RESUMO
ConspectusDue to the advantages of spatiotemporal selectivity and inherent noninvasiveness, cancer phototherapy, which includes both photodynamic therapy (PDT) and photothermal therapy (PTT), has garnered significant attention in recent years as a promising cancer treatment. Despite the commendable progress in this field, persistent challenges remain. In PDT, limitations in dyes manifest as low intersystem crossing (ISC) efficiency and oxygen-dependent photoactivity, resulting in unsatisfactory performance, particularly under hypoxic conditions. Similarly, PTT encounters consistent insufficiencies in the photothermal conversion efficiency (PCE) of dyes. Additionally, the suboptimal phototherapeutic efficacy often exhibits a limited immune response. These factors collectively impose significant constraints on phototherapy in oncological applications, leading to limited tumor inhibition, tumor recurrence, and even metastasis.Unlike strategies that rely on external assistance with complicated systems, manipulating excited-state deactivation pathways in biocompatible dyes offers a universal way to systematically address these challenges. Our group has devoted considerable effort to achieving this goal. In this Account, we present and discuss our journey in optimizing excited-state energy-release pathways through regulating molecular charge transfer based on cyanine dyes, which are renowned for their exceptional photophysical properties and harmonious biocompatibility. The investigation begins with the introduction of amino groups in the meso position of a heptamethine cyanine dye, where the intramolecular charge transfer (ICT) effect causes a significant enlargement of the Stokes shift. Subsequently, ICT induced by introducing functional electron-deficient groups in cyanines is found to decrease the overlap of electron distribution or narrow the energy gaps of molecular frontier orbitals. Such modifications result in a reduction of the energy gaps between singlet and triplet states or an improvement in internal conversion, ultimately promoting phototherapy efficacy in both primary and distant tumors. Furthermore, with the intensification of the charge transfer effect aided by light, photoinduced intramolecular electron transfer occurs in some cyanines, leading to complete charge separation in the excited state. This process enhances the transition to the ground or triplet states, improving tumor phototherapy and inhibiting metastasis by increasing the PCE or the yield of reactive oxygen species, respectively. Shifting focus from intramolecular to intermolecular interactions, we successfully constructed and explored cyanines based on intermolecular charge transfer. These dyes, with excited-state dynamics mimicking natural photosynthesis, generate radicals and facilitate oxygen-independent hypoxic tumor PDT. Finally, we outlined the existing challenges and future directions for optimizing phototherapeutic efficacy by regulating molecular charge transfer. This Account provides molecular-level insights into improving phototherapeutic performance, offering valuable perspectives, and inspiring the development of functional dyes in other application fields.
Assuntos
Carbocianinas , Neoplasias , Carbocianinas/química , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Corantes/química , Corantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fotoquimioterapia , Animais , Fototerapia/métodosRESUMO
Photodynamic therapy (PDT), a therapeutic mode involving light triggering, has been recognized as an attractive oncotherapy treatment. However, nonnegligible challenges remain for its further clinical use, including finite tumor suppression, poor tumor targeting, and limited therapeutic depth. The photosensitizer (PS), being the most important element of PDT, plays a decisive role in PDT treatment. This review summarizes recent progress made in the development of PSs for overcoming the above challenges. This progress has included PSs developed to display enhanced tolerance of the tumor microenvironment, improved tumor-specific selectivity, and feasibility of use in deep tissue. Based on their molecular photophysical properties and design directions, the PSs are classified by parent structures, which are discussed in detail from the molecular design to application. Finally, a brief summary of current strategies for designing PSs and future perspectives are also presented. We expect the information provided in this review to spur the further design of PSs and the clinical development of PDT-mediated cancer treatments.
Assuntos
Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/química , Animais , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Corantes Fluorescentes/química , Humanos , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Elementos de Transição/químicaRESUMO
Heavy-atom-based photosensitizers usually exhibit shortened triplet-state lifetimes, which is not ideal for hypoxic tumor photodynamic therapy. Although several heavy-atom-free photosensitizers possess long triplet-state lifetimes, the clinical applicability is limited by their short excitation wavelengths, poor photon capture abilities, and intrinsically hydrophobic structures. Herein we developed a novel NIR heavy-atom-free photosensitizer design strategy by introducing sterically bulky and electron-rich moieties at the meso position of the pentamethine cyanine (Cy5) skeleton, which simultaneously enhanced intersystem crossing (ISC) and prolonged excited-state lifetime. We found that the 1O2 generation ability is directly correlated to the electron-donating ability of the meso substituent in cyanine, and the excited-state lifetime was simultaneously much elongated when the substituents were anthracene derivatives substituted at the 9-position. Our star compound, ANOMe-Cy5, exhibits intense NIR absorption, the highest 1O2 quantum yield (4.48-fold higher than Cy5), the longest triplet-state lifetime (9.80-fold longer than Cy5), and lossless emission intensity (nearly no change compared with Cy5). Such excellent photophysical properties coupled with its inherently cationic and hydrophilic nature enable the photosensitizer to realize photoablation of solid tumor and antitumor lung metastasis. This study highlights the design of a new generation of NIR photosensitizers for imaging-guided photodynamic cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Corantes Fluorescentes/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/químicaRESUMO
It remains a considerable challenge to realize complete tumor suppression and avoid tumor regrowth by rational design of photosensitizers (PSs) to improve their photon utilization. In this Article, we provide a molecular design (Icy-NBF) based on the oxygen-content-regulated deactivation process of excited states. In the presence of overexpressed nitroreductase in hypoxic cancer cells, Icy-NBF is reduced and converted into a molecule with the same skeleton (Icy-NH2), in which the deactivation of the PS under 808 nm light irradiation proceeds via a different pathway: the excited states deactivation pathway of Icy-NBF involves radiative transition and energy transfer between Icy-NBF and O2; as for Icy-NH2, the deactivation pathway is attributed to non-radiative relaxation. By varying the O2 concentration in tumor cells, the therapeutic mechanism of Icy-NBF under 808 nm light irradiation can be switched between photodynamic and photothermal therapies, which maximizes the advantages of phototherapies with no tumor regrowth. Our study provides help in designing of smart PSs with improvement of photon utilization for efficient tumor photoablation.
Assuntos
Oxigênio/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Terapia Fototérmica/métodos , Linhagem Celular Tumoral , Humanos , CinéticaRESUMO
Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2â¢-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2â¢- through type-I photochemistry, and the generated O2â¢- can further trigger a biocascade to reduce the PDT's demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.
Assuntos
Neoplasias/tratamento farmacológico , Fenotiazinas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Hipóxia Tumoral/efeitos dos fármacos , Animais , Respiração Celular/efeitos dos fármacos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Luz , Células MCF-7 , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Fenotiazinas/síntese química , Fenotiazinas/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Superóxidos/metabolismoRESUMO
Targeting is one of the most important strategies for enhancing the efficacy of cancer photothermal therapy (PTT) and reducing damage to surrounding normal tissues. Compared with the traditional targeting approaches, the active targeting of breast cancer cells in PTT using chemotherapeutic drugs, such as tamoxifen (TAM), in combination with single-molecule photothermal photosensitizers has superior selectivity and therapeutic effects. However, single-molecule drug-targeting photosensitizers for improved PTT efficacy are not widely reported. Accordingly, herein, a near-infrared induced small-molecule photothermal photosensitizer (CyT) is developed that actively targets the estrogen receptors (ERs) of breast cancer cells as well as targets mitochondria by structure-inherent targeting. Cell uptake and cytotoxicity studies using different types of cells show that CyT enhances the efficiency of TAM-based PTT by targeting ER-overexpressing breast cancer cells and selectively killing them. In vivo experiments demonstrate that CyT can be used as a photothermal agent for fluorescence imaging-guided PTT. More importantly, the intravenous injection of CyT results in better targeting and efficiency of tumor inhibition compared with that achieved with the TAM-free control molecule Cy. Thus, the study presents an excellent small-molecule photothermal agent for breast cancer therapy with potential clinical application prospects.
Assuntos
Neoplasias da Mama , Sistemas de Liberação de Medicamentos , Hipertermia Induzida , Fármacos Fotossensibilizantes , Terapia Fototérmica , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , FototerapiaRESUMO
As traditional phototherapy agents, boron dipyrromethene (BODIPY) photosensitizers have attracted increasing attention due to their high molar extinction coefficients, high phototherapy efficacy, and excellent photostability. After being formed into nanostructures, BODIPY-containing nano-photosensitizers show enhanced water solubility and biocompatibility as well as efficient tumor accumulation compared to BODIPY molecules. Hence, BODIPY nano-photosensitizers demonstrate a promising potential for fighting cancer. This review contains three sections, classifying photodynamic therapy (PDT), photothermal therapy (PTT), and the combination of PDT and PTT based on BODIPY nano-photosensitizers. It summarizes various BODIPY nano-photosensitizers, which are prepared via different approaches including molecular precipitation, supramolecular interactions, and polymer encapsulation. In each section, the design strategies and working principles of these BODIPY nano-photosensitizers are highlighted. In addition, the detailed in vitro and in vivo applications of these recently developed nano-photosensitizers are discussed together with future challenges in this field, highlighting the potential of these promising nanoagents for new tumor phototherapies.
Assuntos
Antineoplásicos/farmacologia , Boro/farmacologia , Neoplasias/terapia , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Porfobilinogênio/análogos & derivados , Animais , Antineoplásicos/química , Humanos , Fármacos Fotossensibilizantes/química , Porfobilinogênio/química , Porfobilinogênio/farmacologiaRESUMO
The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of nonselective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near-infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD-L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.
Assuntos
Nanopartículas , Fármacos Fotossensibilizantes , Animais , Camundongos , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/patologia , Imunoterapia , Azepinas/química , Azepinas/farmacologia , Polietilenoglicóis/química , Hipóxia Tumoral/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Raios InfravermelhosRESUMO
Combining photodynamic therapy (PDT) and immune checkpoint blockades is an efficient method to maximize immunotherapeutic outcome by boosting tumor immunogenicity and modulating the immunosuppressive tumor microenvironment. However, the always-on bioactivity of photosensitizers or immune checkpoint inhibitors leads to uncontrollable side effects, limiting the in vivo therapeutic efficacy of treatments. An activatable strategy is of great importance for improving the selectivity during cancer therapy. In this study, a photodynamic immunomodulator, ICy-NLG, is developed by conjugating the photosensitizer ICy-NH2 with the indoleamine 2,3-dioxygenase 1 inhibitor NLG919 through a glutathione (GSH)-cleavable linker to achieve activatable photodynamic immunotherapy. The conjugation considerably suppresses both the PDT effect and the activity of the inhibitor. After ICy-NLG is activated by high levels of GSH in tumor cells, the PDT effect is restored and leads to immunogenic tumor cell death. The released tumor-associated antigens in conjunction with the activated immune checkpoint inhibitor induce a synergistic antitumor immune response, resulting in the growth inhibition of primary and distant tumors and the prevention of lung metastasis in mouse xenograft models.
Assuntos
Neoplasias Pulmonares , Nanopartículas , Fotoquimioterapia , Animais , Camundongos , Humanos , Fotoquimioterapia/métodos , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Microambiente TumoralRESUMO
The hydroxyl radical (â¢OH) is an extremely potent reactive oxygen species that plays a crucial role in photooxidations within the realm of hypoxic tumor therapy. However, the current methods for â¢OH photogeneration typically rely on inorganic materials that require UV/vis light excitation. Consequently, photogenerators based on organic molecules, especially those utilizing near-infrared (NIR) light excitation, are rare. In this study, the concept of photoinduced cascade charge transfer (PICET), which utilizes NIR heavy-atom-free photosensitizers (ANOR-Cy5) to generate â¢OH is introduced. The ANOR-Cy5 photosensitizer, with its flexible hydrophobic structure, enables the formation of nanoparticles in aqueous solutions through molecular assembly. PICET involves a symmetry-breaking charge separation-induced localized charge-separated state, transitioning to a delocalized charge-separated state, which governs the efficiency of â¢OH generation. Thanks to the oxygen-independent nature of â¢OH generation and its robust oxidative properties, the ANOR-Cy5-based photosensitizer demonstrates highly effective photoinduced anti-cancer effects, even under severely hypoxic conditions. This discovery emphasizes the potential for achieving â¢OH photogeneration using a single organic molecule through the engineering of molecular self-assembly, thereby opening up new possibilities for phototherapy and beyond.
Assuntos
Nanopartículas , Neoplasias , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Radical Hidroxila , Elétrons , Fototerapia , Neoplasias/terapia , Nanopartículas/química , HipóxiaRESUMO
Upconverted reactive oxygen species (ROS) photosensitization with one-photon excitation mode is a promising tactic to elongate the excitation wavelengths of photosensitive dyes to near-infrared (NIR) light region without the requirement of coherent high-intensity light sources. However, the photosensitization efficiencies are still finite by the unilateral improvement of excited-state intersystem crossing (ISC) via heavy-atom-effect, since the upconverted efficiency also plays a decisive role in upconverted photosensitization. Herein, a NIR light initiated one-photon upconversion heavy-atom-free small molecule system is reported. The meso-rotatable anthracene in pentamethine cyanine (Cy5) is demonstrated to enrich the populations in high vibrational-rotational energy levels and subsequently improve the hot-band absorption (HBA) efficiency. Moreover, the spin-orbit charge transfer intersystem crossing (SOCT-ISC) caused by electron donated anthracene can further amplify the triplet yield. Benefiting from the above two aspects, the 1 O2 generation significantly increases with over 2-fold improved performance compared with heavy-atom-modified method under upconverted light excitation, which obtains efficient in vivo phototheranostic results and provides new opportunities for other applications such as photocatalysis and fine chemical synthesis.
Assuntos
Dermatite Fototóxica , Neoplasias , Humanos , Neoplasias/terapia , Elétrons , Corantes , AntracenosRESUMO
Rational manipulation of nonradiative decay channels is of crucial significance to improve photothermal conversion efficiency (PCE) and design photothermal agents. We first used the "internal and external combined" nonradiative decay strategy to enhance PCE. Specifically, organic IR-Y6 NPs with strong NIR absorption and high molar extinction coefficient were prepared and characterized. By means of TD-DFT calculations and fs-TA spectroscopy, the dual nonradiative decay channels composed of the free rotor (external strategy) and ultrafast dark excited states (DESs) between S0 and S1 states (internal strategy) were proved, which significantly enhanced PCE, up to 66%. IR-Y6 NPs were applied to a mice tumor model for photoacoustic image-guided photothermal therapy, showing complete tumor ablation ability and good biocompatibility for the normal organs. This work is of significance to deeply understand the nonradiation decay mechanism and rational design of high-performance PTT agents.
Assuntos
Antineoplásicos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Indanos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Teoria da Densidade Funcional , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos da radiação , Humanos , Indanos/síntese química , Indanos/efeitos da radiação , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Modelos Químicos , Nanopartículas/química , Nanopartículas/efeitos da radiação , Técnicas Fotoacústicas , Terapia Fototérmica , Nanomedicina Teranóstica/métodosRESUMO
Photosensitizers (PSs) inevitably release a large amount of energy in the form of fluorescence during photodynamic therapy (PDT). However, under the premise of satisfying fluorescence imaging, a large amount of energy is lost, which limits the efficiency of tumor therapy. Accordingly, in this study, we developed a new strategy (BDP-CR) using the single-molecule Förster resonance energy transfer (smFRET) mechanism to transfer part of the fluorescent energy into heat for combined PDT and photothermal therapy (PTT) featuring the "1 + 1 > 2" amplification effect. Under the 671 nm light irradiation, BDP-CR can produce singlet oxygen (1O2) for PDT based on the BDP moiety and also generate hyperthermia to achieve the PTT effect by exciting CR based on the smFRET effect, which effectively kills cancer cells both in vitro and in vivo. This strategy exhibits a broad absorption peak with strong light-harvesting ability, which improves photon utilization for treatment while realizing fluorescence imaging. Of note, owing to the smFRET effect, we achieve a combination treatment outcome at relatively low concentrations and light doses. Thus, we believe that this design concept will provide a new strategy for single-molecule FRET photosensitizers in combination therapy of cancer with potential clinical application prospects.
RESUMO
Photodynamic therapy (PDT) has been successfully demonstrated for anticancer treatment in vivo. However, tumor metastasis during PDT are still inevitable due to the activation of the epidermal growth factor receptor (EGFR). The current work describes the synthesis of a photosensitizer (PS)-EGFR inhibitor conjugate for PDT with simultaneous tumor metastasis inhibition. The conjugate efficiently internalized into cancer cells and generated reactive oxygen species (ROS) under light, indicating strong cytotoxicity even in hypoxic tumor environment. The presence of an EGFR inhibitor significantly inhibited cell migration and invasion. Accordingly, photoactivation of the conjugate resulted in efficient tumor growth inhibition in a 4T1 tumor-bearing mouse model and suppressed angiogenesis and tumor metastasis during PDT. Therefore, combined PDT and EGFR inhibition strategy provides a new platform for future anticancer treatment with high safety.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Animais , Linhagem Celular Tumoral , Camundongos , Fármacos Fotossensibilizantes/uso terapêutico , Inibidores de Proteínas QuinasesRESUMO
In this study, we reported a tamoxifen modified Ru(ii) polypyridyl complex (Ru-tmxf) as an estrogen receptor (ER) targeted photosensitizer. Ru-tmxf displays enhanced cellular uptake and PDT efficiency toward breast cancer cells with high ER expression due to the specific targeting of tamoxifen to ER and finally localizes in lysosomes. Moreover, Ru-tmxf can be activated by two-photon excitation, generating 1O2 to damage lysosomes and result in cell death.