ABSTRACT
Single-molecule-based synergistic phototherapy holds great potential for antimicrobial treatment. Herein, we report an orthogonal molecular cationization strategy to improve the reactive oxygen species (ROS) and hyperthermia generation of heptamethine cyanine (Cy7) for photodynamic and photothermal treatments of bacterial infections. Cationic pyridine (Py) is introduced at the mesoposition of the asymmetric Cy7 with intramolecular charge transfer (ICT) to construct an atypical electron-transfer triad, which reduces ΔES1-S0, circumvents rapid charge recombination, and simultaneously enhances intersystem crossing (ISC) based on spin-orbit charge-transfer ISC (SOCT-ISC) mechanism. This unique molecular construction produces anti-Stokes luminescence (ASL) because the rotatable CN bond enriched in high vibrational-rotational energy levels improves hot-band absorption (HBA) efficiency. The obtained triad exhibits higher singlet oxygen quantum yield and photothermal conversion efficiency compared to indocyanine green (ICG) under irradiation above 800 nm. Cationization with Py enables the triad to target bacteria via intense electrostatic attractions, as well as biocidal property against a broad spectrum of bacteria in the dark. Moreover, the triad under irradiation can enhance biofilm eradication performance in vitro and statistically improve healing efficacy of MRSA-infected wound in mice. Thus, this work provides a simple but effective strategy to design small-molecule photosensitizers for synergistic phototherapy of bacterial infections. STATEMENT OF SIGNIFICANCE: We developed an orthogonal molecular cationization strategy to enhance the reactive oxygen species and thermal effects of heptamethine cyanine (Cy7) for photodynamic and photothermal treatments of bacterial infections. Specifically, cationic pyridine (Py) was introduced at the mesoposition of the asymmetric Cy7 to construct an atypical electron-transfer triad, which reduced ΔES1-S0, circumvented rapid charge recombination, and simultaneously enhanced intersystem crossing (ISC). This triad, with a rotatable CN bond, produced anti-Stokes luminescence due to hot-band absorption. The triad enhanced antimicrobial performance and statistically improved the healing efficacy of MRSA-infected wounds in mice. This site-specific cationization strategy may provide insights into the design of small molecule-based photosensitizers for synergistic phototherapy of bacterial infections.
Subject(s)
Bacterial Infections , Photochemotherapy , Animals , Mice , Photosensitizing Agents/chemistry , Reactive Oxygen Species , Phototherapy , Coloring Agents , Bacterial Infections/drug therapy , Pyridines/pharmacologyABSTRACT
Synergistic photothermal immunotherapy has attracted widespread attention due to the mutually reinforcing therapeutic effects on primary and metastatic tumors. However, the lack of clinical approval nanomedicines for spatial, temporal, and dosage control of drug co-administration underscores the challenges facing this field. Here, a photothermal agent (Cy7-TCF) and an immune checkpoint blocker (NLG919) are conjugated via disulfide bond to construct a tumor-specific small molecule prodrug (Cy7-TCF-SS-NLG), which self-assembles into prodrug-like nano-assemblies (PNAs) that are self-delivering and self-formulating. In tumor cells, over-produced GSH cleaves disulfide bonds to release Cy7-TCF-OH, which re-assembles into nanoparticles to enhance photothermal conversion while generate reactive oxygen species (ROSs) upon laser irradiation, and then binds to endogenous albumin to activate near-infrared fluorescence, enabling multimodal imaging-guided phototherapy for primary tumor ablation and subsequent release of tumor-associated antigens (TAAs). These TAAs, in combination with the co-released NLG919, effectively activated effector T cells and suppressed Tregs, thereby boosting antitumor immunity to prevent tumor metastasis. This work provides a simple yet effective strategy that integrates the supramolecular dynamics and reversibility with stimuli-responsive covalent bonding to design a simple small molecule with synergistic multimodal imaging-guided phototherapy and immunotherapy cascades for cancer treatment with high clinical value.
Subject(s)
Nanoparticles , Neoplasms , Prodrugs , Humans , Prodrugs/therapeutic use , Theranostic Nanomedicine , Neoplasms/therapy , Phototherapy , Nanoparticles/chemistry , Antigens, Neoplasm , Immunotherapy , Disulfides , Cell Line, TumorABSTRACT
Immunotherapy is an advanced therapeutic strategy of cancer treatment but suffers from the issues of off-target adverse effects, lack of real-time monitoring techniques, and unsustainable response. Herein, an ultrasmall Au nanocluster (NC)-based theranostic probe is designed for second near-infrared window (NIR-II) photoluminescence (PL) imaging-guided phototherapies and photoactivatable cancer immunotherapy. The probe (Au44MBA26-NLG for short) is composed of atomically precise and NIR-II emitting Au44MBA26 NCs (here MBA denotes water-soluble 4-mercaptobenzoic acid) conjugated with immune checkpoint inhibitor 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol (NLG919) via a singlet oxygen (1O2)-cleavable linker. Upon NIR photoirradiation, the Au44MBA26-NLG not only enables NIR-II PL imaging of tumors in deep tissues for guiding tumor therapy but also allows the leverage of photothermal property for cancer photothermal therapy (PTT) and the photogenerated 1O2 for photodynamic therapy (PDT) and releasing NLG919 for cancer immunotherapy. Such a multiple effect modulated by Au44MBA26-NLG prompts the proliferation and activation of effector T cells, upshifts systemic antitumor T-lymphocyte (T cell) immunity, and finally suppresses the growth of both primary and distant tumors in living mice. Overall, this study may provide a promising theranostic nanoplatform toward NIR-II PL imaging-guided phototherapies and photoactivatable cancer immunotherapy.
Subject(s)
Nanoparticles , Neoplasms , Photochemotherapy , Animals , Mice , Luminescence , Cell Line, Tumor , Photochemotherapy/methods , Phototherapy/methods , Immunotherapy , Theranostic Nanomedicine/methodsABSTRACT
Photothermal therapy has become a promising approach as precision medicine to allow spatial control of therapeutic effect only in the site of interest. However, the full potential of PTT has not been realized due to the lack of simple photosensitizers (PSs) that can overcome multistage biological barriers and improve theranostic efficiency. Here, we develop a small molecule-based PS to enhance tumor-specific PTT by programming multistage transport and activation properties in molecular architecture. This PS can self-assemble into stable nanoparticles that accumulate passively in tumor, and then actively internalize through ligand-mediated endocytosis. Subsequently, the programmable degradable linkers are selectively cleaved, enabling size shrinkage for better tumor penetration, binding albumin to enhance the near-infrared fluorescence for low-background imaging, and activating photothermal conversion for tumor suppression. The self-delivery process can be programmed, representing the first multistage small-molecule nano-photosensitizer that overcomes multiple biological barriers and improves the PTT index of tumor. STATEMENT OF SIGNIFICANCE: Photothermal therapy has become a promising approach as precision medicine, but has not been realized due to the lack of simple photosensitizers that can overcome multistage biological barriers and improve theranostic efficiency. In this contribution, we solve this dilemma by developing a small molecule-based photosensitizer by programming multistage transport and activation properties in molecular architecture, which could self-assemble into stable nanoparticles that accumulate passively in tumor, and actively internalized through ligand-mediated endocytosis. Subsequently, the programmable activation by ROS triggered size reduction for tumor penetration and minimized the phototoxicity to normal tissue. The activatable fluorescence and photothermal properties made the photosensitizer intrinsically suitable for multimodal imaging-guided PTT, providing a promising supramolecular nanomedicine towards tumor precise diagnosis and therapy.
Subject(s)
Nanoparticles , Neoplasms , Humans , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Photosensitizing Agents/chemistry , Photothermal Therapy , Cell Line, Tumor , Ligands , Nanoparticles/therapeutic use , Nanoparticles/chemistry , Neoplasms/drug therapy , Multimodal Imaging , Theranostic Nanomedicine/methods , Phototherapy/methodsABSTRACT
Photothermal therapy has been extensively studied to improve the light-to-heat efficiency for tumor ablation, but could cause severe damage to adjacent healthy tissue due to the thermal transfer, the random distribution of photothermal agents (PTAs), or combination hereof. Herein, we solve this dilemma with a material design strategy to develop a P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN) ABA triblock copolymer by RAFT polymerization, which exhibits both UCST and LCST dual thermo-responsive behaviors in aqueous solution. The P(AAm-co-AN) block with appropriate AN content allows to finely tune its UCST to â¼ 43°C, which can effectively co-assemble with camptothecin (CPT) and Cy7-TCF, a near-infrared (NIR) PTA, realizing the photo-activated "on-demand" release of CPT and Cy7-TCF. The LCST of P(NIPAM-co-DMAa) segment is adjusted to â¼ 53°C by varying DMAa content, enabling an irreversible sol-to-gel transition. The heat transfer in hydrogel and heat dissipation at the interface of hydrogel-adjacent tissue are limited, resulting in selectively cell killing in tumor, with little hyperthermia in adjacent tissues. Moreover, the hydrogel continues to release CPT to enhance the synergistic efficacy of PTT with chemotherapy. These results suggest that dual thermo-responsive polymer can contribute PTT with high selectivity and negligible side effects for precise medicine. STATEMENT OF SIGNIFICANCE: Photothermal therapy exploits the susceptibility of tumor cells toward external light-induced hyperthermia, but can cause severe damage to adjacent healthy tissue due to thermal transfer, random distribution of photothermal agents (PTAs), or combination hereof. Here, we solve this dilemma by developing a P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN) triblock copolymer with UCST and LCST dual thermo-responsive behaviors, realizing the sequential micelle-unimer-hydrogel phase transitions. The polymer can effectively encapsulate PTA/drug, achieve long systemic circulation, accumulate in tumor through EPR effect, regulate drug release by controlling tumor temperature above UCST via irradiation, and finally exhibit a sol-gel transition, eradicating the heat transfer to adjacent tissue. This represents a practicable strategy to guide the design of next-generation polymeric vector that can contribute PTT with negligible side effects.
Subject(s)
Hyperthermia, Induced , Polymers , Drug Liberation , Hydrogels , Hyperthermia, Induced/methods , MicellesABSTRACT
Near-infrared (NIR) photothermal transduction agents (PTAs) with large rigid π-extended and planar structures are prone to aggregate in a physiological environment where their emission is often quenched due to the strong intermolecular dipole-dipole or π-π interactions. This aggregation-caused quenching effect greatly impedes their applications in image-guided photothermal theranostics. Herein, we made an interesting finding that engineering a bioinspired protein corona (PC), once thermodynamically stabilized in preferred orientations on PTA nanoaggregates, can produce brilliant NIR fluorescence with a high quantum yield (â¼6.2%) without compromising their photothermal properties. Both experimental data and computational modeling suggest that the mechanism of fluorescence enhancement is due to the high-affinity binding of nano-sized PTA to albumin, which regulates the molecular conformation and aggregation state of PTA. High spatial and temporal resolution imaging of albumin PC-coated PTA aggregates enables image-guided photothermal therapy for cancer cells in sentinel lymph nodes to remarkably inhibit pulmonary metastasis. Such a treatment combined with the surgical removal of the primary tumor can prolong animal survival, which is a promising candidate for clinical applications in the treatment of advanced metastatic cancers.
Subject(s)
Neoplasms , Protein Corona , Albumins/chemistry , Animals , Cell Line, Tumor , Fluorescence , Neoplasms/therapy , Optical Imaging , Phototherapy , Theranostic Nanomedicine/methodsABSTRACT
Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor-customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self-assembled nanodiscs are modified with tumor-specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)-based 2D nanodiscs Cy7-TCF (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T-ND) not only effectively induces enhanced photothermal tumor ablation under near-infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors' findings suggest that the combination of phage display-based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.
Subject(s)
Nanoparticles , Neoplasms , Cell Line, Tumor , Humans , Infrared Rays , Nanomedicine , Nanoparticles/chemistry , Neoplasms/drug therapy , Phototherapy , Photothermal TherapyABSTRACT
Supramolecular nanomedicines, which use supramolecular design to improve the precision and effectiveness of pharmaceutical practice and optimize pharmacokinetic profiles, have gathered momentum to battle cancer and other incurable diseases, for which traditional small-molecular and macromolecular drugs are less effective. However, the lack of clinical approval of supramolecular assembly-based medicine underscores the challenges facing this field. A 2D nanodisc-based supramolecular structure is formed by a non-ionic heptamethine cyanine (Cy7) dye, which generates fluorescence self-quenching but unique photothermal and photoacoustic properties. These Cy7-based supramolecular nanodiscs exhibit passive tumor-targeting properties to not only visualize the tumor by near-infrared fluorescence imaging and photoacoustic tomography but also induce photothermal tumor ablation under irradiation. Due to the nature of organic small molecule, they induce undetectable acute toxicity in mice and can be eliminated by the liver without extrahepatic metabolism. These findings suggest that the self-assembling cyanine discs represent a new paradigm in drug delivery as single-component supramolecular nanomedicines that are self-delivering and self-formulating, and provide a platform technology for synergistic clinical cancer imaging and therapy.