ABSTRACT
Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.
Subject(s)
Neoplasms , Toll-Like Receptor 7 , Animals , Mice , Toll-Like Receptor 7/agonists , Reactive Oxygen Species , Immunotherapy/methods , Neoplasms/therapy , Adjuvants, Immunologic , Polymers/chemistry , Vaccination , Cell Line, TumorABSTRACT
The aggregation-caused quenching has always limited the high concentration and solid-state applications of carbon nanodots. While the aggregation-induced emission effect, dominated by intramolecular motion, may be an effective means to solve this problem. Here, hydrophobic solid-state red-light carbon nanodots (M-CDs) with 95% yield are synthesized by a one-step hydrothermal method using 2,2'-dithiodibenzoic acid as the carbon source and manganese acetate as the dopant source. The disulfide bond of 2,2'-dithiodibenzoic acid serves as the symmetry center of molecular rotation and Mn catalyzes the synthesis of M-CDs, which promotes the formation of the central graphitic carbon structure. The M-CDs/agar hydrogel composites can achieve fluorescence transition behavior because of the special fluorescence transition properties of M-CDs. When this composite hydrogel is placed in water, water molecules contact with M-CDs through the network structure of the hydrogels, making the aggregated hydrogels of M-CDs fluorescence orange-red under 365 nm excitation. While in dimethyl sulfoxide, water molecules in the hydrogels network are replaced and the M-CDs fluoresce blue when dispersed, providing a potential application in information encryption. In addition, high-performance monochromatic light-emitting diode (LED) devices are prepared by compounding M-CDs with epoxy resin and coating them on 365 nm LED chips.
ABSTRACT
Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor T cells have received clinical approval for monotherapy and combination treatment use in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs) have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here we review the current development of STING-activating therapeutics in both preclinical or clinical stages.
ABSTRACT
Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
Subject(s)
Nanoparticles , Neoplasms , Allografts , Early Detection of Cancer , Humans , KidneyABSTRACT
Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well-established to have antitumour and anti-fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF-LA@DSPE-PEG and MMF-LA@PEG-PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG5k -PLA8k and DSPE- PEG2k , respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti-HCC efficacy of nanoparticles (NPs), whereas NIH-3T3 fibroblasts and highly-fibrotic HCC models were used to explore the anti-fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF-LA@DSPE-PEG achieved significantly higher anti-HCC efficacy than free MMF and MMF-LA@PEG-PLA both in C57BL/6 HCC model and highly-fibrotic HCC models. Immunohistochemistry further confirmed that MMF-LA@DSPE-PEG dramatically reduced cancer-associated fibroblast (CAF) density in tumours, as the expression levels of alpha-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF-LA@DSPE-PEG might act as a rational therapeutic strategy in treating HCC and preventing post-transplant HCC recurrence.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Drug Compounding/methods , Drug Delivery Systems/methods , Mycophenolic Acid/pharmacology , Nanoparticles/therapeutic use , Actins/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Collagen/metabolism , Disease Models, Animal , Endopeptidases/metabolism , Fibroblasts/metabolism , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Linoleic Acid/chemistry , Liver Neoplasms/drug therapy , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Nanoparticles/chemistry , Polymers/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.
Subject(s)
Heart Transplantation , Hematopoietic Stem Cell Transplantation , Nanoparticles , Prodrugs , Animals , Graft Rejection/drug therapy , Graft Rejection/etiology , Graft Rejection/prevention & control , Graft Survival , Humans , Immunosuppressive Agents , Mice , TOR Serine-Threonine KinasesABSTRACT
Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP4), resulting in blocking of GLP-1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP-1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP-1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9-39, a GLP-1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC-1α signalling pathway was activated by sitagliptin stimulating GLP-1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP-1R-induced AMPK/ PGC-1α signalling pathway after SCI.
Subject(s)
Apoptosis/drug effects , Axons/drug effects , Axons/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Nerve Regeneration/drug effects , Sitagliptin Phosphate/pharmacology , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/rehabilitation , Animals , Biomarkers , Cells, Cultured , Disease Models, Animal , Female , Fluorescent Antibody Technique , Glucagon-Like Peptide-1 Receptor/genetics , Locomotion/drug effects , Locomotion/genetics , Mitochondria/drug effects , Mitochondria/metabolism , Neurons/drug effects , Neurons/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Rats , Recovery of Function/drug effects , Signal Transduction/drug effects , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/pathologyABSTRACT
In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC50 values at the range of 3.3-15.0â µm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.
Subject(s)
Antineoplastic Agents , Cisplatin/chemistry , Organometallic Compounds , Ovarian Neoplasms , Ruthenium , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Female , Humans , Mice , Organometallic Compounds/metabolism , Ruthenium/pharmacologyABSTRACT
Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3' or 5' overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830.
Subject(s)
DNA, Neoplasm/genetics , Drug Resistance, Neoplasm/genetics , Kruppel-Like Transcription Factors/genetics , Lung Neoplasms/genetics , Recombinational DNA Repair , Stomach Neoplasms/genetics , Animals , Antineoplastic Agents/therapeutic use , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Binding Sites , Camptothecin/therapeutic use , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , DNA Breaks, Double-Stranded , DNA, Neoplasm/metabolism , Endodeoxyribonucleases , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Genomic Instability , Humans , Hydroxyurea/therapeutic use , Kruppel-Like Transcription Factors/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Mice , Mice, Nude , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoblasts/pathology , Phosphorylation , Protein Binding , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Analysis , Xenograft Model Antitumor AssaysABSTRACT
An efficient annulation of α-imino rhodium carbenes with α,ß-unsaturated ketones has been developed to generate multisubstituted 2,3-dihydropyrrole derivatives. Using the optimized catalyst, this approach is compatible with both cyclic and normal linear α,ß-unsaturated ketones. Further detosylation in the presence of base could produce multisubstituted pyrroles. The new method has the potential to enable the rapid construction of bioactive molecules containing pyrrole rings.
ABSTRACT
BACKGROUND AND AIM: Our previous proteomic research found that chloride intracellular channel 1 (CLIC1) was upregulated in hepatocellular carcinoma (HCC) tissues with portal vein tumor thrombus. The present study aimed to determine the role of CLIC1 in HCC invasion. METHODS: Immunohistochemistry was used to explore protein expression of CLIC1 in 15 cirrhotic tissues and 69 pairs of HCC and paracarcinoma tissues. Small interfering RNA (siRNA) and plasmids were transfected into HepG2 and SMMC7721 cells, and the in vitro function of CLIC1 in these cells were assessed with cell counting kit-8 assays, cell apoptosis assays, scratch assays, and transwell assays. Microarray analysis was also performed to further explore the candidate genes related to CLIC1. RESULTS: Our results confirmed that upregulated CLIC1 expression was significantly correlated with vascular invasion (P = 0.034) in HCC tissues. Knockdown of CLIC1 decreased cell viability and the invasive potency of HepG2 cells, whereas CLIC1 overexpression resulted in an opposite effect in SMMC7721 cells. Microarray analysis identified 618 genes that were differentially expressed (fold change ≥ 2, P < 0.05) between HepG2 cells transfected with CLIC1 siRNA and the negative control. Further studies indicate that knockdown of CLIC1 increased maspin expression and reduced vascular endothelial growth factor (VEGF), matrixmetalloproteinase-2 (MMP2), MMP9, MMP11, and MMP12 expression. In contrast, overexpression of CLIC1 decreased maspin expression and increased VEGF, MMP2, MMP12, and MMP13 expression. CONCLUSIONS: CLIC1 protein expression is significantly correlated with vascular invasion, and the present study suggests a previously unknown mechanism of CLIC1-mediated control of HCC invasiveness by targeting maspin.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Chloride Channels/physiology , Gene Expression Regulation, Neoplastic/genetics , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Serpins/genetics , Serpins/metabolism , Adult , Aged , Carcinoma, Hepatocellular/blood supply , Cell Movement , Female , Hep G2 Cells , Humans , Liver Neoplasms/blood supply , Male , Middle Aged , Neoplasm Invasiveness/geneticsABSTRACT
A small library of water-soluble N-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd-NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki-Miyaura coupling of various unnatural amino acids and proteins bearing p-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC-stabilized metal complexes have potential utility in cellular systems.
Subject(s)
Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Organometallic Compounds/chemistry , Palladium/chemistry , Catalysis , Methane/chemistry , Molecular StructureABSTRACT
Drug-loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality.
Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Drug Carriers , Polymers/chemistry , Prodrugs/chemistry , Antineoplastic Agents/pharmacology , Camptothecin/administration & dosage , Camptothecin/pharmacology , Irinotecan , Microscopy, Electron, Transmission , Prodrugs/administration & dosage , Prodrugs/pharmacologyABSTRACT
Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.
ABSTRACT
Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.
Subject(s)
Hydrogels , Infrared Rays , Animals , Mice , Hydrogels/chemistry , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Nanoparticles/chemistry , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Mice, Inbred C57BL , Immunotherapy , Female , Polyesters/chemistryABSTRACT
Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the STING pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment (TME). The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic TME, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.
ABSTRACT
Organ transplantation is the preferred paradigm for patients with end-stage organ failures. Despite unprecedented successes, complications such as immune rejection, ischemia-reperfusion injury, and graft dysfunction remain significant barriers to long-term recipient survival after transplantation. Conventional immunosuppressive drugs have limited efficacy because of significant drug toxicities, high systemic immune burden, and emergence of transplant infectious disease, leading to poor quality of life for patients. Nanoparticle-based drug delivery has emerged as a promising medical technology and offers several advantages by enhancing the delivery of drug payloads to their target sites, reducing systemic toxicity, and facilitating patient compliance over free drug administration. In addition, nanotechnology-based imaging approaches provide exciting diagnostic methods for monitoring molecular and cellular changes in transplanted organs, visualizing immune responses, and assessing the severity of rejection. These noninvasive technologies are expected to help enhance the posttransplantation patient survival through real time and early diagnosis of disease progression. Here, we present a comprehensive review of nanotechnology-assisted strategies in various aspects of organ transplantation, including organ protection before transplantation, mitigation of ischemia-reperfusion injury, counteraction of immune rejection, early detection of organ dysfunction posttransplantation, and molecular imaging and diagnosis of immune rejection.
Subject(s)
Graft Rejection , Molecular Imaging , Organ Transplantation , Reperfusion Injury , Humans , Organ Transplantation/adverse effects , Molecular Imaging/methods , Graft Rejection/immunology , Graft Rejection/prevention & control , Reperfusion Injury/etiology , Reperfusion Injury/prevention & control , Reperfusion Injury/immunology , Nanotechnology/methods , Animals , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Graft Survival , Predictive Value of Tests , Nanomedicine/methods , Nanoparticles , Treatment OutcomeABSTRACT
Phase-transformable ionic conductors (PTICs) show significant prospects for functional applications due to their reversible resistance switching property. However, the representative design principle of PTICs is utilizing the melt-crystallization transition of ionic liquids, and the resistance switching temperatures of such PTICs cannot be tuned as desired. Herein, a new strategy is proposed to design PTICs with on-demand resistance switching temperatures by using the melt-crystallization transition of polymer cocrystal phase, whose melting temperature shows a linear relationship with the polymer compositions. Owing to the melt of polymer cocrystal domains and the tunable migration of ions in the resistance switching region, the obtained PTICs display ultrahigh temperature sensitivity with a superior temperature coefficient of resistance of -8.50% °C-1 around human body temperature, as compared to various ionic conductors previously reported. Therefore, the PTICs can detect tiny temperature variation, allowing for the intelligent applications for overheating warning and heat dissipation. It is believed that this work may inspire future researches on the development of advanced soft electrical devices.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. METHODS: Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. FINDINGS: Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. INTERPRETATION: The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. FUNDING: This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Nanoparticles , TOR Serine-Threonine Kinases , Xenograft Model Antitumor Assays , Animals , Humans , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Nanoparticles/chemistry , Mice , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Morpholines/chemistry , Morpholines/pharmacology , MTOR Inhibitors/pharmacology , MTOR Inhibitors/chemistry , Disease Models, AnimalABSTRACT
Drug resistance is one of the major obstacles for successful chemotherapy of malignant tumors including cervical cancer. To overcome this problem, a lot of efforts have been made, and drug nanoformulation may be a possible solution. Maytansine and its derivatives, the powerful tubulin polymerization inhibitors, have superior anti-tumor activity toward multiple malignant tumors compared with most anti-tumor drugs including doxorubicin, camptothecin, and cabazitaxel in current clinical studies. Nevertheless, they are hard to be accepted as clinical drugs due to their systemic toxicity to the human body, no tumor targeting, and insolubility in aqueous solutions. In this work, a strategy, called PUFAylation, has been developed to modify maytansinoid (DM1) with a polyunsaturated fatty acid (PUFA) to solve these problems by covalently coupling DM1 and docosahexaenoic acid (DHA). Two types of PUFAylated prodrugs (i.e., dSS-DM1 and dMT-DM1), prepared through different linking strategies via a thiol-disulfide exchange reaction and maleimide-thiol reaction, respectively, can self-assemble in aqueous solution to form nanoassemblies (NAs) for preclinical study by intravenous injection. In a BALB/c nude mouse model bearing cell-derived xenografts, there was no significant weight loss in mouse groups treated with dSS-DM1 NAs and dMT-DM1 NAs. In contrast, the mice with intravenous injection of free DM1 suffered a significant weight loss during the treatment. At the same time, dMT-DM1 NAs exhibit similar anti-tumor effects to free DM1 (p > 0.05). Overall, by modification of the chemotherapeutic drugs, the systemic toxicity and side effects of DM1 can be effectively reduced without sacrificing its anti-tumor effect. Particularly, dMT-DM1 NAs had shown superior therapeutic effects against drug-resistant cervical cancer and may be a potential alternative for clinical treatment of cervical cancer with paclitaxel resistance. Furthermore, this DM1-formulated platform may be applied to other anticancer agents due to its simplicity.