Inducing Immunogenic Cancer Cell Death through Oxygen-Economized Photodynamic Therapy with Nitric Oxide-Releasing Photosensitizers.

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) for eradication of cancer cells. Its effectiveness is governed by the oxygen content, which is scarce in the hypoxic tumor microenvironment. We report herein two zinc(II) phthalocyanines substituted with two or four nitric oxide (NO)-releasing moieties, namely ZnPc-2NO and ZnPc-4NO, which can suppress the mitochondrial respiration, thereby sparing more intracellular oxygen for PDT. Using HT29 human colorectal adenocarcinoma cells and A549 human lung carcinoma cells, we have demonstrated that both conjugates release NO upon interaction with the intracellular glutathione, which can reduce the cellular oxygen consumption rate and adenosine triphosphate generation and alter the mitochondrial membrane potential. They can also relieve the hypoxic status of cancer cells and decrease the expression of hypoxia-inducible factor protein HIF-1α. Upon light irradiation, both conjugates can generate ROS and induce cytotoxicity even under a hypoxic condition, overcoming the oxygen-dependent nature of PDT. Interestingly, the photodynamic action of ZnPc-2NO elicits the release of damage-associated molecular patterns, inducing the maturation of dendritic cells and triggering an antitumor immune response. The immunogenic cell death caused by this oxygen-economized PDT has been demonstrated through a series of in vitro and in vivo experiments.

Magnetic Particle Imaging: From Tracer Design to Biomedical Applications in Vasculature Abnormality.

Magnetic particle imaging (MPI) is an emerging non-invasive tomographic technique based on the response of magnetic nanoparticles (MNPs) to oscillating drive fields at the center of a static magnetic gradient. In contrast to magnetic resonance imaging (MRI), which is driven by uniform magnetic fields and projects the anatomic information of the subjects, MPI directly tracks and quantifies MNPs in vivo without background signals. Moreover, it does not require radioactive tracers and has no limitations on imaging depth. This article first introduces the basic principles of MPI and important features of MNPs for imaging sensitivity, spatial resolution, and targeted biodistribution. The latest research aiming to optimize the performance of MPI tracers is reviewed based on their material composition, physical properties, and surface modifications. While the unique advantages of MPI have led to a series of promising biomedical applications, recent development of MPI in investigating vascular abnormalities in cardiovascular and cerebrovascular systems, and cancer are also discussed. Finally, recent progress and challenges in the clinical translation of MPI are discussed to provide possible directions for future research and development.

A Tetrazine-Caged Carbon-Dipyrromethene as a Bioorthogonally Activatable Fluorescent Probe.

A water-soluble 1,2,4,5-tetrazine-substituted carbon-dipyrromethene (C-DIPY) was synthesized from the previously reported carbonyl pyrrole dimer through a two-step procedure. Owing to the presence of a tetrazine moiety, the fluorescence emission of this compound was largely quenched in phosphate-buffered saline at pH 7.4. Upon addition of a bicyclo[6.1.0]non-4-yne (BCN) derivative, the tetrazine-based quenching component of the compound was disrupted through the inverse electron-demand Diels-Alder reaction to restore the fluorescence in up to 6.6-fold. This bioorthogonal activation was also demonstrated using U-87 MG human glioblastoma cells, in which the fluorescence intensity of this C-DIPY could be enhanced by 8.7-fold upon post-incubation with the BCN derivative. The results showed that this tetrazine-caged C-DIPY can serve as a bioorthogonally activatable fluorescent probe for bioimaging. The compound, however, was found to reside preferentially in the lysosomes instead of the mitochondria of the cells as predicted based on its cationic character, which could be attributed to its energy-dependent endocytic cellular uptake pathway, for which lysosomes are the end station.

Near-infrared-activated anticancer platinum(IV) complexes directly photooxidize biomolecules in an oxygen-independent manner.

Conventional light-driven cancer therapeutics require oxygen and visible light to indirectly damage biomolecules, limiting their efficacy in deep, hypoxic tumours. Here we report the use of near-infrared-activated small-molecule Pt(IV) photooxidants to directly oxidize intracellular biomolecules in an oxygen-independent manner, achieving controllable and effective elimination of cancer stem cells. These Pt(IV) complexes accumulate in the endoplasmic reticulum and show low toxicity in the dark. Upon irradiation, the resultant metal-enhanced photooxidation effect causes them to robustly photooxidize survival-related biomolecules, induce intense oxidative stress, disrupt intracellular pH (pHi) homeostasis and initiate nonclassical necrosis. In vivo experiments confirm that the lead photooxidant can effectively inhibit tumour growth, suppress metastasis and activate the immune system. Our study validates the concept of metal-enhanced photooxidation and the subsequent chemotherapeutic applications, supporting the development of such localized photooxidants to directly damage intracellular biomolecules and decrease pHi as a strategy for effective metal-based drugs.

Photodynamic Therapy: An Innovative and Versatile Treatment Modality Triggered by Light.

Guest Editors Pui-Chi Lo, Dennis Ng, Ravindra Pandey, and Petr Zimcik introduce the Special Collection on Photodynamic Therapy and give an overview of the developments and challenges in this exciting field.

Enzyme-Responsive Double-Locked Photodynamic Molecular Beacon for Targeted Photodynamic Anticancer Therapy.

An advanced photodynamic molecular beacon (PMB) was designed and synthesized, in which a distyryl boron dipyrromethene (DSBDP)-based photosensitizer and a Black Hole Quencher 3 moiety were connected via two peptide segments containing the sequences PLGVR and GFLG, respectively, of a cyclic peptide. These two short peptide sequences are well-known substrates of matrix metalloproteinase-2 (MMP-2) and cathepsin B, respectively, both of which are overexpressed in a wide range of cancer cells either extracellularly (for MMP-2) or intracellularly (for cathepsin B). Owing to the efficient Förster resonance energy transfer between the two components, this PMB was fully quenched in the native form. Only upon interaction with both MMP-2 and cathepsin B, either in a buffer solution or in cancer cells, both of the segments were cleaved specifically, and the two components could be completely separated, thereby restoring the photodynamic activities of the DSBDP moiety. This PMB could also be activated in tumors, and it effectively suppressed the tumor growth in A549 tumor-bearing nude mice upon laser irradiation without causing notable side effects. In particular, it did not cause skin photosensitivity, which is a very common side effect of photodynamic therapy (PDT) using conventional "always-on" photosensitizers. The overall results showed that this "double-locked" PMB functioned as a biological AND logic gate that could only be unlocked by the coexistence of two tumor-associated enzymes, which could greatly enhance the tumor specificity in PDT.

Cupric-ion-promoted fabrication of oxygen-replenishing nanotherapeutics for synergistic chemo and photodynamic therapy against tumor hypoxia.

Mixing a glutathione (GSH)-responsive carboxy zinc(II) phthalocyanine (ZnPc*) and CuSO4·5H2O in water with or without the presence of the anticancer drug SN38 resulted in the formation of self-assembled nanotherapeutics labeled as ZnPc*/Cu/SN38@NP and ZnPc*/Cu@NP, respectively. The Cu2+ ions not only promoted the self-assembly of the carboxy phthalocyanine through metal complexation, but also catalyzed the transformation of H2O2 to oxygen via a catalase-like reaction, rendering an oxygen-replenishing property to the nanosystems. Both nanosystems exhibited high stability in aqueous media, but the nanoparticles disassembled gradually in an acidic or GSH-enriched environment and inside human colorectal adenocarcinoma HT29 cells, releasing the encapsulated therapeutic components. The disassembly process together with the activation by the intracellular GSH led to relaxation of the intrinsic quenching of the nanophotosensitizers and restoration of the photoactivities of ZnPc*. Under a hypoxic condition, ZnPc*/Cu/SN38@NP could attenuate the intracellular hypoxia level and maintain the photodynamic activity due to its Cu2+-promoted oxygen-replenishing ability. The photodynamic effect of ZnPc* and the anticancer effect of SN38 worked cooperatively, causing substantial apoptotic cell death. The dual therapeutic actions could also effectively inhibit the tumor growth in HT29 tumor-bearing nude mice without initiating notable adverse effects to the mice. STATEMENT OF SIGNIFICANCE: The oxygen-dependent nature of photodynamic therapy generally reduces its efficacy against tumor hypoxia, which is a common characteristic of advanced solid tumors and usually leads to resistance toward various anticancer therapies. We report herein a facile approach to assemble a glutathione-responsive carboxy phthalocyanine-based photosensitizer and an anticancer drug in aqueous media, in which Cu(II) ions were used to promote the self-assembly through metal complexation and catalyze the conversion of H2O2 to oxygen through a catalase-like reaction, making the resulting nanoparticles possessing an oxygen-replenishing property that could promote the photodynamic effect against hypoxic cancer cells and tumors. The use of Cu(II) ions to achieve the aforementioned dual functions in the fabrication of advanced nano-photosensitizing systems has not been reported.

Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway.

Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.

A tetrazine-responsive isonitrile-caged photosensitiser for site-specific photodynamic therapy.

We report herein a versatile and efficient bioorthogonal strategy to actualise targeted delivery and site-specific activation of photosensitisers for precise antitumoural photodynamic therapy. The strategy involved the use of an isonitrile-caged distyryl boron dipyrromethene-based photosensitiser, labelled as NC-DSBDP, of which the photoactivities could be specifically activated upon conversion of the meso ester substituent to carboxylate initiated by the [4 + 1] cycloaddition with a tetrazine derivative. By using two tetrazines conjugated with a galactose moiety or the GE11 peptide, labelled as gal-Tz and GE11-Tz, we could selectively label the cancer cells overexpressed with the asialoglycoprotein receptor and the epidermal growth factor receptor respectively. Upon encountering the internalised NC-DSBDP, these tetrazines triggered the "ester-to-carboxylate" transformation of this compound, activating its fluorescence and reactive oxygen species generation inside the target cells. The bioorthogonal activation was also demonstrated in vivo, leading to effective photo-eradication of the tumour in nude mice.

Self-adjuvanting cancer nanovaccines.

Nanovaccines, a new generation of vaccines that use nanoparticles as carriers and/or adjuvants, have been widely used in the prevention and treatment of various diseases, including cancer. Nanovaccines have sparked considerable interest in cancer therapy due to a variety of advantages, including improved access to lymph nodes (LN), optimal packing and presentation of antigens, and induction of a persistent anti-tumor immune response. As a delivery system for cancer vaccines, various types of nanoparticles have been designed to facilitate the delivery of antigens and adjuvants to lymphoid organs and antigen-presenting cells (APCs). Particularly, some types of nanoparticles are able to confer an immune-enhancing capability and can themselves be utilized for adjuvant-like effect for vaccines, suggesting a direction for a better use of nanomaterials and the optimization of cancer vaccines. However, this role of nanoparticles in vaccines has not been well studied. To further elucidate the role of self-adjuvanting nanovaccines in cancer therapy, we review the mechanisms of antitumor vaccine adjuvants with respect to nanovaccines with self-adjuvanting properties, including enhancing cross-presentation, targeting signaling pathways, biomimicking of the natural invasion process of pathogens, and further unknown mechanisms. We surveyed self-adjuvanting cancer nanovaccines in clinical research and discussed their advantages and challenges. In this review, we classified self-adjuvanting cancer nanovaccines according to the underlying immunomodulatory mechanism, which may provide mechanistic insights into the design of nanovaccines in the future.

Postnatal eye size in mice is controlled by SREBP2-mediated transcriptional repression of Lrp2 and Bmp2.

Eye size is a key parameter of visual function, but the precise mechanisms of eye size control remain poorly understood. Here, we discovered that the lipogenic transcription factor sterol regulatory element-binding protein 2 (SREBP2) has an unanticipated function in the retinal pigment epithelium (RPE) to promote eye size in postnatal mice. SREBP2 transcriptionally represses low density lipoprotein receptor-related protein 2 (Lrp2), which has been shown to restrict eye overgrowth. Bone morphogenetic protein 2 (BMP2) is the downstream effector of Srebp2 and Lrp2, and Bmp2 is suppressed by SREBP2 transcriptionally but activated by Lrp2. During postnatal development, SREBP2 protein expression in the RPE decreases whereas that of Lrp2 and Bmp2 increases as the eye growth rate reduces. Bmp2 is the key determinant of eye size such that its level in mouse RPE inversely correlates with eye size. Notably, RPE-specific Bmp2 overexpression by adeno-associated virus effectively prevents the phenotypes caused by Lrp2 knock out. Together, our study shows that rapid postnatal eye size increase is governed by an RPE-derived signaling pathway, which consists of both positive and negative regulators of eye growth.

A Tumor-Targeting Dual-Stimuli-Activatable Photodynamic Molecular Beacon for Precise Photodynamic Therapy.

A multifunctional photodynamic molecular beacon (PMB) has been designed and synthesized which contains an epidermal growth factor receptor (EGFR)-targeting cyclic peptide and a trimeric phthalocyanine skeleton in which the three zinc(II) phthalocyanine units are each substituted with a glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS) quencher and are linked via two cathepsin B-cleavable GFLG peptide chains. This tailor-made conjugate is fully quenched in the native form due to the photoinduced electron transfer effect of the DNBS moieties and the self-quenching of the phthalocyanine units. It can target the EGFR overexpressed in cancer cells, and after receptor-mediated endocytosis, it can be activated selectively by the co-existence of intracellular GSH and cathepsin B, both of which are also overproduced in cancer cells, in terms of fluorescence emission and singlet oxygen generation. The cell-selective behavior of this PMB has been demonstrated using a range of cancer cells with different expression levels of EGFR, while the stimuli-responsive properties have been studied both in vitro and in various aqueous media. The overall results show that this advanced PMB, which exhibits several levels of control of the tumor specificity, is a promising photosensitizer for precise antitumoral photodynamic therapy.

Microparticles: biogenesis, characteristics and intervention therapy for cancers in preclinical and clinical research.

Extracellular vesicles (EVs), spherical biological vesicles, mainly contain nucleic acids, proteins, lipids and metabolites for biological information transfer between cells. Microparticles (MPs), a subtype of EVs, directly emerge from plasma membranes, and have gained interest in recent years. Specific cell stimulation conditions, such as ultraviolet and X-rays irradiation, can induce the release of MPs, which are endowed with unique antitumor functionalities, either for therapeutic vaccines or as direct antitumor agents. Moreover, the size of MPs (100-1000 nm) and their spherical structures surrounded by a lipid bilayer membrane allow MPs to function as delivery vectors for bioactive antitumor compounds, with favorable phamacokinetic behavior, immunostimulatory activity and biological function, without inherent carrier-specific toxic side effects. In this review, the mechanisms underlying MP biogenesis, factors that influence MP production, properties of MP membranes, size, composition and isolation methods of MPs are discussed. Additionally, the applications and mechanisms of action of MPs, as well as the main hurdles for their applications in cancer management, are introduced.

Dual Cathepsin B and Glutathione-Activated Dimeric and Trimeric Phthalocyanine-Based Photodynamic Molecular Beacons for Targeted Photodynamic Therapy.

Two dual stimuli-activated photosensitizers were developed, in which two or three glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS)-substituted zinc(II) phthalocyanine units were connected via one or two cathepsin B-cleavable Gly-Phe-Leu-Gly peptide linker(s). These dimeric and trimeric phthalocyanines were fully quenched in the native form due to the photoinduced electron transfer to the DNBS substituents and the self-quenching of the phthalocyanine units. In the presence of GSH and cathepsin B, or upon internalization into A549 and HepG2 cancer cells, these probes were activated through the release of free phthalocyanine units. The intracellular fluorescence intensity was increased upon post-incubation with GSH ester or reduced upon pre-treatment with a cathepsin B inhibitor. Upon light irradiation, these photosensitizers became highly cytotoxic with IC50 values of 0.21-0.39 µM. The photocytotoxicity was also dependent on the intracellular GSH and cathepsin B levels. The results showed that these conjugates could serve as smart photosensitizers for targeted photodynamic therapy.

Encapsulating an acid-activatable phthalocyanine-doxorubicin conjugate and the hypoxia-sensitive tirapazamine in polymeric micelles for multimodal cancer therapy.

A zinc(ii) phthalocyanine (ZnPc) was conjugated to doxorubicin (Dox) via an acid-labile hydrazone linker. The resulting ZnPc-Dox conjugate was then encapsulated into polymeric micelles formed through self-assembly of a block copolymer of poly(ethylene glycol) and poly(d,l-lactide) both in the absence and presence of the hypoxia-activated prodrug tirapazamine (TPZ) to give ZnPc-Dox@micelles and ZnPc-Dox/TPZ@micelles respectively. These polymeric micelles exhibited an excellent stability in aqueous media, but underwent disassembly in an acidic environment. Upon internalisation into HT29 human colorectal carcinoma cells, fluorescence due to ZnPc and Dox could be observed in the cytoplasm and nucleus respectively for both nanosystems. This observation suggested the disassembly of the polymeric micelles and the cleavage of the hydrazone linker in ZnPc-Dox in the acidic intracellular compartments. These micelles were slightly cytotoxic against HT29 cells in the dark due to the chemotherapeutic effect of Dox and/or TPZ. Upon light irradiation, ZnPc-Dox@micelles showed higher cytotoxicity. The IC50 value under a normoxic condition (0.35 µM based on ZnPc-Dox) was significantly lower than that under hypoxia (>1 µM). With an additional therapeutic component, ZnPc-Dox/TPZ@micelles exhibited higher photocytotoxicity with IC50 values of 0.20 µM and 0.78 µM under normoxia and hypoxia respectively. It is believed that the photodynamic action of this nanosystem consumed the intracellular oxygen and hence triggered the hypoxia-mediated chemotherapeutic action of TPZ. The multimodal antitumor effects of these polymeric micelles were also validated on HT29 tumour-bearing nude mice.

Role of intravital imaging in nanomedicine-assisted anti-cancer therapy.

Although nanomedicines have provided promising anti-tumor effects in cancer animal models, their clinical success remains limited. One of the most significant barriers in the clinical translation of nanomedicines is that they consist of multiple components, each of which may have different toxicities and therapeutic effects. Intravital imaging provides high spatial and temporal resolution for visualizing nanomedicine-mediated interactions between immune cells and tumor cells in real-time. Intravital imaging can facilitate the in vivo evaluation of the properties and effects of nanomedicines, such as their ability to cross the tumor vasculature, specifically eliminate the cancer cells, and modulate the immune cells found in the tumor microenvironment (TME). Thus, intravital imaging can provide direct evidence of nanomedicine's intravital behavior to better understand mechanism and accelerate clinical translation. In this review, we summarize several applications and latest advances in intravital imaging in nanomedicine-assisted anti-cancer therapy and discuss future perspectives in the field.

Injectable Hydrogel as a Unique Platform for Antitumor Therapy Targeting Immunosuppressive Tumor Microenvironment.

Cancer immunotherapy can boost the immune response of patients to eliminate tumor cells and suppress tumor metastasis and recurrence. However, immunotherapy resistance and the occurrence of severe immune-related adverse effects are clinical challenges that remain to be addressed. The tumor microenvironment plays a crucial role in the therapeutic efficacy of cancer immunotherapy. Injectable hydrogels have emerged as powerful drug delivery platforms offering good biocompatibility and biodegradability, minimal invasion, convenient synthesis, versatility, high drug-loading capacity, controlled drug release, and low toxicity. In this review, we summarize the application of injectable hydrogels as a unique platform for targeting the immunosuppressive tumor microenvironment.

Shifting the absorption to the near-infrared region and inducing a strong photothermal effect by encapsulating zinc(II) phthalocyanine in poly(lactic-co-glycolic acid)-hyaluronic acid nanoparticles.

By using an oil-in-water single emulsion method, a series of multifunctional hybrid nanoparticles (NPs) were prepared which consisted of a core of poly(lactic-co-glycolic acid) (PLGA) with a lipoid shell of n-hexadecylamine-substituted hyaluronic acid (HA), encapsulating a zinc(II) phthalocyanine-based photosensitizer (ZnPc). As determined by laser light scattering, these hybrid NPs labeled as ZnPc@PLGA-HA NPs possessed a hydrodynamic diameter of 280 nm and a surface charge of -30 mV, showing high stability in serum. The Q-band absorption of ZnPc exhibited a large red-shift from 674 nm for free ZnPc in dimethylsulfoxide to 832 nm for this nanosystem in water. Upon light irradiation at 808 nm, the encapsulated ZnPc induced a strong photothermal effect instead of photodynamic action, which is usually observed for ZnPc-containing NPs. The tumor-targeting effect of these NPs due to the HA coating was investigated against the human colorectal adenocarcinoma HT29 cells and human lung carcinoma A549 cells, both of which overexpress cluster determinant 44 (CD44) receptors, using the CD44-negative human normal hepatic LO2 cells as a negative control. The photothermal cell-killing effect of these NPs was significantly higher for the two CD44-positive cell lines than that for the negative control. Their in vivo photothermal efficacy was also examined on HT29 tumor-bearing nude mice. Upon irradiation, the NPs caused significant temperature increase at the tumor site and ablation of the tumor. The results showed that these multifunctional NPs could serve as an effective photothermal agent for targeted photothermal therapy. Statement of significance Phthalocyanines are well-known photosensitizers for photodynamic therapy. By encapsulating these molecules into various nanoplatforms, a range of multifunctional photosensitizing systems have been developed for cancer therapy. In this study, we have demonstrated that by careful selection of phthalocyanines and the nanocarriers, as well as the self-assembly and encapsulation methods, the encapsulated phthalocyanine molecules could switch the photoinduced action from photodynamic therapy to photothermal therapy as a result of the enhanced aggregation of the macrocyclic molecules in the nanoparticles. The unique packing of the molecules also resulted in a large red-shift of the Q-band absorption to 832 nm, facilitating the in vitro and in vivo photothermal treatment.

Ferric Ion Driven Assembly of Catalase-like Supramolecular Photosensitizing Nanozymes for Combating Hypoxic Tumors.

A facile approach to assemble catalase-like photosensitizing nanozymes with a self-oxygen-supplying ability was developed. The process involved Fe3+ -driven self-assembly of fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids. By adding a zinc(II) phthalocyanine-based photosensitizer (ZnPc) and the hypoxia-inducible factor 1 (HIF-1) inhibitor acriflavine (ACF) during the Fe3+ -promoted self-assembly of Fmoc-protected cysteine (Fmoc-Cys), the nanovesicles Fmoc-Cys/Fe@Pc and Fmoc-Cys/Fe@Pc/ACF were prepared, which could be disassembled intracellularly. The released Fe3+ could catalyze the transformation of H2 O2 enriched in cancer cells to oxygen efficiently, thereby ameliorating the hypoxic condition and promoting the photosensitizing activity of the released ZnPc. With an additional therapeutic component, Fmoc-Cys/Fe@Pc/ACF exhibited higher in vitro and in vivo photodynamic activities than Fmoc-Cys/Fe@Pc, demonstrating the synergistic effect of ZnPc and ACF.

Glutathione- and light-controlled generation of singlet oxygen for triggering drug release in mesoporous silica nanoparticles.

A combined stimulus-responsive photosensitiser and drug release system based on mesoporous silica nanoparticles was prepared. This nanoplatform encapsulated molecules of zinc(ii) phthalocyanine substituted with a glutathione-cleavable 2,4-dinitrobenzenesulfonate quencher and doxorubicin linked via a singlet-oxygen-cleavable 9,10-dialkoxyanthracene linker. In the presence of glutathione (in mM range) and upon irradiation (λ > 610 nm), the phthalocyanine units were activated by detaching from the quenching component to emit fluorescence and generate singlet oxygen. The latter subsequently cleaved the 9,10-dialkoxyanthracene linker to trigger the release of a doxorubicin derivative. The glutathione- and light-controlled activation and drug-release processes on this nanoplatform were demonstrated in phosphate buffered saline. The activation in fluorescence emission by intracellular thiols was also shown inside HepG2 human hepatocellular carcinoma cells. Upon irradiation, the nanosystem exhibited high cytotoxicity due to the photodynamic effect of the activated phthalocyanine units, but the cytotoxic effect of the released Dox moieties was not notable probably due to their reduced cytotoxicity as a result of the pendant substituent and the low drug loading in the nanoparticles.