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1.
J Colloid Interface Sci ; 663: 810-824, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38447396

ABSTRACT

Nanozymes, as nanomaterials with natural enzyme activities, have been widely applied to deliver various therapeutic agents to synergistically combat the progression of malignant tumors. However, currently common inorganic nanozyme-based drug delivery systems still face challenges such as suboptimal biosafety, inadequate stability, and inferior tumor selectivity. Herein, a super-stable amino acid-based metallo-supramolecular nanoassembly (FPIC NPs) with peroxidase (POD)- and glutathione oxidase (GSHOx)-like activities was fabricated via Pt4+-driven coordination co-assembly of l-cysteine derivatives, the chemotherapeutic drug curcumin (Cur), and the photosensitizer indocyanine green (ICG). The superior POD- and GSHOx-like activities could not only catalyze the decomposition of endogenous hydrogen peroxide into massive hydroxyl radicals, but also deplete the overproduced glutathione (GSH) in cancer cells to weaken intracellular antioxidant defenses. Meanwhile, FPIC NPs would undergo degradation in response to GSH to specifically release Cur, causing efficient mitochondrial damage. In addition, FPIC NPs intrinsically enable fluorescence/photoacoustic imaging to visualize tumor accumulation of encapsulated ICG in real time, thereby determining an appropriate treatment time point for tumoricidal photothermal (PTT)/photodynamic therapy (PDT). In vitro and in vivo findings demonstrated the quadruple orchestration of catalytic therapy, chemotherapeutics, PTT, and PDT offers conspicuous antineoplastic effects with minimal side reactions. This work may provide novel ideas for designing supramolecular nanoassemblies with multiple enzymatic activities and therapeutic functions, allowing for wider applications of nanozymes and nanoassemblies in biomedicine.


Subject(s)
Curcumin , Nanoparticles , Neoplasms , Photochemotherapy , Humans , Amino Acids , Combined Modality Therapy , Indocyanine Green/pharmacology , Neoplasms/drug therapy , Coloring Agents , Oxidation-Reduction , Cell Line, Tumor
2.
J Colloid Interface Sci ; 652(Pt A): 329-340, 2023 Dec 15.
Article in English | MEDLINE | ID: mdl-37597414

ABSTRACT

The rapid scavenging of reactive oxygen species (ROS) by glutathione (GSH) and insufficient endogenous hydrogen peroxide (H2O2) in tumor cells are the major factors greatly restricting the efficacy of chemodynamic therapy (CDT). Herein, we developed a tumor microenvironment (TME)-responsive Cu-based metal-mesoporous organosilica nanoplatform integrating vitamin k3 (VK3), which could deplete GSH and specifically regenerate H2O2 for amplified CDT of cancer. Once the CuO@MON-PEG/VK3 nanoparticles entered into the tumor cells through enhanced permeability and retention (EPR) effect, the organosilicon shell and CuO core would be successively degraded upon the triggering of GSH and endo/lysosomal acidity. Subsequently, the enriched tetrasulfide bridges and released Cu2+ could consume GSH substantially, thus triggering Fenton-like reaction for CDT. Furthermore, the released VK3 could be catalyzed by the highly expressed quinone oxidoreductase-1 (NQO1) inside tumor cells to generate sufficient H2O2 through a "reversible" redox cycle, which in turn promoted Cu+-mediated Fenton-like reaction. Both in vitro and in vivo studies demonstrated that this nanoplatform could achieve synergistic CDT against tumor through synergistic cycling regeneration of ROS and dual GSH exhaustion with excellent biosafety. Our finding highlight the promising potential of CuO@MON-PEG/VK3 nanoplatform with multiple oxidative stress amplification for highly efficient tumor therapy.


Subject(s)
Nanoparticles , Neoplasms , Humans , Copper/pharmacology , Reactive Oxygen Species , Hydrogen Peroxide/pharmacology , Glutathione , Hydrogen-Ion Concentration , Cell Line, Tumor , Tumor Microenvironment
3.
J Mater Chem B ; 11(9): 1891-1903, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36744515

ABSTRACT

Iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation play key roles in ferroptosis, which has been an attractive strategy to kill tumor cells. However, the rapid annihilation of hydroxyl radicals (˙OH) produced from the Fenton reaction has become a major obstacle in inducing lipid peroxidation in cells. In this study, we develop a nano-delivery system of unsaturated phospholipid (Lip) and polyacrylic acid (PAA) functionalized FeOCl nanosheets (FeOCl@PAA-Lip). In this system, the ˙OH radicals produced from the Fenton reaction between FeOCl nanosheets and endogenous H2O2 of tumor cells attack Lip on the nanosheets in situ to initiate the lipid peroxidation chain reaction, which not only realizes free radical conversion but also leads to the amplification of ROS and lipid peroxides, thus enhancing tumor ferroptosis. The in vitro and in vivo results confirmed that FeOCl@PAA-Lip nanosheets exhibited specific tumor cell-killing effects, good biocompatibility, long circulation time, low side effects, high tumor targeting and an excellent tumor inhibition rate (73%). The Lip functionalization strategy offers a paradigm of enhancing ferroptosis treatment by conversion of ˙OH/phospholipid radicals/lipid peroxyl radicals and strengthening lipid peroxidation.


Subject(s)
Ferroptosis , Reactive Oxygen Species , Phospholipids , Hydrogen Peroxide/pharmacology , Lipid Peroxidation
4.
ACS Biomater Sci Eng ; 8(5): 1942-1955, 2022 05 09.
Article in English | MEDLINE | ID: mdl-35357802

ABSTRACT

The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu2+-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu+-mediated •OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.


Subject(s)
Multifunctional Nanoparticles , Neoplasms , Glutathione/therapeutic use , Humans , Hypoxia/drug therapy , Indocyanine Green/pharmacology , Indocyanine Green/therapeutic use , Neoplasms/drug therapy , Tirapazamine/therapeutic use , Tumor Microenvironment
5.
ACS Appl Mater Interfaces ; 12(48): 53682-53690, 2020 Dec 02.
Article in English | MEDLINE | ID: mdl-33205941

ABSTRACT

Tumor cells are rich in antigens, which provide a reliable antigen library for the design of personalized vaccines. However, an effective tumor vaccine vector that can efficiently deliver antigens to lymphoid organs to stimulate strong CD8+ cytotoxic T-lymphocyte immune response is still lacking. Here we designed a dual-antigen delivery system based on hepatitis B virus core antigen virus-like particles (HBc VLPs). We first confirmed that different antigen-loaded HBc VLP monomers could be assembled into nanoparticles (hybrid VLPs). Hybrid VLPs could slightly enhance bone marrow-derived dendritic cell maturation in vitro. Strikingly, hybrid VLPs could generate antigen-specific antitumor immunity and innate immunity in vivo which could significantly inhibit tumor growth or metastatic formation in a subcutaneous tumor or lung metastatic tumor model, respectively. Moreover, dual-epitope vaccination generated enhanced T-cell responses that potently inhibited tumor growth and metastatic formation. Together, this study provides a new powerful concept for cancer immunotherapy and suggests a novel design for VLP-based personalized nanomedicine.

6.
Analyst ; 145(16): 5553-5562, 2020 Aug 21.
Article in English | MEDLINE | ID: mdl-32613211

ABSTRACT

A rapid molecular diagnostic technique targeting circulating tumor DNA (ctDNA) has become one of the most clinically significant liquid biopsy methods for non-invasive and timely diagnosis of cancer. Herein, a sensitive detection system of ctDNA based on a fluorescence resonance energy transfer (FRET) system using upconversion nanoparticles (UCNPs) and gold nanocages (AuNCs) was constructed. Through the doping of Yb and Tm ions, the excitation and emission wavelengths of UCNPs were adjusted to 980 nm and 806 nm, respectively. Subsequently, UCNPs and AuNCs with the corresponding wavelength absorption were linked by complementary pairing of surface-modified DNA to form near-infrared fluorescent nanoprobes (NIR probes). Targeting DNA mutation recognition and signal transduction were realized by using NIR probes through the toehold-mediated strand displacement reaction. This method could detect a single point mutation of the KRAS gene with a wide detection range from 5 pM to 1000 pM and the limit of detection reached 6.30 pM. More importantly, the stable and highly specific NIR probes could be directly used in the serum environment without complicated pretreatment and amplification processes in advance. It could be envisioned that this specific and sensitive ctDNA detection strategy has great potential in clinical diagnosis and monitoring of diverse malignant tumors.


Subject(s)
Circulating Tumor DNA , Nanoparticles , Fluorescence Resonance Energy Transfer , Gold
7.
J Mater Chem B ; 8(26): 5667-5681, 2020 07 08.
Article in English | MEDLINE | ID: mdl-32500886

ABSTRACT

Carrier-free nanotheranostics directly assembled by using clinically used photosensitizers and chemotherapeutic drugs are a promising alternative to tumor theranostics. However, the weak interaction-driven assembly still suffers from low structural stability against disintegration, lack of targeting specificity, and poor stimulus-responsive property. Moreover, almost all exogenous ligands possess no therapeutic effect. Enlightened by the concept of metal-organic frameworks, we developed a novel self-recognizing metal-coordinated nanotheranostic agent by the coordination-driven co-assembly of photosensitizer indocyanine green (ICG) and chemo-drug methotrexate (MTX, also served as a specific "targeting ligand" towards folate receptors), in which ferric (FeIII) ions acted as a bridge to tightly associate ICG with MTX. Such carrier-free metal-coordinated nanotheranostics with high dual-drug payload (∼94 wt%) not only possessed excellent structural and physiological stability, but also exhibited prolonged blood circulation. In addition, the nanotheranostics could achieve the targeted on-demand drug release by both stimuli of internal lysosomal acidity and external near-infrared laser. More importantly, the nanotheranostics could self-recognize the cancer cells and selectively target the tumors, and therefore they decreased toxicity to normal tissues and organs. Consequently, the nanotheranostics showed strongly synergistic potency for tumor photo-chemotherapy under the precise guidance of magnetic resonance/photoacoustic/fluorescence imaging, thereby achieving highly effective tumor curing efficiency. Considering that ICG and bi-functional MTX are approved by the Food and Drug Administration, and FeIII ions have high biosafety, the self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics may hold potential applications in tumor theranostics.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Indocyanine Green/pharmacology , Methotrexate/pharmacology , Photosensitizing Agents/pharmacology , Phototherapy , Theranostic Nanomedicine , Animals , Antimetabolites, Antineoplastic/chemical synthesis , Antimetabolites, Antineoplastic/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Indocyanine Green/chemical synthesis , Indocyanine Green/chemistry , Magnetic Resonance Imaging , Methotrexate/chemical synthesis , Methotrexate/chemistry , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Optical Imaging , Particle Size , Photoacoustic Techniques , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Surface Properties
8.
Nanomedicine (Lond) ; 15(14): 1391-1409, 2020 06.
Article in English | MEDLINE | ID: mdl-32495692

ABSTRACT

Aim: To explore the therapeutic effect of nanoparticle-based dual-targeting delivery of antitumor agents for glioblastoma treatment. Materials & methods: A hepatitis B core protein-virus-like particle (VLP)-based dual-targeting delivery system was designed with the primary brain targeting peptide TGN for blood-brain barrier penetration and tumor vascular preferred ligand RGD (arginine-glycine-aspartic acid) for glioblastoma targeting. Chemo- and gene-therapeutic agents of paclitaxel and siRNA were co-packaged inside the vehicle. Results: The results demonstrated efficient delivery of the packaged agents to invasive tumor sites. The combination of chemo- and gene-therapies demonstrated synergistic antitumor effects through enhancing necrosis and apoptosis, as well as being able to inhibit tumor invasion with minimal cytotoxicity. Conclusion: Our hepatitis B core-VLP-based dual-targeting delivery of chemo- and gene-therapeutic agents possesses a synergistic antitumor effect for glioblastoma therapy.


Subject(s)
Glioblastoma , Nanoparticles , Cell Line, Tumor , Drug Delivery Systems , Glioblastoma/drug therapy , Glioblastoma/genetics , Humans , Paclitaxel/therapeutic use , RNA, Small Interfering/genetics , RNA, Small Interfering/therapeutic use
9.
Biomaterials ; 240: 119849, 2020 05.
Article in English | MEDLINE | ID: mdl-32087458

ABSTRACT

More than 30% of patients with epilepsy progress to drug-resistant epilepsy, leading to a significant increase in morbidity and mortality of epilepsy. The limitation of epileptic drug to reach the epileptogenic focus is the critical reason, and the blood-brain barrier (BBB) plays a crucial role. Here, we successfully constructed a hepatitis B core (HBc) protein nanocage (NC) with the insertion of brain target TGN peptide for facilitating epileptic drug phenytoin delivery to the brain. Our results demonstrated that this nanocage can specifically and efficiently target the brain tissue by 2.4 fold and increase the antiepileptic efficiency of phenytoin about 100 fold in pilocarpine induced models of epilepsy. Both in vivo mice and in vitro human neural three-dimensional cortical organoids demonstrated high penetration ability. These functions are achieved through the facilitation of brain target peptide TGN rather than disruption of brain blood barrier. In summary, we presented an efficient antiepileptic drug delivery nanocage for the treatment of refractory epilepsy. Moreover, this therapeutic modulation also provides promising strategy for other intractable neurological disease.


Subject(s)
Epilepsy , Phenytoin , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Anticonvulsants , Blood-Brain Barrier/metabolism , Epilepsy/drug therapy , Humans , Mice , Phenytoin/therapeutic use
10.
ACS Biomater Sci Eng ; 6(3): 1764-1775, 2020 03 09.
Article in English | MEDLINE | ID: mdl-33455389

ABSTRACT

Molybdenum disulfide quantum dots (MoS2 QDs) represent an emerging class of two-dimensional (2D) atomically layered transition metal dichalcogenide nanostructures with few nanometers in lateral size, which show attractive potential as versatile platforms for theranostic applications in various neurological disorders. However, the potential impacts of MoS2 QDs on microglia remain unclear. In this report, we showed that exposure of microglia to MoS2 QDs triggered NLRP3 inflammasome activation as revealed by the cleavage of the inactive precursor of caspase-1 to its active form and the increased release of downstream pro-inflammatory cytokines, resulting in microglia cell death that occurred through caspase-1-dependent pyroptosis. We also found that MoS2 QDs activated autophagy, and suppression of autophagy by specific inhibitors potentiated MoS2 QD-induced pyroptosis. Additionally, MoS2 QDs stimulated mitochondria-derived reactive oxygen species (mtROS) generation in BV-2 cells. However, ROS scavengers could diminish the MoS2 QD-mediated NLRP3 inflammasome activation and pyroptotic cell death in microglia. Overall, our findings identified pyroptosis as a cellular response to MoS2 QD exposure in microglial cells, affording novel insights into the neurotoxicity of MoS2 QDs and facilitating the rational design and application of functional MoS2 QDs in neuroscience.


Subject(s)
Pyroptosis , Quantum Dots , Autophagy , Disulfides , Inflammasomes , Microglia , Molybdenum/toxicity , NLR Family, Pyrin Domain-Containing 3 Protein , Quantum Dots/toxicity , Reactive Oxygen Species
11.
Bioconjug Chem ; 30(11): 2939-2946, 2019 11 20.
Article in English | MEDLINE | ID: mdl-31644261

ABSTRACT

The progression of hepatic fibrosis can lead to cirrhosis and hepatic failure, but the development of antifibrotic drugs have faced the challenges of poor effectiveness and targeted specificity. Herein, a theranostic strategy was carried to encapsulate a natural medicine (Quercetin, QR) into hepatitis B core (HBc) protein nanocages (NCs) for imaging and targeted treatment of hepatic fibrosis. It was noted that nanoparticles (RGD-HBc/QR) with surface-displayed RGD targeting ligand exhibit a rather high selectivity toward activated HSCs via the binding affinity with integrin αvß3, and an efficient inhibition of proliferation and activation of hepatic stellate cells (HSCs) in vitro and in vivo. Once encapsulated in quercetin-gadolinium complex and/or labeled with the NIR fluorescent probes (Cy5.5), the resulting nanoparticles (RGD-HBc/QGd) show great potential as NIR fluorescent and magnetic resonance imaging contrast agents for hepatic fibrosis in vivo. Therefore, the multifunctional integrin-targeted nanoparticles could selectively deliver QR to the activated HSCs, and may provide an effective antifibrotic theranostic strategy.


Subject(s)
Cell Proliferation , Hepatic Stellate Cells/drug effects , Liver Cirrhosis/drug therapy , Nanoparticles/administration & dosage , Quercetin/pharmacology , Theranostic Nanomedicine , Animals , Cells, Cultured , Fluorescent Dyes/chemistry , Gadolinium/chemistry , Hepatic Stellate Cells/cytology , Humans , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Quercetin/administration & dosage , Quercetin/chemistry
12.
ACS Appl Mater Interfaces ; 11(17): 15262-15275, 2019 May 01.
Article in English | MEDLINE | ID: mdl-30964624

ABSTRACT

Nanoparticles camouflaged by red blood cell (RBC) membranes have attracted considerable attention owing to reservation of structure of membrane and surface proteins, endowing prominent cell-specific function including biocompatibility, prolonged circulation lifetime, and reduced reticular endothelial system (RES) uptake ability. Considering the drawbacks of carrier-free nanomedicine including the serious drug burst release, poor stability, and lack of immune escape function, herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin (10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged circulation, controlled drug release, and synergistic chemo-photothermal therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs) exhibited a diameter of ∼150 nm with core-shell structure, high drug payload (∼92 wt %), and reduced RES uptake function. Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of near-infrared laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional instability by heat-mediated membrane disruption and pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli accomplished highly efficient apoptosis in cancer cells and remarkable ablation of tumors by chemo-PTT. This biomimetic nanoplatform based on carrier-free, small molecular drug coassemblies integrating imaging capacity as a promising theranostic system provides potential for cancer diagnosis and combinational therapy.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Biomimetics , Camptothecin/analogs & derivatives , Cell Membrane/chemistry , Infrared Rays , Nanoparticles/chemistry , Neoplasms/therapy , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Camptothecin/chemistry , Camptothecin/pharmacology , Camptothecin/therapeutic use , Erythrocytes/cytology , Erythrocytes/metabolism , HeLa Cells , Humans , Hydrogen-Ion Concentration , Indocyanine Green/chemistry , Male , Mice , Mice, Nude , Nanoparticles/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Phototherapy , Rats , Rats, Sprague-Dawley
14.
ACS Biomater Sci Eng ; 5(2): 1057-1070, 2019 Feb 11.
Article in English | MEDLINE | ID: mdl-33405796

ABSTRACT

A defective lysosome-autophagy degradation pathway contributes to a variety of endothelial-to-mesenchymal transition (EndMT)-related cardiovascular diseases. Molybdenum disulfide quantum dots (MoS2 QDs) are nanoscale sizes in the planar dimensions and atomic structures of transition metal dichalcogenides (TMDs) materials with excellent physicochemical and biological properties, making them ideal for various biomedical applications. In this study, water-soluble MoS2 QDs with an average diameter of about 3.4 nm were synthesized by using a sulfuric acid-assisted ultrasonic method. The as-prepared MoS2 QDs exhibited low cytotoxicity of less than 100 µg/mL in both human umbilical vein endothelial cells and human coronary artery endothelial cells and showed novel biological properties to prevent EndMT and promote angiogenesis in vitro. We found that MoS2 QDs treatment-induced transcription factor (TFEB) mediated lysosomal biogenesis, which could cause autophagy activation. Importantly, using in vitro transforming growth factor (TGF)-ß-induced EndMT model, we demonstrated that the cardiovascular protective effect of MoS2 QDs against EndMT acted through triggering TFEB nucleus translocation and restoring an impairment of autophagic flux, whereas genetic suppression of TFEB impaired the protective action of MoS2 QDs against EndMT. Taken together, these results gain novel insights into the mechanisms by which MoS2 QDs regulate EndMT and facilitate the development of MoS2-based nanoagents for the treatment of EndMT-related cardiovascular diseases.

15.
ACS Biomater Sci Eng ; 5(9): 4442-4454, 2019 Sep 09.
Article in English | MEDLINE | ID: mdl-33438410

ABSTRACT

The medical application of nanotechnology is promising for cancer chemotherapy. However, most of the small-molecule drug assemblies still have such disadvantages as serious drug leakage and nonideal synergistic mechanisms, resulting in undesired therapeutic effect. Both nucleoside analogue-based clofarabine (CA) and methotrexate (MTX) were used as the first-line anticancer medication. However, a single-agent chemotherapy still faced many challenges including low bioavailability and toxic side effects to normal tissues due to nonspecific biodistribution of drugs. Herein, we designed and fabricated novel viral-mimicking and carry-free nanodrugs (CA-MTX NPs) via molecular recognition-driven precise self-assembly between CA and MTX. After introduction of mild acid-responsive PEG-lipid on the surface of CA-MTX NPs, the synthetic nanodrugs with a diameter of ∼150 nm exhibited tumor microenvironment-activated characteristics and self-targeting property. The results suggested that our nanodrugs could achieve superior tumor accumulation and synergistically promote the tumor suppression by collaboratively inhibiting dNTP pools. We foresaw that the well-designed smart nanodrugs delivery system would open a new avenue in synergistic cancer therapeutics.

16.
Adv Mater ; 30(28): e1707567, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29786899

ABSTRACT

In recent years, hepatitis B core protein virus-like particle (HBc VLP) is an impressive biomaterial, which has attracted considerable attention due to favorable properties such as structural stability, high uptake efficiency, and biocompatibility in biomedical applications. Heretofore, only a few attempts have been made to apply it in physical, chemical, and biological therapy for cancer. In this study, a tumor-targeting RGD-HBc VLP is first fabricated through genetic engineering. For image-guided cancer phototherapy, indocyanine green (ICG) is loaded into RGD-HBc VLP via a disassembly/reassembly pathway and electrostatic attraction with high efficiency. The self-assembled stable RGD-HBc VLP significantly improves body retention (fourfold longer), aqueous stability, and target specificity of ICG. Remarkably, these positive reformations promote more accurate and sensitive imaging of U87MG tumor, as well as prolonged tumor destruction in comparison with free ICG. Moreover, the photothermal and photodynamic effect on tumors are quantitatively differentiated by multiple linear regression analysis. Overall, less-potent medicinal ICG can be perfectly rescued by bioengineered HBc VLP to realize enhanced cancer optotheranostics.


Subject(s)
Neoplasms , Hepatitis B , Humans , Indocyanine Green , Photochemotherapy , Phototherapy
17.
Nano Lett ; 18(5): 3250-3258, 2018 05 09.
Article in English | MEDLINE | ID: mdl-29683683

ABSTRACT

Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of DPPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.


Subject(s)
Delayed-Action Preparations/chemistry , Imidazoles/administration & dosage , Isoindoles/administration & dosage , Melanoma/therapy , Nanoparticles/chemistry , Peptides/administration & dosage , Animals , B7-H1 Antigen/antagonists & inhibitors , Drug Delivery Systems , Imidazoles/therapeutic use , Immunotherapy , Isoindoles/therapeutic use , Mice , Mice, Nude , Peptides/therapeutic use , Tumor Microenvironment/drug effects
18.
Nanotheranostics ; 2(1): 87-95, 2018.
Article in English | MEDLINE | ID: mdl-29291165

ABSTRACT

To accomplish effective cancer imaging and integrated therapy, the multifunctional nanotheranostic Fe3O4-MTX@HBc core-shell nanoparticles (NPs) were designed. A straightforward method was demonstrated for efficient encapsulation of magnetic NPs into the engineered virus-like particles (VLPs) through the affinity of histidine tags for the methotrexate (MTX)-Ni2+ chelate. HBc144-His VLPs shell could protect Fe3O4-MTX NPs from the recognition by the reticuloendothelial system as well as could increase their cellular uptake efficiency. Through our well-designed tactic, the photothermal efficiency of Fe3O4 NPs were obviously improved in vitro and in vivo upon near-infrared (NIR) laser irradiation. Moreover, Magnetic resonance imaging (MRI) results showed that the Fe3O4-MTX@HBc core-shell NPs were reliable T2-type MRI contrast agents for tumor imaging. Hence the Fe3O4-MTX@HBc core-shell NPs may act as a promising theranostic platform for multimodal cancer treatment.

19.
ACS Biomater Sci Eng ; 4(2): 663-674, 2018 Feb 12.
Article in English | MEDLINE | ID: mdl-33418754

ABSTRACT

The impairment of autophagy involves oxidative stress-induced cellular senescence, leading to endothelial dysfunctions and the onset of cardiovascular diseases. As molybdenum disulfide nanoparticles (MoS2 NPs), representative transition metal dichacogenide materials, have great potential as a multifunctional therapeutic agent against various disorders, the present study aimed to investigate whether MoS2 NPs prevents hydrogen peroxide (H2O2)-induced endothelial senescence by modulating autophagic process. Our results showed that pretreatment with MoS2 NPs inhibited H2O2-induced endothelial senescence and improved endothelial functions. Exposure of H2O2 increased p62 level and blocked the fusion of autophagosomes with lysosomes, indicating of impaired autophagic flux in senescent endothelial cells. However, MoS2 NPs pretreatment efficiently suppressed cellular senescence through triggering autophagy and resisting impaired autophagic flux. Furthermore, the genetic inhibition of autophagy by siRNA against Beclin 1 or ATG-5 directly abrogated the protective action of MoS2 NPs on endothelial cells against H2O2-induced senescence.Thus, these results suggested that MoS2 NPs rescue endothelial cells from H2O2-induced senescence by improving autophagic flux, and provide valuable information for the rational design of MoS2-based nanomaterials for therapeutic use in senescence-related diseases.

20.
RSC Adv ; 8(33): 18647-18655, 2018 May 17.
Article in English | MEDLINE | ID: mdl-35541095

ABSTRACT

This study reports a multifunctional core/shell nanoparticle (NP) that can be used for amplified magnetic resonance image (MRI), enhanced photothermal therapy (PTT) and magnetic hyperthermia therapy (MHT) due to its surface coating with a porous shell. Importantly, by means of introducing the surface coating of a porous shell, it helps entrap large quantities of water around NPs and allow more efficient water exchange, leading to greatly improved MR contrast signals. Besides, the porous shell helps the near-infrared (NIR) absorbance of the core, and then the extremely enhanced thermal effect can be obtained under synergistic combination of PTT and MHT. By synthesizing multifunctional porous MnFe2O4/PB as an example, we found that the transversal relaxivity (r 2) of MnFe2O4 NPs might improve from 112.11 to 123.46 mM-1 s-1, and the specific absorption rate (SAR) of MnFe2O4/PB nanoparticles reached unprecedented levels of up to 4800 W g-1 compared with the SAR 1182 W g-1 of PTT under an 808 nm laser and 180 W g-1 of MHT under an external AC magnetic field. Meanwhile, when MnFe2O4 was decorated on PB nanoparticles, the magnetic properties became lower slightly, but the synergistic photothermal/magnetic hyperthermia conversion was enhanced greatly. Subsequently, in vitro T 1-T 2 dual-modal MRI, PTT and MHT results verified that MnFe2O4/PB could serve as an excellent MRI/PTT/MHT theranostic agent. Furthermore, the MnFe2O4/PB NPs were applied as a T 1-T 2 dual-modal MRI, PTT and MHT theranostic agent for in vivo MRI-guided photothermal and magnetic hyperthermia ablation of tumors by intratumoral injection in 4T1 tumor-bearing mice. The T 1-T 2 dual-modal MR imaging result shows a significantly contrast in the tumor site. The MPB-mediated PTT and MHT result shows high therapeutic efficiency as a result of high photothermal and magnetic hyperthermia conversion efficiency. The multifunctional NPs have a great potential application for future clinical tumorous diagnosis and treatment.

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