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Glioblastoma (GBM), the most prevalent and aggressive primary malignant brain tumor, exhibits profound immunosuppression and demonstrates a low response rate to current immunotherapy strategies. Manganese cations (Mn2+) directly activate the cGAS/STING pathway and induce the unique catalytic synthesis of 2'3'-cGAMP to facilitate type I IFN production, thereby enhancing innate immunity. Here, a telodendrimer and Mn2+-based nanodriver (PLHM) with a small size is developed, which effectively target lymph nodes through the blood circulation and exhibit tumor-preventive effects at low doses of Mn2+ (3.7 mg kg-1). On the other hand, the PLHM nanodriver also exhibits apparent antitumor effects in GBM-bearing mice via inducing in vivo innate immune responses. The combination of PLHM with doxorubicin nanoparticles (PLHM-DOX NPs) results in superior inhibition of tumor growth in GBM-bearing mice due to the synergistic potentiation of STING pathway functionality by Mn2+ and the presence of cytoplasmic DNA. These findings demonstrate that PLHM-DOX NPs effectively stimulate innate immunity, promote dendritic cell maturation, and orchestrate cascaded infiltration of CD8 cytotoxic T lymphocytes within glioblastomas characterized by low immunogenicity. These nanodivers chelated with Mn2+ show promising potential for tumor prevention and antitumor effects on glioblastoma by activating the STING pathway.
Assuntos
Doxorrubicina , Glioblastoma , Manganês , Proteínas de Membrana , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/prevenção & controle , Animais , Manganês/química , Manganês/farmacologia , Camundongos , Doxorrubicina/farmacologia , Doxorrubicina/química , Humanos , Linhagem Celular Tumoral , Proteínas de Membrana/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/metabolismo , Nanopartículas/química , Imunidade Inata/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
The diagnosis and evaluation of traumatic brain injury (TBI) are crucial steps toward the treatment and prognosis of patients. A common question remains as to whether it is possible to introduce an ideal device for signal detection and evaluation that can directly connect digital signals with TBI, thereby enabling prompt response of the evaluation signal and sensitive and specific functioning of the detection process. Herein, a method is presented utilizing polymetric porous membranes with TRTK-12 peptide-modified nanochannels for the detection of S100B (a TBI biomarker) and assessment of TBI severity. The method leverages the specific bonding force between TRTK-12 peptide and S100B protein, along with the nanoconfinement effect of nanochannels, to achieve high sensitivity (LOD: 0.002 ng mL-1) and specificity (∆I/I0: 44.7%), utilizing ionic current change as an indicator. The proposed method, which is both sensitive and specific, offers a simple yet responsive approach for real-time evaluation of TBI severity. This innovative technique provides valuable scientific insights into the advancement of future diagnostic and therapeutic integration devices.
Assuntos
Biomimética , Lesões Encefálicas Traumáticas , Humanos , Peptídeos , Lesões Encefálicas Traumáticas/diagnóstico , Prognóstico , Biomarcadores , Subunidade beta da Proteína Ligante de Cálcio S100RESUMO
Tumor cells activate DNA repair pathways to combat the oxidative damage induced by reactive oxygen species (ROS), contributing to their resistance to photodynamic therapy (PDT). Herein, a self-delivery photodynamic sensitizer is developed to enhance oxidative damage by blocking the DNA repair pathway through poly(ADP-ribose) polymerase (PARP) inhibition. Specifically, the photodynamic sensitizer (CeOla) is constructed based on the self-assembly of the photosensitizer chlorine e6 (Ce6) and the PARP inhibitor olaparib (Ola). Of note is that carrier free CeOla has a high drug content and favorable water stability, which could be effectively internalized by tumor cells for robust PDT upon light irradiation. Moreover, CeOla could inhibit the activation of PARP, promote the upregulation of γ-H2AX and reduce the expression of Rad51, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. As a consequence, the self-delivery CeOla greatly promotes the tumor cell apoptosis and shows a high antitumor performance with low side effects. It serves as a novel platform for the development of self-delivery nanomedicine to overcome oxidative resistance in tumor treatment.
Assuntos
Antineoplásicos , Fotoquimioterapia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Antineoplásicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Dano ao DNA , Poli(ADP-Ribose) Polimerases/metabolismo , Linhagem Celular TumoralRESUMO
Although photodynamic therapy (PDT) is a promising antitumor strategy for tumor treatment, the short half-life and the limited diffusion distance of reactive oxygen species (ROS) greatly hamper its antitumor efficacy. Moreover, tumor cells develop antioxidative microenvironments to weaken the oxidative damage caused by PDT. Herein, a plasma membrane-targeted photooxidant (designated as SCPP) is prepared by the self-assembly of a chimeric peptide (Pal-K(PpIX)-R4) and sorafenib. Plasma membrane-targeted SCPP could enhance lipid peroxidation (LPO) through in situ PDT upon light irradiation. Moreover, sorafenib-mediated chemotherapy could block cystine/glutamate antiporter xCT (SLC7A11) to inhibit the syntheses of intracellular GSH and glutathione peroxidase 4 (GPX4), which would destroy the antioxidant defense system of tumors. As a consequence, SCPP achieves a highly efficient tumor inhibition through enhanced PDT and ferroptosis therapy. This study might provide guidance for multisynergistic tumor therapy with a sophisticated mechanism under unfavorable conditions.
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Mitochondrial uncouplers are capable of maximizing cell respiration to induce local hypoxia, which provides a promising target for bioreductive therapy. In this work, we develop a metal-coordinated mitochondria protonophore uncoupler (designated as Cu-BAQ) for O2-exhausting enhanced bioreductive therapy. In brief, carrier free Cu-BAQ is self-assembled by copper ion (Cu2+), mitochondria protonophore uncoupler (BAM15) and bioreductive drug (AQ4N), which possesses a favorable stability and an improved bioavailability. After intravenous administration, nanosized Cu-BAQ prefers to accumulate at tumor site for effective cellular uptake. Moreover, the Cu2+-coordinated nanomedicine of Cu-BAQ exhibits a glutathione (GSH) responsive drug release behavior and the released BAM15 could promote the mitochondria uncoupling to maximize the cell respiration. As a result, the excessive O2 consumption would induce local hypoxia to activate AQ4N for enhanced bioreductive therapy. In vivo investigations demonstrate that Cu-BAQ is able to regulate tumor hypoxia microenvironment and significantly inhibit tumor growth with a minimized side effect. This GSH-responsive self-delivery nanoplatform provides a new insight for the development of individualized biomedicine for hypoxic tumor precision therapy.
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Mitocôndrias , Nanomedicina , Linhagem Celular Tumoral , Humanos , Hipóxia , Microambiente TumoralRESUMO
Abnormal tumor metabolism causes the hypoxic microenvironment, which greatly limits the efficacy of photodynamic therapy (PDT). In this work, a strategy of metabolic reprogramming is proposed to economize O2 for enhanced PDT against hypoxic tumors. The carrier-free O2 -economizer (designated as LonCe) is prepared based on the metabolic antitumor drug of Lonidamine (Lon) and the photosensitizer of chlorin e6 (Ce6). By virtue of intermolecular interactions, Lon and Ce6 self-assemble into nanosized LonCe with favorable stability and high drug contents. Compared with Ce6, LonCe exhibits an improved cellular uptake and photodynamic property for tumor treatment. Moreover, LonCe is capable of inhibiting cell metabolism and mitochondrial respiration to remit the tumor hypoxia, which would promote reactive oxygen species (ROS) production and elevate the PDT efficacy on tumor suppression. In vivo experiments indicate that intravenously injected LonCe prefers to accumulate at the tumor site for highly efficient PDT regardless of the hypoxic environment. Besides, the self-delivery LonCe is fabricated without any carriers, which avoids the excipients induced system toxicity and immunogenicity in vivo. This carrier-free nanomedicine with cell respiratory inhibition mechanism would expedite the development and clinical translation of photodynamic nanoplatforms in tumor treatment.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Excipientes , Humanos , Hipóxia/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Hipóxia TumoralRESUMO
Tumor vascular blockade is a promising strategy for adjuvant cancer treatment. In this work, a self-delivery nanomedicine is developed based on a vascular disruptor and photosensitizer for tumor synergistic therapy. Specifically, this nanomedicine (designated as CeCA) is comprised of combretastatin A4 (CA4) and chlorine e6 (Ce6) by self-assembly technique. Among which, CA4 could not only induce tubulin inhibition for chemotherapy but also disrupt the vasculature to cause tumor hemorrhage. Moreover, Ce6 is able to generate lots of singlet oxygen (1O2) for synergistic photodynamic therapy (PDT) under light irradiation. It is interesting that the carrier-free CeCA possessed a favorable stability and an improved cellular uptake behavior. After intravenous administration, CeCA prefers to accumulate at tumor site for vascular disruption-supplemented chemo-photodynamic therapy. Notably, CeCA is prepared without additional carriers, which avoids the system toxicity raised by excipients. Consequently, CeCA greatly inhibits the tumor growth and leads to a low side effect in vivo. It might open a window in the development of self-supplementary nanomedicine for synergistic tumor treatment.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Doxorrubicina , Nanomedicina , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Tumor cells adapt to excessive oxidative stress by actuating reactive oxygen species (ROS)-defensing system, leading to a resistance to oxidation therapy. In this work, self-delivery photodynamic synergists (designated as PhotoSyn) are developed for oxidative damage amplified tumor therapy. Specifically, PhotoSyn are fabricated by the self-assembly of chlorine e6 (Ce6) and TH588 through π-π stacking and hydrophobic interactions. Without additional carriers, nanoscale PhotoSyn possess an extremely high drug loading rate (up to 100%) and they are found to be fairly stable in aqueous phase with a uniform size distribution. Intravenously injected PhotoSyn prefer to accumulate at tumor sites for effective cellular uptake. More importantly, TH588-mediated MTH1 inhibition could destroy the ROS-defensing system of tumor cells by preventing the elimination of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG), thereby exacerbating the oxidative DNA damage induced by the photodynamic therapy (PDT) of Ce6 under light irradiation. As a consequence, PhotoSyn exhibit enhanced photo toxicity and a significant antitumor effect. This amplified oxidative damage strategy improves the PDT efficiency with a reduced side effect by increasing the lethality of ROS without generating superabundant ROS, which would provide a new insight for developing self-delivery nanoplatforms in photodynamic tumor therapy in clinic.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Estresse Oxidativo , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de OxigênioRESUMO
Multidrug resistance (MDR) is one of the prime reasons for the failure of cancer chemotherapy, which continues to be a great challenge to be solved. In this work, α-tocopherol succinate (α-TOS) and doxorubicin (DOX)-based self-delivery nanomedicine (designated as α-TD) is prepared to combat drug resistance for cancer synergistic chemotherapy. Carrier-free α-TD possesses a fairly high drug loading rate and improves the cellular uptake via the endocytosis pathway. More importantly, the apoptotic inducer α-TOS could elevate the reactive oxygen species (ROS) generation, disrupt mitochondrial function and reduce adenosine 5'-triphosphate (ATP) production, which facilitate the intracellular drug retention while decreasing its efflux. As a result, α-TD achieves a considerable synergistic chemotherapeutic effect against drug resistant cancer cells. Moreover, it also exhibits a preferable inhibitory effect on tumor growth with a low system toxicity in vivo. This synergistic drug self-delivery strategy would open a new window for developing carrier-free nanomedicine for overcoming drug resistance in cancer therapy.
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Antineoplásicos , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Células MCF-7 , NanomedicinaRESUMO
Photodynamic therapy (PDT) often suffers from the exacerbated tumor hypoxia and the heterogeneous distribution of photosensitizers, leading to an inefficient ROS productivity and availability. In this work, a mitochondria targeted O2 economizer (designated as Mito-OxE) is developed to improve PDT efficiency by alleviating tumor hypoxia and enhancing the subcellular localization of photosensitizers. Specifically, the photosensitizer of protoporphyrin IX (PpIX) is modified with the hydrophilic polyethylene glycol and the lipophilic cation of triphenylphosphine (TPP) to fabricate the biocompatible mitochondria targeted photosensitizers (designated as Mito-PSs). And Mito-OxE is prepared by using Mito-PSs to load the mitochondrial oxidative phosphorylation inhibitors of atovaquone (ATO). Benefiting from the targeting capability of TPP, Mito-OxE can selectively accumulate in mitochondria after cellular uptake. Subsequently, the mitochondrial respiration would be suppressed to with the participation of ATO, resulting in a local hypoxia mitigation for enhanced PDT. Compared with Mito-PSs, Mito-OxE maximizes the therapeutic effect against hypoxic tumors under light irradiation. This design of mitochondria targeted O2 economizer would advance the development of targeted drug delivery system for effective PDT regardless of hypoxic microenvironment.
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Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Hipóxia/metabolismo , Mitocôndrias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Hipóxia TumoralRESUMO
The development of photodynamic therapy (PDT) is severely limited by short half-life of singlet oxygen (1O2) and the hypoxic microenvironment. In this work, a plasma membrane targeted photodynamic O2 economizer (designated as P-POE) is developed to improve the subcellular delivery of photosensitizers and alleviate the tumor hypoxia for enhanced PDT effect. After self-assembly into nanomicelles, P-POE has a relatively high stability and a favorable photochemical performance, which are conducive to boosting the 1O2 production. Besides, the plasma membrane anchoring of P-POE contributes to enhancing the preferential retention and cellular accumulation of photosensitizers on tumor tissues and cells. More importantly, P-POE-induced mitochondrial respiratory depression is demonstrated to reduce the O2 consumption of tumor cells to relieve the hypoxia. Consequently, P-POE still exhibits a robust PDT effect against hypoxic tumors, which greatly inhibits the proliferation of breast cancer with low adverse reactions. This innovative combination of subcellular targeting and hypoxic alleviation would advance the development of individualized drug delivery systems for photodynamic therapy against hypoxic tumors.
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Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Membrana Celular , Humanos , Hipóxia/tratamento farmacológico , Oxigênio , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Oxygen-dependent photodynamic therapy (PDT) could exacerbate tumor hypoxia to induce the upregulation of hypoxia-inducible factor-1α (HIF-1α), which would promote tumor growth and metastasis. In this paper, a self-remedied nanomedicine is developed based on a photosensitizer and a HIF-1α inhibitor to surmount the Achilles' heel of PDT for enhanced antitumor efficacy. Specifically, the nanomedicine (designated as CYC-1) is prepared by the self-assembly of chlorine e6 (Ce6) and 3-(5'-hydroxy-methyl-2'-furyl)-1-benzylindazole (YC-1) through π-π stacking and hydrophobic interactions. Of special note, carrier-free CYC-1 holds an extremely high drug loading rate and avoids excipient-triggered adverse reactions. Intravenously administered CYC-1 prefers to accumulate in the tumor tissue for effective cellular uptake. More importantly, it is verified that CYC-1 is capable of inhibiting the HIF-1α activity, thereby improving its PDT efficacy on tumor suppression. Besides, CYC-1 has the overwhelming superiority in restraining tumor proliferation over the combined administration of Ce6 and YC-1, which highlights the advantage of this self-remedied strategy in drug delivery and tumor therapy. This study sheds light on the development of self-delivery nanomedicine for efficient PDT against malignancies.
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Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Nanomedicina , Nanopartículas/química , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Self-delivery of photosensitizer and immune modulator to tumor site is highly recommendable to improve the photodynamic immunotherapy yet remains challenging. Herein, self-delivery photoimmune stimulators (designated as iPSs) are developed for photodynamic sensitized tumor immunotherapy. Carrier-free iPSs are constructed by optimizing the noncovalent interactions between the pure drugs of chlorine e6 (Ce6) and NLG919, which avoid the excipients-raised toxicity and immunogenicity. Intravenously administrated iPSs prefer to passively accumulate on tumor tissues for a robust photodynamic therapy (PDT) with the induction of immunogenetic cell death (ICD) cascade to activate cytotoxic T lymphocytes (CTLs) and initiate antitumor immune response. Meanwhile, the concomitant delivery of NLG919 inhibits the activation of indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse the immunosuppressive tumor microenvironment. Ultimately, the photodynamic sensitized immunotherapy with iPSs efficiently inhibit the primary and distant tumor growth with a low system toxicity, which would shed light on the development of self-delivery nanomedicine for clinical transformation in tumor precision therapy.
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A self-accelerated biocatalyst (Bio-Cat) was developed based on BSA and GOx crosslinked nanoproteins for glucose-initiated tumor starvation and chemodynamic therapy. Bio-Cat could catalyze the glucose to elevate the intracellular H2O2 level and accelerate the conversion of Fe3+/Fe2+, resulting in an effective starvation therapy and an accelerated Fenton reaction for chemodynamic therapy.
Assuntos
Glucose/metabolismo , Neoplasias/metabolismo , Biocatálise , Glucose Oxidase/metabolismo , Humanos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Development of antitumor agents with high efficiency and low toxicity is one of the most important goals for biomedical research. However, most traditional therapeutic strategies were limited due to their non-specificity and abnormal tumor microenvironments, causing a poor therapeutic efficiency and severe side effects. In this paper, a tumor targeted self-synergistic nanoplatform (designated as PAO@PCN@HA) was developed for chemotherapy sensitized photodynamic therapy (PDT) against hypoxic tumors. The efficient drug loading of phenylarsine oxide (PAO) in porphyrinic metal organic framework of PCN-224 as well as the surface modification of hyaluronic acid (HA) improved the targeted drug delivery and reduced the side effects of PAO at the therapeutic dose. Particularly, PAO as an arsenical-based chemotherapeutic agent could not only induce cell apoptosis by generating reactive oxygen species (ROS), but also regulate tumor microenvironments to improve the PDT effect of PCN-224 by mitigating hypoxia and consuming cellular GSH. Both in vitro and in vivo investigations confirmed an effective self-synergy of PAO@PCN@HA in hypoxic tumor therapy with a low systemic toxicity. This integration of microenvironment adjustment with tumor targeted self-synergistic mechanism might provide a new insight for the development of arsenic-based antitumor strategy for clinical applications.
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Antineoplásicos , Arsênio , Neoplasias , Fotoquimioterapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Arsênio/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente TumoralRESUMO
Simultaneous inhibitions of primary tumor growth and distant metastasis are very critical for cancer patients to improve their survival and cure rates. Although photodynamic therapy (PDT) shows great potential for primary tumor treatment, it often exacerbates hypoxia with a reduced therapeutic efficacy and subsequently contributes to carcinoma progression and metastatic dissemination. To solve these issues, self-delivery photodynamic nanoinhibitors (PNI) are developed for tumor targeted therapy and metastasis inhibition. PNI are composed of a carbonic anhydrase inhibitor (CAi), a hydrophilic poly(ethylene glycol) (PEG) linker, and a hydrophobic photosensitizer protoporphyrin IX (PpIX). Such self-delivery design of PNI avoids the premature release and heterogeneous distribution of CAi and PpIX to enhance the availability and synergism. Briefly, the CAi-based nanoinhibitors improve the selectivity of CAi for specific recognition and inhibition of tumor-associated isoform carbonic anhydrase (CA) IX, which would not only facilitate the targeted drug delivery of PNI but also regulate the hypoxia-induced signaling cascade and PDT resistance. Benefiting from the CA IX inhibition and targeted PDT, PNI exhibit a robust inhibitory effect on primary tumor growth and distant metastasis. This targeted self-delivery strategy sheds light on the photosensitizer-based molecular design to overcome the defect of traditional PDT.
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In recent years, epigenetics has attracted great attentions in the field of biomedicine, which is used to denote the heritable changes in gene expression without any variation in DNA sequence, including DNA methylation, histone modification and so on. Inspired by it, a simple and versatile amino acids modification strategy is proposed in this paper to regulate the subcellular distribution of photosensitizer for plasma membrane targeted photodynamic therapy (PDT). Particularly, the plasma membrane anchoring ability and photo toxicity of the photosensitizer against different cell lines could be effectively manipulated at a single amino acid level. Systematic researches indicate that the number and variety of amino acids have a significant influence on the plasma membrane targeting effect of the photosensitizer. Furthermore, after self-assembling into nanoparticles, the obtained nano photosensitizers (NPs) also exhibit a good biocompatibility and plasma membrane targeting ability, which are conducive to enhancing the PDT therapeutic effect under light irradiation. Both in vitro and in vivo investigations confirm a robust tumor inhibition effect of NPs with a good biocompatibility. This epigenetics-inspired photosensitizer modification strategy would contribute to the development of structure-based drug design for tumor precision therapy.