ABSTRACT
Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy for inducing post-translational knockdown of target proteins in disease treatment. The degradation of bromodomain-containing protein 4 (BRD4), an essential nuclear protein for gene transcription, induced by PROTAC is proposed as an epigenetic approach to treat breast cancer. However, the poor membrane permeability and indiscriminate distribution of PROTAC in vivo results in low bioavailability, limiting its development and application. Herein, a nano "targeting chimera" (abbreviated as L@NBMZ) consisting of BRD4-PROTAC combined with a photosensitizer, to serve as the first augmenter for photo-driven pyroptosis in breast cancer, is developed. With excellent BRD4 degradation ability, high biosafety, and biocompatibility, L@NBMZ blocks gene transcription by degrading BRD4 through proteasomes in vivo, and surprisingly, induces the cleavage of caspase-3. This type of caspase-3 cleavage is synergistically amplified by light irradiation in the presence of photosensitizers, leading to efficient photo-driven pyroptosis. Both in vitro and in vivo outcomes demonstrate the remarkable anti-cancer efficacy of this augmenter, which significantly inhibits the lung metastasis of breast cancer in vivo. Thus, the photo-PROTAC "targeting chimera" augmenter construction strategy may pave a new way for expanding PROTAC applications within anti-cancer paradigms.
Subject(s)
Breast Neoplasms , Photosensitizing Agents , Proteolysis , Pyroptosis , Transcription Factors , Humans , Pyroptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Proteolysis/drug effects , Cell Line, Tumor , Animals , Transcription Factors/metabolism , Female , Cell Cycle Proteins/metabolism , Mice , Caspase 3/metabolism , Light , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bromodomain Containing ProteinsABSTRACT
The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.
Subject(s)
Fluorescent Dyes , Precision Medicine , Cell Line, Tumor , Drug Delivery Systems , Fluorescence , Theranostic NanomedicineABSTRACT
Ultrasound-triggered remote control of biomolecular functions in cells provides unique advantages for us to interrogate nature. However, strategies to design therapeutic ultrasound-responsive functional molecules remain elusive, and rare ultrasound-cleavable chemical bonds have been developed to date. Herein, therapeutic ultrasound (1 MHz)-induced scission of urea bonds for drug release is demonstrated for the first time. Such a transformation has been verified to be initiated by hydroxyl radicals generated in the interior of cavitation bubbles, occurring specifically at the cavitation bubble-liquid interface. A series of urea-bond-containing prodrugs based on methylene blue (MB), namely MBUs, are designed. Upon sonication with low-intensity therapeutic ultrasound, the urea bonds linked with primary amines can be selectively cleaved, and free MB is released in a physiologically relevant environment, accompanied by recovered absorbance, fluorescence, and photosensitivity. Moreover, an FDA-approved alkylating agent (i.e., melphalan) bearing urea bond is also developed (MBU-Mel), successfully achieving ultrasound-triggered drug release in deep-seated cancer cells (mimic with 1 cm pigskin), showing the scalability of our ultrasound-responsive molecule platform in bioactive molecules release. This may set the starting point for therapeutic ultrasound-induced drug release, making a forward step in "sonopharmacology".
Subject(s)
Prodrugs , Urea , Alkylating Agents , Amines , Melphalan , Methylene Blue/pharmacologyABSTRACT
Elucidating the underlying photochemical mechanisms of action (MoA) of photodynamic therapy (PDT) may allow its efficacy to be improved and could set the stage for the development of new classes of PDT photosensitizers. Here, we provide evidence that "photoredox catalysis in cells," wherein key electron transport pathways are disrupted, could constitute a general MoA associated with PDT. Taking the cellular electron donor nicotinamide adenine dinucleotide as an example, we have found that well-known photosensitizers, such as Rose Bengal, BODIPY, phenoselenazinium, phthalocyanine, and porphyrin derivatives, are able to catalyze its conversion to NAD+. This MoA stands in contrast to conventional type I and type II photoactivation mechanisms involving electron and energy transfer, respectively. A newly designed molecular targeting photocatalyst (termed CatER) was designed to test the utility of this mechanism-based approach to photosensitizer development. Photoexcitation of CatER induces cell pyroptosis via the caspase 3/GSDME pathway. Specific epidermal growth factor receptor positive cancer cell recognition, high signal-to-background ratio tumor imaging (SBRTI = 12.2), and good tumor growth inhibition (TGI = 77.1%) are all hallmarks of CatER. CatER thus constitutes an effective near-infrared pyroptotic cell death photo-inducer. We believe the present results will provide the foundation for the synthesis of yet-improved phototherapeutic agents that incorporate photocatalytic chemistry into their molecular design.
Subject(s)
Antineoplastic Agents , Neoplasms , Photochemotherapy , Photosensitizing Agents , Antineoplastic Agents/pharmacology , Catalysis , Cell Line, Tumor , Humans , Neoplasms/diagnostic imaging , Neoplasms/therapy , Photochemotherapy/methods , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/pharmacologyABSTRACT
Efficiency of standard chemotherapy is dramatically hindered by intrinsic multidrug resistance (MDR). Recently, to amplify therapeutic efficacy, photodynamic therapy (PDT)-induced mitochondrial dysfunction by decorating targeting moieties on nanocarriers has obtained considerable attention. Nevertheless, low targeting efficiency, complex synthesis routes, and difficulty in releasing contents become the major obstacles in further clinical application. Herein, an ingenious liposomal-based nanomedicine (L@BP) was fabricated by encapsulating a mitochondria-anchored photosensitizer (Cy-Br) and paclitaxel (PTX) for realizing enhanced cooperation therapy. At the cellular level, L@BP could hurdle endosomal traps to localize and implement PDT in mitochondria. Intriguingly, the PDT-induced in situ mitochondrial dysfunction led to intracellular ATP reduction, which triggered the downregulated P-glycoprotein transportation capacity and thus resulted in diminishing the efflux of chemotherapeutic agents and increasing drug uptake by drug-resistant cells. The prepared nanomedicine eminently accumulated in the tumor site and acquired enhanced therapeutic efficiency on PTX-resistant lung cancer cells, which possessed great potential in circumventing MDR tumors.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Carriers/chemistry , Drug Resistance, Multiple/drug effects , Liposomes/chemistry , Mitochondria/drug effects , Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Resistance, Neoplasm/drug effects , Female , Humans , Indoles/therapeutic use , Liposomes/pharmacokinetics , Liposomes/toxicity , Membrane Potential, Mitochondrial/drug effects , Mice, Inbred BALB C , Mice, Nude , Paclitaxel/therapeutic use , Photochemotherapy , Photosensitizing Agents/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
A rigid hemicyanine CSZ-J and a flexible molecule ESZ-J were synthesized. In particular, the conformationally restrained CSZ-J had higher fluorescence quantum yields, longer fluorescence lifetimes and higher triplet state quantum yields. CSZ-J could generate highly cytotoxic ROS simultaneously via type I and type II processes. This will contribute to the design and development of new photosensitizers in the future.
Subject(s)
Antineoplastic Agents/pharmacology , Carbocyanines/pharmacology , Photochemotherapy , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemistry , Carbocyanines/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Molecular Conformation , Photosensitizing Agents/chemistry , Reactive Oxygen Species/metabolismABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Carbocyanines/pharmacology , Fluorescent Dyes/pharmacology , Photochemotherapy , Photosensitizing Agents/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carbocyanines/chemical synthesis , Carbocyanines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Density Functional Theory , Drug Screening Assays, Antitumor , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Molecular Structure , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistryABSTRACT
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.