signaling as a common pathway downstream of EHF and AJUBA. Applicably, dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo. In conclusion, EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway. Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.
ABSTRACT
To date, five siRNA-based medications have received clinical approval and have demonstrated remarkable therapeutic efficacy in treating various diseases. However, their application has been predominantly limited to liver-specific diseases due to constraints in siRNA delivery capabilities. In this study, we have developed a siRNA delivery system utilizing clinically approved mPEG-b-PLGA, a cationic lipid, and an ionizable lipid. We optimized this system by carefully adjusting their mass ratios, resulting in highly efficient gene silencing. Furthermore, the optimized nanoparticle formulation, which encapsulates siRNA targeting CD47, induces a robust immune response. This response effectively suppresses the progression of melanoma tumors by blocking this critical immune checkpoint.
Subject(s)
Melanoma , Nanoparticles , Polyesters , Polyethylene Glycols , Humans , RNA, Small Interfering , Polymers , Melanoma/drug therapy , Immunotherapy , LipidsABSTRACT
Immune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune checkpoint inhibitor therapy because of immune evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate immune cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes tumor immune evasion in a CD8+ T cell-dependent manner by activating STAT1/PD-L1 in tumor cells. Mechanistically, HKDC1 binds to and presents cytosolic STAT1 to IFNGR1 on the plasma membrane following IFNγ-stimulation by associating with cytoskeleton protein ACTA2, resulting in STAT1 phosphorylation and nuclear translocation. HKDC1 inhibition in combination with anti-PD-1/PD-L1 enhances in vivo T cell antitumor response in liver cancer models in male mice. Clinical sample analysis indicates a correlation among HKDC1 expression, STAT1 phosphorylation, and survival in patients with hepatocellular carcinoma treated with atezolizumab (anti-PD-L1). These findings reveal a role for HKDC1 in regulating immune evasion by coupling cytoskeleton with STAT1 activation, providing a potential combination strategy to enhance antitumor immune responses.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Humans , Male , Mice , B7-H1 Antigen , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cytoskeleton/metabolism , Hexokinase/metabolism , Immune Evasion , Liver Neoplasms/pathology , STAT1 Transcription Factor/metabolism , Tumor EscapeABSTRACT
In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.
Subject(s)
Autophagy , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Proteolysis , Mutant Proteins/metabolism , Mutant Proteins/pharmacology , Cell Line, Tumor , Peptides/metabolism , Lipids/pharmacologyABSTRACT
Ribonucleic acids (RNAs) enable disease-related gene inhibition, expression, and editing and represent promising therapeutics in various diseases. The efficacy of RNA relies heavily on the presence of a secure and effective delivery system. Herein, we found that RNA could be hydrophobized by cationic lipid and ionizable lipid and conveniently coassemble with amphiphilic polymer to achieve micelle-like nanoparticles (MNP). The results of the study indicate that MNP exhibits a high level of efficiency in delivering RNA. Besides, the MNP encapsulating siRNA that targets CD47 and PD-L1 remarkably blocked these immune checkpoints in a melanoma tumor model and elicited a robust immune response. Moreover, the MNP encapsulating the mRNA of OVA achieved antigen translation and presentation, leading to an effective antitumor immunoprophylaxis outcome against OVA-expressing melanoma model. Our findings suggest that RNA hydrophobization could serve as a viable approach for delivering RNA, thereby facilitating the exploration of RNA therapy in disease treatment.
Subject(s)
Melanoma , Nanoparticles , Neoplasms , Humans , Immunotherapy , Nanoparticles/therapeutic use , RNA, Small Interfering/genetics , RNA, Small Interfering/therapeutic use , Micelles , Lipids , Neoplasms/therapyABSTRACT
Efficiently reawakening immune cells, including T cells and macrophages, to eliminate tumor cells is a promising strategy for cancer treatment, but remains a huge challenge nowadays. Herein, a nanoassembly formed by doxorubicin (DOX)-conjugated polyphosphoester (PP-(hDOX)) and CD47-targeting siRNA (siCD47) via electrostatic and π-π stacking interactions, termed as PP-(hDOX&siCD47), was developed to reawaken the T cell and macrophage-mediated anticancer activity. The PP-(hDOX&siCD47) could efficiently blockade antiphagocytic signal by downregulation of CD47 expression to reactive macrophage-mediated anticancer immunotherapy. Moreover, the conjugated DOX of PP-(hDOX&siCD47) can perform the chemotherapy towards tumor cells and also elicit the T cell-mediated anticancer immune response via immunogenic cell death (ICD) effect. Therefore, the PP-(hDOX&siCD47) treatment could significantly increase M1-like macrophages proportion and tumor infiltration of CD8+ T cells, while the proportions of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were considerably reduced in tumor tissue, eventually achieving significantly tumor growth inhibition. Overall, this study provides a simple siRNA and DOX codelivery approach to simultaneously elicit the macrophage- and T cell-mediated anticancer immune response for cancer therapy.
Subject(s)
CD47 Antigen , Neoplasms , RNA, Small Interfering/metabolism , CD8-Positive T-Lymphocytes/metabolism , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Immunotherapy , Macrophages/metabolism , Immunity , Cell Line, Tumor , Neoplasms/drug therapyABSTRACT
T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long-term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate-based hydrogel with abundant ß-cyclodextrin (ALG-ßCD) sites is developed and intratumorally injected to recruit CCR9+ CD8+ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane-decorated anti-PD1 antibody (Ad-aPD1) would hitchhike on recruited CCR9+ CD8+ T cells to achieve the improved intratumoral accumulation of Ad-aPD1. Moreover, the Ad-PD1 and Ad-PDL1 antibodies are immobilized in the ALG-ßCD hydrogel through supramolecular host-guest interactions of Ad and ßCD, which facilitate engagement between CD8+ T cells and tumor cells and reinvigorate CD8+ T cells to avoid exhaustion. Based on this treatment strategy, T cell-mediated anticancer activity is promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16-F10 tumor models.
Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Humans , Hydrogels/metabolism , Immunotherapy , Neoplasms/therapy , Neoplasms/metabolismABSTRACT
The topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin (SN38), has demonstrated potent anticancer activity. However, its clinical application is hindered by its low solubility and high crystallization propensity, which further complicates its encapsulation into nanoparticles for systemic delivery. Herein, we explore the utilization of lipid-assisted poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) nanoparticles to achieve ultrahigh loading capability for SN38. Through the introduction of cationic, anionic, or neutral lipids, the SN38 loading efficiency and loading capacity is elevated to >90% and >10% respectively. These lipids efficiently attenuate the intermolecular π-π stacking of SN38, thereby disrupting its crystalline structure. Moreover, we assess the therapeutic activity of SN38-loaded formulations in various tumor models and identify an anionic lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) sodium salt (DOPG)-assisted formulation that exhibits the highest anticancer activity and has favorable biosafety. Overall, our findings present a simple and robust strategy to achieve ultrahigh loading efficiency of SN38 using commonly employed PEG-b-PLA nanoparticles, opening up a new avenue for the systemic delivery of SN38.
Subject(s)
Nanoparticles , Neoplasms , Humans , Polyethylene Glycols/chemistry , Nanoparticles/chemistry , Fatty Alcohols , Polyesters , Cell Line, TumorABSTRACT
Acute kidney injury (AKI) is closely associated with the overproduction of reactive oxygen species (ROS), which can cause multiple organ dysfunctions without timely treatment. However, only supportive treatments are currently available for AKI in clinics. Here, we developed nanomaterials of hyperbranched polyphosphoester (PPE) containing abundant thioether (S-PPE NP) and thioketal bonds (TK-PPE NP). Our data demonstrates that S-PPE NP exhibits an excellent capability of absorbing and scavenging multiple types of ROS, including H2O2, â¢OH, and â¢O2-, via thioether oxidation to sulfone or sulfoxide; it was also determined that S-PPE NP efficiently eliminates intracellular ROS, thus preventing cellular damage. Moreover, S-PPE NP was able to efficiently accumulate in the injured kidneys of AKI-bearing mice. As a result, the administration of S-PPE NP provided a superior therapeutic effect in AKI-bearing mice by downregulating ROS- and inflammation-related signaling pathways, thus reducing cell apoptosis. This thioether-containing polymer represents a promising broad-spectrum ROS scavenger that can be used for effective AKI treatments.
ABSTRACT
BACKGROUND: Hemodialysis patients are prone to gastrointestinal bleeding, and Mallory-Weiss syndrome (MWS) is one of the causes. Mallory-Weiss syndrome is often induced by severe vomiting, manifests as upper gastrointestinal bleeding, and is self-limited with a good prognosis. However, mild vomiting in hemodialysis patients can lead to the occurrence of MWS, and the mild early symptoms are easy to misdiagnose, leading to the aggravation of the disease. CASE PRESENTATION: In this paper, we report four hemodialysis patients with MWS. All patients displayed symptoms of upper gastrointestinal bleeding. The diagnosis of MWS was confirmed by gastroscopy. One patient had a history of severe vomiting; however, the other three reported histories of mild vomiting. Three patients received the conservative hemostasis treatment, and the gastrointestinal bleeding stopped. One patient underwent the gastroscopic and interventional hemostasis treatments. The conditions of three of the patients improved. Unfortunately, one of the patients died due to the cardia insufficiency. CONCLUSIONS: We think that the mild symptoms of MWS are easily covered up by other symptoms. This may lead to delays in diagnosis and treatment. For patients with severe symptoms, gastroscopic hemostasis is still the first choice, and interventional hemostasis can also be considered. For patients with mild symptoms, drug hemostasis is the first consideration.
Subject(s)
Mallory-Weiss Syndrome , Humans , Conservative Treatment/adverse effects , Death , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/therapy , Mallory-Weiss Syndrome/complications , Mallory-Weiss Syndrome/diagnosis , Vomiting , Adolescent , Middle Aged , Aged , Male , FemaleABSTRACT
Cancer nanomedicine treatment aims to achieve highly specific targeting and localization to cancer cells. Coating of nanoparticles with cell membranes endows them with homologous cellular mimicry, enabling nanoparticles to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused a human-derived HCT116 colon cancer cell membrane (cM) with a red blood cell membrane (rM) to fabricate an erythrocyte-cancer cell hybrid membrane (hM). Oxaliplatin and chlorin e6 (Ce6) co-encapsulated reactive oxygen species-responsive nanoparticles (NPOC) were camouflaged by hM and obtained a hybrid biomimetic nanomedicine (denoted as hNPOC) for colon cancer therapy. hNPOC exhibited prolonged circulation time and recognized homologous targeting ability in vivo since both rM and HCT116 cM proteins were maintained on the hNPOC surface. hNPOC showed enhanced homologous cell uptake in vitro and considerable homologous self-localization in vivo, producing effective synergistic chemophotodynamic therapy efficacy under irradiation with a homologous HCT116 tumor compared to that with a heterologous tumor. Together, the biomimetic hNPOC nanoparticles showed prolonged blood circulation and preferential cancer cell-targeted function in vivo to provide a bioinspired strategy for chemophotodynamic synergistic therapy of colon cancer.
Subject(s)
Colonic Neoplasms , Nanoparticles , Humans , Bionics , Erythrocyte Membrane/metabolism , Phototherapy , Colonic Neoplasms/drug therapy , Reactive Oxygen Species/metabolism , Cell Line, TumorABSTRACT
The abnormal activation of epidermal growth factor receptor (EGFR) drives the development of non-small cell lung cancer (NSCLC). The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR mutation. However, free osimertinib administration exhibits an inadequate response in vivo, with only â¼3% patients demonstrating a complete clinical response. Consequently, we designed a biomimetic nanoparticle (CMNP@Osi) comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery, thereby supporting a dual-target strategy for enhancing osimertinib efficacy. After intravenous injection, CMNP@Osi accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous targeting. Osimertinib is subsequently released into the cytoplasm, where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC cells. Thus, this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.
ABSTRACT
Nanomedicines for combining chemotherapy and sonodynamic therapy (SDT) have enormous potential in squamous cell carcinoma treatment. However, the therapeutic efficacy of noninvasive SDT is severely limited because the generation of reactive oxygen species (ROS) by sonosensitizers is highly dependent on the levels of intracellular excess glutathione (GSH) in the tumor cells. To overcome this barrier, a red blood cell (RBC) membrane-camouflaged nanomedicine consisting of GSH-sensitive polyphosphoester (SS-PPE) and ROS-sensitive polyphosphoester (S-PPE) was designed for the simultaneous delivery of the sonosensitizer hematoporphyrin (HMME) and chemotherapeutic agent docetaxel (DTXL) for effectively enhanced antitumor efficacy. In vitro and in vivo studies demonstrated that HMME-driven ROS generation under ultrasound (US) inhibited SCC7 cell proliferation and accelerated DTXL release to further kill tumor cells via the hydrophobic-hydrophilic transition of the nanoparticle core. Meanwhile, the disulfide bond of SS-PPE effectively consumes GSH to prevent ROS consumption. This biomimetic nanomedicine provides GSH depletion and amplified ROS generation capabilities to achieve a novel synergistic chemo-SDT strategy for squamous cell carcinomas.
Subject(s)
Carcinoma, Squamous Cell , Nanoparticles , Neoplasms , Ultrasonic Therapy , Humans , Reactive Oxygen Species , Biomimetics , Cell Line, Tumor , Nanoparticles/chemistry , Docetaxel/pharmacology , Carcinoma, Squamous Cell/drug therapy , Glutathione , Neoplasms/pathologyABSTRACT
Low immune infiltration severely hinders the efficacy of cancer immunotherapy. Here, we developed a manganese-phenolic network platform (TMPD) to boost antitumor immunity via a stimulator of interferon gene (STING)-amplified activation cascade. TMPD is based on doxorubicin (DOX)-loaded PEG-PLGA nanoparticles and further coated with manganese (Mn2+)-tannic acid (TA) networks. Mechanistically, DOX-based chemotherapy and Mn2+-mediated chemodynamic therapy effectively promoted immunogenic cell death (ICD), characterized by abundant damage-associated molecular pattern (DAMP) exposure, which subsequently enhanced dendritic cells' (DCs) presentation of antigens. DOX-elicited DNA damage simultaneously caused cytoplasmic leakage of intracellular double-stranded DNA (dsDNA) as the STING signal initiator, while Mn2+ mediated significant upregulation in the expression of a STING pathway-related protein thereby amplifying the STING signal. Systemic intravenous administration of TMPD remarkably promoted DC maturation and CD8+ T cell infiltration, thus eliciting strong antitumor effects. Meanwhile, the released Mn2+ could serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Moreover, TMPD combined with immune checkpoint blockade (ICB) immunotherapy significantly inhibited tumor growth and lung metastasis. Collectively, these findings indicate that TMPD has great potential in activating robust innate and adaptive immunity for MRI guided cancer chemo-/chemodynamic/immune therapy.
Subject(s)
Manganese , Neoplasms , Humans , Magnetic Resonance Imaging , Immunotherapy , Up-Regulation , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Sorafenib is the first line drug for hepatocellular carcinoma (HCC) therapy. However, HCC patients usually acquire resistance to sorafenib treatment within 6 months. Recent evidences have shown that anticancer drugs with antiangiogenesis effect (e.g., sorafenib) can aggravate the hypoxia microenvironment and promote the infiltration of more tumor-associated macrophages (TAMs) into the tumor tissues. Therefore, repolarization of TAMs phenotype could be expected to not only eliminate the influence of TAMs on sorafenib lethality to HCC cells, but also provide an additional anticancer effect to achieve combination therapy. However, immune side effects remain a great challenge due to the non-specific macrophage repolarization in normal tissues. We herein employed a tumor microenvironment (TME) pH-responsive nanoplatform to concurrently transport sorafenib and modified resiquimod (R848-C16). This nanoparticle (NP) platform is made with a TME pH-responsive methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) copolymer. After intravenous administration, the co-delivery NPs could highly accumulate in the tumor tissues and then respond to the TME pH to detach their surface PEG chains. With this PEG detachment to enhance uptake by TAMs and HCC cells, the co-delivery NPs could combinatorially inhibit HCC tumor growth via sorafenib-mediated lethality to HCC cells and R848-mediated repolarization of TAMs into tumoricidal M1-like macrophages. STATEMENT OF SIGNIFICANCE: Anticancer drugs with antiangiogenesis effect (e.g., sorafenib) can aggravate the hypoxia microenvironment and promote the infiltration of more tumor-associated macrophages (TAMs) into the tumor tissues to restrict the anticancer effect. In this work, we designed and developed a tumor microenvironment (TME) pH-responsive nanoplatform for systemic co-delivery of sorafenib and resiquimod in hepatocellular carcinoma (HCC) therapy. These co-delivery NPs show high tumor accumulation and could respond to the TME pH to enhance uptake by TAMs and HCC cells. With the sorafenib-mediated lethality to HCC cells and R848-mediated repolarization of TAMs, the co-delivery NPs show a combinational inhibition of HCC tumor growth in both xenograft and orthotopic tumor models.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Nanoparticles , Humans , Sorafenib , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Angiogenesis Inhibitors/therapeutic use , Cell Line, Tumor , Antineoplastic Agents/therapeutic use , Macrophages/pathology , Tumor Microenvironment , Nanoparticles/therapeutic useABSTRACT
Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlink m -PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.
ABSTRACT
The passive diffusion performance of nanocarriers results in inefficient drug transport across multiple biological barriers and consequently cancer therapy failure. Here, a magnetically driven amoeba-like nanorobot (amNR) is presented for whole-process active drug transport. The amNR is actively extravasated from blood vessels and penetrated into deep tumor tissue through a magnetically driven deformation effect. Moreover, the acidic microenvironment of deep tumor tissue uncovers the masked targeting ligand of amNR to achieve active tumor cell uptake. Furthermore, the amNR rapidly releases the encapsulated doxorubicin (DOX) after alternating magnetic field application. The amNRs eventually deliver DOX into ≈92.3% of tumor cells and completely delay tumor growth with an inhibition rate of 96.1%. The deformable amNRs, with the assistance of magnetic field application, provide a facile strategy for whole-process active drug transport.
Subject(s)
Amoeba , Biological Transport , Doxorubicin , Magnetic FieldsABSTRACT
Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , RNA, Long Noncoding , Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Liver Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Transcription Factors/geneticsABSTRACT
Multifunctional magnet-fluorescent nanocomposites are widely applied in biomedical applications. Incorporating biocompatible quantum dots with highly ferrimagnetic magnetic nanoparticles into one nanoplatform for achieving efficient magnetic hyperthermia therapy (MHT) is very important. Herein, we reported an amphiphilic block copolymer with a flowable hydrophobic chain to encapsulate highly ferrimagnetic magnetic nanoparticles and ZnS/InP quantum dots via a facile self-assembly method. The obtained ferrimagnetic fluorescent micelle (FMFM) exhibited a uniform diameter of about 180 nm. In stark contrast, larger aggregation (400 nm in diameter) inevitably occurred using common poly(D,L-lactide) (PLA)-based amphiphilic block copolymer with a rigid hydrophobic chain, which was readily cleared by the reticuloendothelial system (RES). The flowable FMFM exhibited long-term colloidal stability within one month and desired fluorescent stability within 84 h. Benefiting from the high ferrimagnetism, the FMFM revealed excellent magnetic heating effect and magnetic resonance imaging capability. With accurate manipulation under an external magnetic field, FMFM realized in vitro enhanced fluorescence imaging sensitivity and accumulation efficiency at the tumor region, achieving in vitro and vivo improved MHT efficacy.