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Despite the great potential of anti-PD-L1 antibodies for immunotherapy, their low response rate due to an immunosuppressive tumor microenvironment has hampered their application. To address this issue, we constructed a cell membrane-coated nanosystem (mB4S) to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect. In this system, Epirubicin (EPI) as an immunogenic cell death (ICD) inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes (STING) agonist was encapsulated into mB4S. After internalization of mB4S, EPI was acidic-responsively released to induce ICD, which was characterized by an increased level of calreticulin (CRT) exposure and enhanced ATP secretion. Meanwhile, diABZI effectively activated the STING pathway. Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells (DCs) and CD8+ T cells, promoting cytokines secretion, up-regulating M1-like tumor-associated macrophages (TAMs) and down-regulating immunosuppressive myeloid-derived suppressor cells (MDSCs). Therefore, this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+ T cells infiltration, creating an immuno-supportive microenvironment, thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.
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A low-generation lysine dendrimer, SPr-G2, responds to intracellular glutathione to initiate bioorthogonal in situ polymerization, resulting in the formation of large assemblies in mouse breast cancer cells. The intracellular large assemblies of SPr-G2 can interact with lysosomes to induce lysosome expansion and enhance lysosomal membrane permeabilization, leading to major histocompatibility complex class I upregulation on tumor cell surfaces and ultimately tumor cell death. Moreover, the use of the SPr-G2 dendrimer to conjugate the chemotherapeutic drug, camptothecin (CPT), can boost the therapeutic potency of CPT. Excellent antitumor effects in vitro and in vivo are obtained from the combinational treatment of the SPr-G2 dendrimer and CPT. This combinational effect also enhances antitumor immunity through promoting activation of cytotoxic T cells in tumor tissues and maturation of dendritic cells. This study can shed new light on the development of peptide dendritic agents for cancer therapy.
Assuntos
Apresentação de Antígeno , Dendrímeros , Lisossomos , Polimerização , Lisossomos/metabolismo , Lisossomos/química , Animais , Dendrímeros/química , Camundongos , Linhagem Celular Tumoral , Apresentação de Antígeno/efeitos dos fármacos , Camptotecina/farmacologia , Camptotecina/química , Humanos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.
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Antineoplásicos , Nanomedicina , Animais , Nanomedicina/métodos , Camundongos , Humanos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dendrímeros/química , Feminino , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Portadores de Fármacos/químicaRESUMO
The effects of dendron side chains in polymeric conjugates on tumor penetration and antigen presentation are systematically examined. Three polymer-gemcitabine (Gem) conjugates (pG0-Gem, pG1-Gem, pG2-Gem) are designed and prepared. The pG2-Gem conjugate uniquely binds to the mitochondria of tumor cells, thus regulating mitochondrial dynamics. The interaction between the pG2-Gem conjugate and the mitochondria promotes great penetration and accumulation of the conjugate at the tumor site, resulting in pronounced antitumor effects in an animal model. Such encouraging therapeutic effects can be ascribed to immune modulation since MHC-1 antigen presentation is significantly enhanced due to mitochondrial fusion and mitochondrial metabolism alteration after pG2-Gem treatment. Crucially, the drug-free dendronized polymer, pG2, is identified to regulate mitochondrial dynamics, and the regulation is independent of the conjugated Gem. Furthermore, the combination of pG2-Gem with anti-PD-1 antibody results in a remarkable tumor clearance rate of 87.5% and a prolonged survival rate of over 150 days, demonstrating the potential of dendronized polymers as an innovative nanoplatform for metabolic modulation and synergistic tumor immunotherapy.
Assuntos
Desoxicitidina , Gencitabina , Dinâmica Mitocondrial , Nanomedicina , Polímeros , Animais , Nanomedicina/métodos , Humanos , Polímeros/química , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , Dendrímeros/química , Linhagem Celular Tumoral , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Imunomodulação/efeitos dos fármacosRESUMO
Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multifunctional and tunable physiochemical properties in alignment with tumor genetic profiles can achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, this work reviews the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy, and outlines novel strategies for the development of nanomedicine against drug resistance. This work focuses on engineering design, customized delivery, current challenges, and clinical translation of nanomedicine in the application of resistant lung cancer.
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Antineoplásicos , Neoplasias Pulmonares , Neoplasias , Humanos , Nanomedicina , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos AntineoplásicosRESUMO
Micronucleus (MN) is regarded as an abnormal structure in eukaryotic cells which can be used as a biomarker for genetic instability. However, direct observation of MN in living cells is rarely achieved due to the lack of probes that are capable of distinguishing nuclear- and MN-DNA. Herein, a water-soluble terpyridine organic small molecule (ABT) was designed and employed to recognize Zinc-finger protein (ZF) for imaging intracellular MN. The in vitro experiments suggested ABT has a high affinity towards ZF. Further live cell staining showed that ABT could selectively target MN in HeLa and NSC34 cells when combined with ZF. Importantly, we use ABT to uncover the correlation between neurotoxic amyloid ß-protein (Aß) and MN during Alzheimer's disease (AD) progression. Thus, this study provides profound insight into the relationship between Aß and genomic disorders, offering a deeper understanding for the diagnosis and treatment of AD.
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Doença de Alzheimer , Técnicas Biossensoriais , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Células HeLaRESUMO
The combination of chemotherapy and photodynamic therapy (PDT) has the potential to complement single-drug therapies, but chemotherapeutic agents and photosensitizers often have compromised therapeutic efficacies and strong toxic effects. In this study, we exploited nanotechnology to address this challenge by utilizing heparin as a carrier for co-delivery of chemotherapeutic drugs and photosensitizers for synergistic cancer therapy. Specifically, heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa) were synthesized by attaching paclitaxel (PTX), a small molecular chemotherapeutic drug, through a reactive oxygen species (ROS)-responsive linker and Ppa, a photosensitizer, to heparin, respectively. Two conjugates were co-assembled into a nanomedicine, HP-PP nanoparticles (NPs), for controllable co-delivery of Ppa and PTX into tumor cells. HP-PP NPs significantly enhanced the in vitro stability of HP-Ppa and the photostability of Ppa, and the synergistic actions of chemotherapy and PDT were confirmed by both in vitro and in vivo antitumor studies. Notably, HP-PP NPs enhanced tumor accumulation of Ppa up to 11-fold and the treatment of 4T1 tumor-bearing mice with HP-PP NPs resulted in a tumor growth inhibition of 98.1% without systemic toxicity. The strategy of co-assembly of heparin conjugates may offer great potential in enhancing the efficacy of combination therapy. STATEMENT OF SIGNIFICANCE: We proposed a nano-delivery system, HP-PP NPs, which was constructed by co-assembly of heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa), to co-deliver PTX and Ppa for synergistic cancer therapy. HP-PP NPs enhanced the photostability and the in vitro stability of Ppa and HP-Ppa, and induced greater cytotoxicity than HP-PTX NPs or HP-Ppa NPs. This co-delivery system displays enhanced tumor accumulation and has a remarkable synergistic antitumor effect with a tumor growth inhibition of 98.1%.
Assuntos
Nanopartículas , Neoplasias , Animais , Camundongos , Preparações Farmacêuticas , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina , Heparina/farmacologia , Linhagem Celular Tumoral , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológicoRESUMO
Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.
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Neoplasias da Mama , Nanomedicina , Humanos , Feminino , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Fibroblastos/metabolismo , Oxirredução , Microambiente TumoralRESUMO
Targeting metabolic vulnerability of tumor cells is a promising anticancer strategy. However, the therapeutic efficacy of existing metabolism-regulating agents is often compromised due to tolerance resulting from tumor metabolic plasticity, as well as their poor bioavailability and tumor-targetability. Inspired by the inhibitive effect of N-ethylmaleimide on the mitochondrial function, a dendronized-polymer-functionalized metal-phenolic nanomedicine (pOEG-b-D-SH@NP) encapsulating maleimide-modified doxorubicin (Mal-DOX) is developed to enable improvement in the overall delivery efficiency and inhibition of the tumor metabolism via multiple pathways. It is observed that Mal-DOX and its derived nanomedicine induces energy depletion of CT26 colorectal cancer cells more efficiently than doxorubicin, and shifts the balance of programmed cell death from apoptosis toward necroptosis. Notably, pOEG-b-D-SH@NP simultaneously inhibits cellular oxidative phosphorylation and glycolysis, thus potently suppressing cancer growth and peritoneal intestinal metastasis in mouse models. Overall, the study provides a promising dendronized-polymer-derived nanoplatform for the treatment of cancers through impairing metabolic plasticity.
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Neoplasias Colorretais , Nanopartículas , Animais , Camundongos , Nanomedicina , Portadores de Fármacos/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Polímeros , Neoplasias Colorretais/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Signal enhancement of magnetic resonance imaging (MRI) in the diseased region is dependent on the molecular structure of the MRI contrast agent. In this study, a macromolecular contrast agent, Branched-LAMA-DOTA-Cy5.5-Gd (BLDCGd), was prepared to target liver cancer. Due to the affinity of lactose to the Asialoglycoprotein receptor (ASGPR) over-expressed on the surface of liver cancer cells, lactose was selected as the targeting moiety in the contrast agent. A cathepsin B-sensitive tetrapeptide, GFLG, was used as a linkage moiety to construct a cross-linked macromolecular structure of the contrast agent, and the contrast agent could be degraded into fragments for clearance. A small-molecular-weight molecule, DOTA-Gd, and a fluorescent dye, Cy5.5, were conjugated to the macromolecular structure via a thiol-ene click reaction. The contrast agent, BLDCGd, had a high molecular weight (81 kDa) and a small particle size (59 ± 12 nm). Its longitudinal relaxivity (12.62 mM-1 s-1) was 4-fold that of the clinical agent DTPA-Gd (3.42 mM-1 s-1). Signal enhancement of up to 184% was observed at the tumor site in an H22 cell-based mouse model. A high accumulation level of BLDCGd in the liver tumor observed from MRI was confirmed from the fluorescence images obtained from the same contrast agent. BLDCGd showed no toxicity to HUVECs and H22 cells in vitro, and low blood chemistry indexes and no distinct histopathological abnormalities were also observed in vivo after injection of BLDCGd since it could be metabolized through the kidneys according to the in vivo MRI results of major organs. Therefore, the branched macromolecule BLDCGd could have great potential as an efficacious and bio-safe nanoscale MRI contrast agent for clinical diagnosis of liver cancer.
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Neoplasias Hepáticas , Polímeros , Camundongos , Animais , Meios de Contraste/farmacologia , Meios de Contraste/química , Lactose/farmacologia , Substâncias Macromoleculares , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
Tumor cells are dominant in the nutritional competition in the tumor microenvironment, and their metabolic abnormalities often lead to microenvironmental acidosis and nutrient deprivation, thereby impairing the function of immune cells and diminishing the antitumor therapeutic effect. Herein, a branched polymeric conjugate and its efficacy in attenuating the metabolic competition of tumor cells are reported. Compared with the control nanoparticles prepared from its linear counterpart, the branched-conjugate-based nanoparticles can more efficiently accumulate in the tumor tissue and interfere with the metabolic processes of tumor cells to increase the concentration of essential nutrients and reduce the level of immunosuppressive metabolites in the TME, thus creating a favorable environment for infiltrated immune cells. Its combined treatment with an immune checkpoint inhibitor (ICI) achieves an enhanced antitumor effect. The work presents a promising approach for targeting metabolic competition in the TME to enhance the chemo-immunotherapeutic effect against cancers.
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Imunoterapia , Neoplasias , Humanos , Sistemas de Liberação de Medicamentos , Neoplasias/terapia , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Timely detection and accurate staging of liver fibrosis still remains a challenge. Herein, we report a hyaluronic acid (HA)-based magnetic resonance (MR)/fluorescence imaging agent, HA-Target-Cy5.5-DOTA-Gd (HTCDGd) with oxyamine groups to target allysine in the fibrous tissue, and a control agent, HA-Cy5.5-DOTA-Gd (HCDGd) without the targeting group was also prepared. Both agents have a nanoscale size with a high relaxivity, and show a rapid blood clearance rate and great biosafety. Compared to HCDGd, interaction of the targeting oxyamine groups in HTCDGd with allysine of collagen in the fibrosis tissue facilitates high accumulation of HTCDGd in the liver and allows sensitive and long-term detection of liver fibrosis at the early stage (Ishak = 3) and the late stage (Ishak = 5) in animal models via its enhanced MR signal. Those results are confirmed by fluorescence images. Overall, HTCDGd has been demonstrated as an effective agent for non-invasive and accurate diagnosis of liver fibrosis.
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Ácido Hialurônico , Cirrose Hepática , Animais , Meios de Contraste , Fluorescência , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
INTRODUCTION: Small-molecular drugs are extensively used in cancer therapy, while they have issues of nonspecific distribution and consequent side effects. Nanomedicines that incorporate chemotherapeutic drugs have been developed to enhance the therapeutic efficacy of these drugs and reduce their side effects. One of the promising strategies is to prepare nanomedicines by harnessing the unique tumor microenvironment (TME). AREAS COVERED: The TME contains numerous cell types that specifically express specific antibodies on the surface. The physicochemical environment is characterized with a low pH, hypoxia, and a high redox potential resulting from tumor-specific metabolism. Therefore, intelligent nanomedicines designed based on the characteristics of the tumor microenvironment can be divided into two groups: the first group which is rapidly responsive to extracellular chemical/biological factors in the TME and the second one which actively and/or specifically targets cellular components in the TME. EXPERT OPINION: In this paper, we review recent progress of nanomedicines by harnessing the TME and illustrate the principles and advantages of different strategies for designing nanomedicines, which are of great significance for exploring novel nanomedicines or translating current nanomedicines into clinical practice. We will discuss the challenges and prospects of preparing nanomedicines to utilize or alter the TME for achieving effective, safe anticancer treatment.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
Nanoparticles (NPs)-based cancer therapeutics are generally impeded by poor drug penetration into solid tumors due to their dense tumor extracellular matrix (ECM). Herein, pH/redox-responsive dendritic polymer-based NPs are developed to amplify the neighboring effect for improving drug penetration and driving cell apoptosis via combination therapy. Pyropheophorbide a (Ppa) is conjugated with PEGylated dendritic peptides via disulfide bonds and doxorubicin (DOX) encapsulated in the conjugate to construct dual-responsive NPs, PDPP@D. Delayed released DOX and Ppa from PDPP@D exert their combination therapeutic effect to induce cell apoptosis, and then they are liberated out of dying cells to amplify the neighboring effect, resulting in their diffusion through the dense ECM and penetration into solid tumors. Transcriptome studies reveal that PDPP@D leads to irreversible stress on the endoplasmic reticulum and inhibits cell protection through blocking the IRE1-dependent survival pathway and unleashing the DR5-mediated caspase activity to promote cell death. The strategy of amplifying the neighboring effect of NPs through combination therapy may offer great potential in enhancing drug penetration and eradicating solid tumors.
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Dendrímeros , Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina/química , Estresse do Retículo Endoplasmático , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológicoRESUMO
Efficient penetration and retention of therapeutic agents in tumor tissues can be realized through rational design of drug delivery systems. Herein, a polymer-dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), is presented, which allows a cathepsin-B-triggered stealthy-to-sticky structural transformation. The compositions and ratios are optimized through dissipative particle dynamics simulations. GFLG-DP displays tumor-specific transformation and the consequently released dendron-Ppa is found to effectively accumulate on the tumor cell membrane. The interaction between the dendron-Ppa and the tumor cell membrane results in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in the solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with the endoplasmic reticulum disrupts cell homeostasis, making tumor cells more vulnerable and susceptible to photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems.
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Dendrímeros , Nanopartículas , Neoplasias , Antracenos , Linhagem Celular Tumoral , Dendrímeros/química , Homeostase , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , PolímerosRESUMO
Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, a combination nanotherapeutic is developed by using two amphiphilic conjugates, hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo antitumor studies confirm the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations reveal that tumor suppression is associated with disruption of metabolic homeostasis, leading to reduced protein translation. This study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into the rational design of synergistic nanotherapeutics for combination therapy.
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Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Homeostase , Neoplasias/tratamento farmacológico , PolietilenoglicóisRESUMO
Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug-delivery vehicles. Herein, an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. The hydrophobic-dye-based photosensitizer chlorin e6 (Ce6) is employed for encapsulation in the prodrug nanoparticles (NPs) to obtain an LDBCs-based drug-delivery system (LD-DOX/Ce6) that offers a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 is degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggests that LD-DOX/Ce6 with laser irradiation treatment significantly induces apoptosis, DNA damage, and cell cycle arrest. The combination treatment can not only suppress tumor growth, but also significantly reduce tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFß pathway, angiogenesis, and the hypoxia pathway. LD-DOX/Ce6 displays a synergistic chemo-photodynamic antitumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study demonstrates the potential of the biodegradable and tumor-microenvironment-responsive LDBCs as an intelligent multifunctional drug-delivery vehicle for high-efficiency cancer combination therapy.
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Nanopartículas , Fotoquimioterapia , Porfirinas , Pró-Fármacos , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Nanopartículas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/farmacologia , Pró-Fármacos/farmacologiaRESUMO
Supramolecular self-assemblies of dendritic peptides with well-organized nanostructures have great potential as multifunctional biomaterials, yet the complex self-assembly mechanism hampers their wide exploration. Herein, a self-stabilized supramolecular assembly (SSA) constructed from a PEGylated dendritic peptide conjugate (PEG-dendritic peptide-pyropheophorbide a, PDPP), for augmenting tumor retention and therapy, is reported. The supramolecular self-assembly process of PDPP is concentration-dependent with multiple morphologies. By tailoring the concentration of PDPP, the supramolecular self-assembly is driven by noncovalent interactions to form a variety of SSAs (unimolecular micelles, oligomeric aggregates, and multi-aggregates) with different sizes from nanometer to micrometer. SSAs at 100 nm with a spherical shape possess extremely high stability to prolong blood circulation about 4.8-fold higher than pyropheophorbide a (Ppa), and enhance tumor retention about eight-fold higher than Ppa on day 5 after injection, which leads to greatly boosting the in vivo photodynamic therapeutic efficiency. RNA-seq demonstrates that these effects of SSAs are related to the inhibition of MET-PI3K-Akt pathway. Overall, the supramolecular self-assembly mechanism for the synthetic PEGylated dendritic peptide conjugate sheds new light on the development of supramolecular assemblies for tumor therapy.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Clorofila/análogos & derivados , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/metabolismo , Polietilenoglicóis/metabolismo , Animais , Clorofila/metabolismo , Modelos Animais de Doenças , Camundongos , NanopartículasRESUMO
Histones are the alkali proteins in eukaryotic somatic chromatin cells which constitute the nucleosome structure together with DNA. Their abnormality is often associated with multiple tumorigenesis and other human diseases. Nevertheless, a simple and efficient super-resolution method to visualize histone distribution at the subcellular level is still unavailable. Herein, a Zn(II) terpyridine complex with rich-electronic azide units, namely, TpZnA-His, was designed and synthesized. The initial in vitro and in silico studies suggested that this complex is able to detect histones rapidly and selectively via charge-charge interactions with the histone H3 subunit. Its live cell nuclear localization, red-emission tail, and large Stokes shift allowed super-resolution evaluation of histone distributions with a clear distinction against nuclear DNA. We were able to quantitatively conclude three histone morphology alternations in live cells including condensation, aggregation, and cavity during activating histone acetylation. This work offers a better understanding as well as a versatile tool to study histone-involved gene transcription, signal transduction, and differentiation in cells.
Assuntos
Azidas , Histonas , Cromatina , Humanos , Nucleossomos , ZincoRESUMO
BACKGROUND: Macromoleculization of nitroxides has been an effective strategy to improve low relaxivities and poor in vivo stability, however, nitroxides-based metal-free magnetic resonance imaging (MRI) macromolecular contrast agents (mCAs) are still under-performed. These mCAs do not possess a high nitroxides content sufficient for a cumulative effect. Amphiphilic nanostructures in these mCAs are not stable enough for highly efficient protection of nitroxides and do not have adequate molecular flexibility for full contact of the paramagnetic center with the peripheral water molecules. In addition, these mCAs still raise the concerns over biocompatibility and biodegradability due to the presence of macromolecules in these mCAs. RESULTS: Herein, a water-soluble biodegradable nitroxides-based mCA (Linear pDHPMA-mPEG-Ppa-PROXYL) was prepared via covalent conjugation of a nitroxides (2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl, PROXYL) onto an enzyme-sensitive linear di-block poly[N-(1, 3-dihydroxypropyl) methacrylamide] (pDHPMA). A high content of PROXYL up to 0.111 mmol/g in Linear pDHPMA-mPEG-Ppa-PROXYL was achieved and a stable nano-sized self-assembled aggregate in an aqueous environment (ca. 23 nm) was formed. Its longitudinal relaxivity (r1 = 0.93 mM- 1 s- 1) was the highest compared to reported nitroxides-based mCAs. The blood retention time of PROXYL from the prepared mCA in vivo was up to ca. 8 h and great accumulation of the mCA was realized in the tumor site due to its passive targeting ability to tumors. Thus, Linear pDHPMA-mPEG-Ppa-PROXYL could provide a clearly detectable MRI enhancement at the tumor site of mice via the T1WI SE sequence conventionally used in clinical Gd3+-based contrast agents, although it cannot be compared with DTPA-Gd in the longitudinal relaxivity and the continuous enhancement time at the tumor site of mice. Additionally, it was demonstrated to have great biosafety, hemocompatibility and biocompatibility. CONCLUSIONS: Therefore, Linear pDHPMA-mPEG-Ppa-PROXYL could be a potential candidate as a substitute of metal-based MRI CAs for clinical application.