RESUMO
Background: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME). Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH-responsive CaCO3, targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO3 nanoparticles released TAPP and Ca2+, with TAPP generating 1O2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H2O2 and also exhibited a strong PTT effect. Results: CuS@TAPP-CaCO3/HA (CTCH) delivered an enhanced ability to release more Ca2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy. Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications.
Assuntos
Carbonato de Cálcio , Cálcio , Nanopartículas , Microambiente Tumoral , Humanos , Animais , Nanopartículas/química , Cálcio/química , Carbonato de Cálcio/química , Carbonato de Cálcio/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Células HeLa , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Ácido Hialurônico/química , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/farmacocinética , Porfirinas/administração & dosagem , Terapia Fototérmica/métodos , Concentração de Íons de Hidrogênio , Terapia por Ultrassom/métodos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas em MulticamadasRESUMO
Antitumor agents often lack effective penetration and accumulation to achieve high therapeutic efficacy in treating solid tumors. Nanomotor-based nanomaterials offer a potential solution to address this obstacle. Among them, nitric oxide (NO) based nanomotors have garnered attention for their potential applications in nanomedicine. However, there widespread clinical adoption has been hindered by their complex preparation processes. To address this limitation, we have developed a NO-driven nanomotor utilizing a convenient and scalable nanogel preparation procedure. These nanomotors, loaded with the fluorescent probe / sonosensitizer chlorin e6 (Ce6), were specifically engineered for sonodynamic therapy. Through comprehensive in vitro investigations using both 2D and 3D cell models, as well as in vivo analysis of Ce6 fluorescent signal distribution in solid tumor models, we observed that the self-propulsion of these nanomotors significantly enhances cellular uptake and tumor penetration, particularly in solid tumors. This phenomenon enables efficient access to challenging tumor regions and, in some cases, results in complete tumor coverage. Notably, our nanomotors have demonstrated long-term in vivo biosafety. This study presents an effective approach to enhancing drug penetration and improving therapeutic efficacy in tumor treatment, with potential clinical relevance for future applications.
Assuntos
Clorofilídeos , Nanogéis , Neoplasias , Óxido Nítrico , Porfirinas , Animais , Óxido Nítrico/administração & dosagem , Óxido Nítrico/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/metabolismo , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Linhagem Celular Tumoral , Nanogéis/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Polietilenoglicóis/química , Camundongos Nus , Polietilenoimina/química , Camundongos Endogâmicos BALB C , Corantes Fluorescentes/química , Corantes Fluorescentes/administração & dosagem , Feminino , Camundongos , Terapia por Ultrassom/métodos , Nanoestruturas/administração & dosagemRESUMO
Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.
Assuntos
Apoptose , Clorofilídeos , Diterpenos , Neoplasias Hepáticas , Camundongos Nus , Fenantrenos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Espécies Reativas de Oxigênio , Animais , Humanos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/farmacocinética , Diterpenos/administração & dosagem , Concentração de Íons de Hidrogênio , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Apoptose/efeitos dos fármacos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Compostos de Epóxi/administração & dosagem , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Proliferação de Células/efeitos dos fármacos , Polietilenoglicóis/química , Terapia CombinadaRESUMO
The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.
Assuntos
Clorofilídeos , Glutationa , Fotoquimioterapia , Fármacos Fotossensibilizantes , Pró-Fármacos , Tirapazamina , Glutationa/metabolismo , Fotoquimioterapia/métodos , Tirapazamina/farmacologia , Animais , Camundongos , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Pró-Fármacos/farmacologia , Porfirinas/farmacologia , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Port wine stains (PWS) are vascular malformations, and photodynamic therapy (PDT) is a promising treatment. Emerging drug delivery methods employ nanoparticles (NPs) to enhance drug permeability and retention in diseased blood vessels and improve drug bioavailability. (-) -epigallocatechin-3-gallate glycine (EGCG) has anti-angiogenetic effects and boosts photodynamic therapy. Chlorin e6 (Ce6) is capable of efficiently producing singlet oxygen, rendering it a very promising photosensitizer for utilization in nanomedicine. MATERIAL AND METHODS: EGCG-Ce6-NPs were synthesized and characterized using various techniques. The photodynamic effects of EGCG-Ce6-NPs on endothelial cells were evaluated. The compatibility and toxicity of the nanoparticle was tested using the CCK-8 assay. The intracellular uptake of the nanoparticle was observed using an inverted fluorescence microscope, and the intracellular fluorescence intensity was detected using flow cytometry. The ROS generation and apoptosis induced by EGCG-Ce6-NPs was observed using confocal laser scanning microscopy and flow cytometry respectively. RESULTS: EGCG-Ce6-NPs exhibited stability, spherical shape of uniform size while reducing the particle diameter, low polydisperse profile and retaining the ability to effectively generate singlet oxygen. These characteristics suggest promising potential for enhancing drug permeability and retention. Additionally, EGCG-Ce6-NPs demonstrated good compatibility with endothelial cells and enhanced intracellular uptake of Ce6. Furthermore, EGCG-Ce6-NPs increased activation efficiency, induced significant toxicity, more reactive oxygen species, and a higher rate of late apoptosis after laser irradiation. CONCLUSION: This in vitro study showed the potentials EGCG-Ce6-NPs for the destruction of endothelial cells in vasculature.
Assuntos
Catequina , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/farmacocinética , Fotoquimioterapia/métodos , Nanopartículas/química , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/farmacocinética , Catequina/química , Humanos , Porfirinas/farmacologia , Porfirinas/farmacocinética , Células Endoteliais/efeitos dos fármacos , Polifenóis/farmacologia , Apoptose/efeitos dos fármacos , Oxigênio Singlete/metabolismo , Sobrevivência Celular/efeitos dos fármacosRESUMO
Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity and uncontrolled drug release due to their lack of targeting. To improve the bioavailability of drugs and reduce side effects, we have developed a mixed micelle of nanomedicine composed of two prodrugs with surface modified monoclonal antibody for cancer therapy. In this system, Nimotuzumab was used as targeting ligands of the mixed micelles (named as DCMMs) that is composed of polymer-doxorubicin prodrug (abbreviated as PEG-b-P(GMA-ss-DOX)) and maleimide polyethylene glycol-chlorin e6 (abbreviated as Mal-PEG-Ce6). The mixed micelles modified with Nimotuzumab (named as NTZ-DCMMs) bind to overexpressed EGFR receptors on Hepatoma-22 (H22) cells. Disulfide bonds in PEG-b-P(GMA-ss-DOX) are disrupted in tumor microenvironment, inducing the reduction-responsive release of DOX and leading to tumor cell apoptosis. Simultaneously, Chlorin e6 (Ce6) produced plenty of singlet oxygen (1O2) under laser irradiation to kill tumor cells. In vivo biological distribution and antineoplastic effect experiments demonstrate that NTZ-DCMMs enhanced drug enrichment at tumor sites through targeting function of antibody, dramatically suppressing tumor growth and mitigating cardiotoxicity of drugs. All results prove that NTZ-DCMMs have the ability to actively target H22 cells and quickly respond to tumor microenvironment, which is expected to become an intelligent and multifunctional drug delivery carrier for efficient chemotherapy and photodynamic therapy of hepatoma. STATEMENT OF SIGNIFICANCE: Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity due to their lack of targeting. Therefore, it's necessary to develop effective, targeted, and collaborative treatment strategies. We construct a mixed micelle of nanomedicine based on two polymer prodrugs and modified with monoclonal antibody on surface for cancer therapy. Under the tumor cell microenvironment, the disulfide bonds of polymer-ss-DOX were broken, effectively triggering DOX release. The photosensitizer Ce6 could generate a large amount of ROS under light, which synergistically promotes tumor cell apoptosis. By coupling antibodies to the hydrophilic segments of polymer micelles, drugs can be specifically delivered. Compared with monotherapy, the combination of chemotherapy and photodynamic therapy can significantly enhance the therapeutic effect of liver cancer.
Assuntos
Clorofilídeos , Doxorrubicina , Micelas , Nanomedicina , Fotoquimioterapia , Porfirinas , Pró-Fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Doxorrubicina/farmacologia , Doxorrubicina/química , Animais , Fotoquimioterapia/métodos , Linhagem Celular Tumoral , Nanomedicina/métodos , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/farmacocinética , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Camundongos , Polímeros/química , Polímeros/farmacologia , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Apoptose/efeitos dos fármacosRESUMO
PURPOSE: Immune checkpoint inhibitors (ICIs) and sonodynamic therapy (SDT) are types of immunotherapy. In order to combine soluble programmed cell death protein 1 (sPD-1)-mediated immune checkpoint therapy and chlorin e6 (Ce6)-assisted SDT, nanobubbles (NBs) were generated to simultaneously load sPD-1 and Ce6. MATERIALS AND METHODS: The sPD-1/Ce6-NBs, which were prepared by thin-film hydration and mechanical oscillation, had a stable physical condition, and delivered sPD-1 and Ce6 in a targeted manner. NBs could strengthen tumor suppression by increasing tumor-targeting accumulation of Ce6 and sPD-1, and by inducing ultrasound-targeted NB destruction. A mouse H22 cell hepatoma xenograft model was used to evaluate the synergetic immunotherapeutic effect and mechanism of sPD-1/Ce6-NBs. RESULTS: By observing the tumor inhibition rate, tissue and cell apoptosis, apoptosis-related genes and protein expression, the best immunotherapeutic effect was exhibited by the sPD-1/Ce6-NBs group. The immunotherapeutic mechanism initially demonstrated that when tumor cells were transfected by sPD-1 delivered by NBs, which downregulated the expression of programmed death-ligand 1 (PD-L1) in tumor cells, and blocked the PD-1/PD-L1 signaling pathway, which improved T-cell-mediated tumor inhibition. Furthermore, ICIs combined with SDT induced immunogenic cell death by translocating calreticulin to the cell surface and then synergistically enhancing antitumor immune responses. CONCLUSION: In conclusion, sPD-1/Ce6-NBs were successfully designed. Ultrasound-mediated sPD-1/Ce6-NBs are potentially effective delivery systems for combination immunotherapy of hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Imunoterapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Nanopartículas/química , Porfirinas/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Clorofilídeos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Porfirinas/farmacocinética , Porfirinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Carga TumoralRESUMO
Passing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide-drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide-porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.
Assuntos
Fármacos Anti-HIV/farmacocinética , Barreira Hematoencefálica/metabolismo , Peptídeos/farmacocinética , Porfirinas/farmacocinética , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Transporte Biológico , Linhagem Celular , Descoberta de Drogas , Células HEK293 , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Porfirinas/química , Porfirinas/farmacologiaRESUMO
Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate in tumor tissue and disassemble upon protonation of their tertiary amines in response to the acidic tumor environment, exposing the contained DBCO and Ce6. The selective, highly specific click reactions between DBCO and azide groups enable Ce6 to be anchored on the tumor cell surface. Upon laser irradiation, the cell membrane is severely damaged by the cytotoxic reactive oxygen species, resulting in remarkable cellular apoptosis. Taken together, the membrane-localized PDT by our bioorthogonal pretargeting strategy to anchor activatable photosensitizers on the plasma membrane provides a simple but effective method for enhancing the therapeutic efficacy of photosensitizers in anticancer therapy.
Assuntos
Membrana Celular/metabolismo , Ciclo-Octanos/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Linhagem Celular Tumoral , Clorofilídeos , Ciclo-Octanos/farmacocinética , Ciclo-Octanos/uso terapêutico , Humanos , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Receptores Artificiais/metabolismoRESUMO
The topical photodynamic therapy (PDT) is mainly used in the treatment of dermato-oncological diseases. The distribution and functionality of the photosensitizer Tetrahydroporphyrin-Tetratosylat (THPTS) was investigated using microscopic and spectroscopic methods after topical application to excised porcine skin followed by irradiation. The distribution of THPTS was determined by two-photon tomography combined with fluorescence lifetime imaging (TPT/FLIM) and confocal Raman microspectroscopy (CRM). The radicals were quantified and characterized by electron paramagnetic resonance (EPR) spectroscopy. Results show a penetration depth of THPTS into the skin down to around 12 ± 5 µm. A penetration of THPTS through the stratum corneum was not clearly observable after 1 h penetration time, but cannot be excluded. The irradiation within the phototherapeutic window (spectral range of visible and near infrared light in the range ≈ 650-850 nm) is needed to activate THPTS. An incubation time of 10 min showed the highest radical production. A longer incubation time affected the functionality of THPTS, whereby significant less radicals were detectable. During PDT mainly reactive oxygen species (ROS) and lipid oxygen species (LOS) are produced. Overall, the irradiation dose per se influences the radical types formed in skin. While ROS are always prominent at low doses, LOS increase at high doses, independent of previous skin treatment and the irradiation wavelength used.
Assuntos
Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Pele/metabolismo , Administração Cutânea , Animais , Raios Infravermelhos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Espécies Reativas de Oxigênio/análise , Análise Espaço-Temporal , Suínos , Fatores de Tempo , Distribuição Tecidual/efeitos da radiaçãoRESUMO
AIMS: To construct a self-assembly supramolecular drug delivery system (DDS) to co-deliver chlorin e6 (Ce6) and tripeptide tyroseroleutide (YSL) and evaluate the anti-tumour effects. METHODS: A supramolecular DDS was constructed via self-assembly of Ce6 and YSL based on π-π stacking and hydrogen-bond interaction. The size, morphology, stability, in vitro drug release, cellular uptake, cytotoxicity, pharmacokinetics analysis and pharmacodynamics analysis were respectively studied. RESULTS: Ce6-YSL nanoparticles with a uniform size of 75 ± 3.5 nm (PDI = 0.128) and monodispersed spherical morphology were constructed. The nanoparticles exhibited good stability with zeta potential -21.2 ± 1.73 mV. Under the weak acidic conditions, the accumulative drug release was 82.8% (w/w) (pH = 6.0) and 91.5% (w/w) (pH = 5.0), respectively, indicating that nanoparticles performed smart responsive properties and achieved controlled release characteristics in acidic tumour microenvironment. In addition, nanoparticles could easily enter the tumour cells and induce ROS production and inhibit cell proliferation in SMMCC-7721 cells with IC50 value 3.4 ± 0.023 µg/mL under laser irradiation. Furthermore, the nanoparticles could retain a much higher blood concentration in vivo and displayed excellent antitumor effect in tumour-bearing mice, showing no influence on body weight. CONCLUSIONS: This self-assembly supramolecular DDS can be used for combination of photodynamic therapy and chemotherapy in future research.
Assuntos
Antineoplásicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Clorofilídeos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/análise , Nanopartículas/uso terapêutico , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Ratos Sprague-DawleyRESUMO
The major limitations of photodynamic therapy (PDT) are the poor tissue penetration of excitation light and the neutralization of reactive oxygen species (ROS) generated by overexpressed glutathione (GSH) in cancer cells. Despite tremendous efforts to design nanoplatforms, PDT still suffers from unsatisfactory effects. Furthermore, the residual of nanomaterials in the body has restricted their clinical application. To address these issues, Janus nanocomposites containing an Yb/Er codoped NaYF4 upconverting nanocrystal head and a disulfide-bridged mesoporous organosilicon body (UCN/MON) with loaded chlorin e6 (Ce6) were designed. On one hand, the upconverting nanocrystal head can convert near-infrared (NIR) light into visible light to activate Ce6 to release ROS. On the other hand, the silica body can be degraded though a redox reaction with GSH, to not only improve the tumor selectivity of the photosensitizer by redox- and pH-triggered Ce6 release, but also diminish the concentration of GSH in cancer cells to reduce the depletion of ROS. Thereby, an enhanced PDT triggered by NIR irradiation was achieved. Furthermore, UCN/MONs showed a higher clearance rate after therapeutic actions than nonbiodegradable UCN/MSNs due to their biocompatibility. Taken together, this work revealed the potential of UCN/MONs for highly efficient and NIR-induced PDT, highlighting the prospects of UCN/MONs in the clinic.
Assuntos
Antineoplásicos/uso terapêutico , Glutationa/metabolismo , Nanocompostos/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Clorofilídeos , Érbio/química , Érbio/efeitos da radiação , Érbio/uso terapêutico , Feminino , Fluoretos/química , Fluoretos/farmacocinética , Fluoretos/efeitos da radiação , Fluoretos/uso terapêutico , Humanos , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Nanocompostos/efeitos da radiação , Nanopartículas/química , Nanopartículas/efeitos da radiação , Nanopartículas/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/efeitos da radiação , Dióxido de Silício/química , Dióxido de Silício/metabolismo , Dióxido de Silício/farmacocinética , Oxigênio Singlete/metabolismo , Itérbio/química , Itérbio/efeitos da radiação , Itérbio/uso terapêutico , Ítrio/química , Ítrio/farmacocinética , Ítrio/efeitos da radiação , Ítrio/uso terapêuticoRESUMO
This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e6, a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives 3a, 3b, 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16-F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16-F10 cells. Apparently, simultaneous introduction of amino acid residue and n-hexyloxy chain in chlorin e6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a, 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives, especially 3c and 8, might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT.
Assuntos
Aminoácidos/química , Aminoácidos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Células A549 , Aminoácidos/farmacocinética , Aminoácidos/uso terapêutico , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofilídeos , Desenho de Fármacos , Células HeLa , Humanos , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Ratos Sprague-DawleyRESUMO
Recent cancer immunotherapy has attracted much attention due to high specificity and recurrence prevention of tumor. Nevertheless, its therapeutic effects are still challenging in solid cancer. To establish superior antitumor immunity, chlorin e6 (Ce6)-loaded pH sensitive carbon dots were investigated (Ce6@IDCDs). At tumoral pH 6.5, Ce6 was released four times compared with the release at physiological pH 7.4 due to an imbalance between hydrophilic and hydrophobic forces via protonation of imidazole groups in Ce6@IDCDs. This result led to the superior singlet oxygen generating activity of Ce6@IDCDs without Ce6 quenching. The maturation effects of dendritic cells after co-incubation with supernatant media obtained from Ce6@IDCDs with laser-treated cells at pH 6.5 were much higher than at physiological pH. Furthermore, Ce6@IDCDs following a laser at pH 6.5 significantly promoted calreticulin exposure and high-mobility group box 1 release, as major immunogenic cell death markers. In bilateral CT-26-bearing mice model, the Ce6@IDCDs elicited significant antitumoral effects at laser treated-primary tumor regions via therapeutic reactive oxygen species. Furthermore, Ce6@IDCDs upon laser irradiation induced a large amount of activated CD8+ T cells, natural killer cells, and mature dendritic cells recruitment into tumoral tissue and hampered tumor growth even at untreated sites approximately four-fold compared with those of others. Overall, this pH-sensitive immunoinducer can accomplish primary and distant tumor ablation via photomediated cancer immunotherapy.
Assuntos
Carbono/química , Células Dendríticas/efeitos dos fármacos , Imunoterapia/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Calreticulina/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Clorofilídeos , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/química , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/efeitos da radiação , Nanopartículas/ultraestrutura , Neoplasias/imunologia , Neoplasias/radioterapia , Tamanho da Partícula , Porfirinas/química , Porfirinas/farmacocinética , Radiossensibilizantes/química , Radiossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/uso terapêutico , Espectroscopia de Infravermelho com Transformada de Fourier , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Photodynamic therapy is a clinically approved procedure for the treatment of neoplastic and other non-malignant diseases. Meso-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP) is a photosensitizing agent which has been used in many applications. However, the use of TMPyP topically is limited due to its hydrophilicity. To overcome this problem, TMPyP was loaded in ethosomes. Three ethosomal formulae (A), (B) and (C) were prepared and characterized. Preparation (A) was chosen to be used in the in vitro and in vivo study, having the greatest encapsulation efficiency, the smallest size and the highest cumulative release percentage. The results of in vitro permeation study revealed that the ethosomal TMPyP was superior to the drug in the free form with permeation flux (3.92⯵gâ¯cm-2â¯h-1). In the in vivo animal study done on Swiss albino mice, after 19 days of Ehrlich tumor implantation, the group treated with the ethosomal preparation showed significantly smaller tumor size (143.28⯱â¯13.2â¯mm3) compared to the group treated with the free TMPyP (219⯱â¯11.9â¯mm3). It showed also significant longer survival time (21 days) compared to that treated with the free drug (18.2⯱â¯1.2 days). Based on the obtained results, transdermal delivery of TMPyP was potentiated by incorporating it in ethosomes.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Animais , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Absorção Cutânea , Análise de SobrevidaRESUMO
Vesicular photothermal therapy agents (PTAs) are highly desirable in photothermal therapy (PTT) for their excellent light-harvesting ability and versatile hollow compartments. However, up to now, the reported vesicular PTAs are generally self-assembled from small molecules like liposomes, and polymer vesicles have seldom been used as PTAs due to the unsatisfactory photothermal conversion efficiency resulting from the irregular packing of chromophores in the vesicle membranes. Here we report a nano-sized polymer vesicle from hyperbranched polyporphyrins with favorable photothermal stability and extraordinarily high photothermal efficiency (44.1%), showing great potential in imaging-guided PTT for tumors through in vitro and in vivo experiments. These excellent properties are attributed to the in situ supramolecular polymerization of porphyrin units inside the vesicle membrane into well-organized 1D monofilaments driven by π-π stacking. We believe the supramolecular polymerization-enhanced self-assembly process reported here will shed a new light on the design of supramolecular materials with new structures and functions.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Hipertermia Induzida/métodos , Nanopartículas/química , Fototerapia/métodos , Polímeros/química , Porfirinas/química , Animais , Dicroísmo Circular , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Membranas Artificiais , Camundongos , Camundongos Nus , Microscopia Eletrônica de Varredura , Simulação de Dinâmica Molecular , Células NIH 3T3 , Nanopartículas/uso terapêutico , Nanopartículas/ultraestrutura , Polimerização , Polímeros/síntese química , Polímeros/farmacocinética , Polímeros/uso terapêutico , Porfirinas/síntese química , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Ratos , Espectrometria de Fluorescência , Temperatura , Transplante HeterólogoRESUMO
Selectively attenuating the protection offered by heat shock protein 90 (HSP90), which is indispensable for the stabilization of the essential regulators of cell survival and works as a cell guardian under oxidative stress conditions, is a potential approach to improve the efficiency of cancer therapy. Here, we designed a biodegradable nanoplatform (APCN/BP-FA) based on a Zr(iv)-based porphyrinic porous coordination network (PCN) and black phosphorus (BP) sheets for efficient photodynamic therapy (PDT) by enhancing the accumulation of the nanoplatforms in the tumor area and attenuating the protection of cancer cells. Owing to the favorable degradability of BP, the nanosystem exhibited accelerated the release of the HSP90 inhibitor tanespimycin (17-AAG) and an apparent promotion in the reactive oxygen species (ROS) yield of PCN as well as expedited the degradation of the PCN-laden BP nanoplatforms. Both in vitro and in vivo results revealed that the elevated amounts of ROS and reduced cytoprotection in tumor cells were caused by the nanoplatforms. This strategy may provide a promising method for attenuating cytoprotection to aid efficient photodynamic therapy.
Assuntos
Estruturas Metalorgânicas/química , Neoplasias/tratamento farmacológico , Fósforo/química , Fotoquimioterapia/métodos , Animais , Benzoquinonas/química , Benzoquinonas/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/uso terapêutico , Estruturas Metalorgânicas/farmacocinética , Estruturas Metalorgânicas/uso terapêutico , Camundongos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/metabolismo , Fósforo/farmacocinética , Fósforo/uso terapêutico , Porosidade , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Zircônio/química , Zircônio/farmacocinética , Zircônio/uso terapêuticoRESUMO
Combining functional proteins with small molecular drugs into one entity may endow distinct synergistic advantages. However, on account of completely different physicochemical properties of such payloads, co-delivery through systemic administration for therapeutic purpose is challenging. Herein, we designed the protein-drug conjugate HSAP-DC-CAT (human serum albumin/Pt (IV)-dibenzocyclooctyne/chlorin e6-catalase) by modification of CAT and cisplatin pro-drug loaded HSA with pH-sensitive azide linker 3-(azidomethyl)-4-methyl-2,5-furandione (AzMMMan) followed by click chemistry assembly with DC. The dynamic covalent bonds between linker and proteins, on the one hand, can bridge proteins and small molecular drugs in the intermediate state for systemic delivery in the harsh in vivo environment; on the other hand, it can trigger traceless cleavage and release of drugs and proteins with full bioactivity in acidic microenvironment of tumor. The multifunctional HSAP-DC-CAT provides efficient cytosolic transduction in vitro, excellent blood half-lives after systemic administration, and significant antitumor outcome via integrated cisplatin-based chemotherapy and Ce6-based photodynamic therapy enhanced by catalase-induced manipulation of tumor hypoxia microenvironment. This study describes a universal formulation strategy for protein and small molecular drug by a bifunctional linker through amide reaction and click chemistry, with traceless in vivo release of therapeutic units.
Assuntos
Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Catalase/farmacologia , Cisplatino/farmacologia , Fotoquimioterapia , Porfirinas/farmacologia , Pró-Fármacos/farmacologia , Radiossensibilizantes/farmacologia , Albumina Sérica Humana/química , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Catalase/química , Catalase/farmacocinética , Linhagem Celular Tumoral , Clorofilídeos , Cisplatino/química , Cisplatino/farmacocinética , Química Click , Preparações de Ação Retardada , Portadores de Fármacos , Composição de Medicamentos , Feminino , Concentração de Íons de Hidrogênio , Camundongos Nus , Porfirinas/química , Porfirinas/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Radiossensibilizantes/química , Radiossensibilizantes/farmacocinética , Hipóxia Tumoral , Microambiente TumoralRESUMO
Although photodynamic therapy (PDT) has been clinically applied tumor hypoxia still greatly restricts the performance of this oxygen-dependent oncological treatment. The delivery of oxygen donors to tumor may produce excessive reactive oxygen species (ROS) and damage the peripheral tissues. Herein, we developed a strategy to solve the hypoxia issue by enhancing the lethality of ROS. Before PDT, the ROS-defensing system of the cancer cells was obstructed by an inhibitor to MTH1, which is a key for the remediation of ROS-caused DNA damage. As a result, both nuclei and mitochondrial DNA damages were increased, remarkably promoting cellular apoptosis. The therapeutic results demonstrated that the performance of PDT can be improved by the MTH1 inhibitor, leading to efficient cancer cell killing effect in the hypoxic tumor. This strategy makes better use of the limited oxygen, holding the promise to achieve satisfactory therapeutic effect by PDT without generating redundant cytotoxic ROS.
Assuntos
Antineoplásicos/farmacologia , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Inibidores Enzimáticos/farmacologia , Melanoma Experimental/tratamento farmacológico , Monoéster Fosfórico Hidrolases/genética , Pirimidinas/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Clorofilídeos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Enzimas Reparadoras do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/antagonistas & inibidores , DNA de Neoplasias/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Composição de Medicamentos/métodos , Inibidores Enzimáticos/química , Feminino , Expressão Gênica , Células HCT116 , Células HeLa , Humanos , Luz , Células MCF-7 , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/química , Porfirinas/farmacocinética , Pirimidinas/química , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor hypoxia is the Achilles heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the tumor hypoxia. In this work, an oxidative phosphorylation inhibitor of atovaquone (ATO) and a photosensitizer of chlorine e6 (Ce6)-based self-delivery nanomedicine (designated as ACSN) were prepared via π-π stacking and hydrophobic interaction for O2-economized PDT against hypoxic tumors. Specifically, carrier-free ACSN exhibited an extremely high drug loading rate and avoided the excipient-induced systemic toxicity. Moreover, ACSN not only dramatically improved the solubility and stability of ATO and Ce6 but also enhanced the cellular internalization and intratumoral permeability. Abundant investigations confirmed that ACSN effectively suppressed the oxygen consumption to reverse the tumor hypoxia by inhibiting mitochondrial respiration. Benefiting from the synergistic mechanism, an enhanced PDT effect of ACSN was observed on the inhibition of tumor growth. This self-delivery system for oxygen-economized PDT might be a potential appealing clinical strategy for tumor eradication.