Tumor cell membrane-based vaccines: A potential boost for cancer immunotherapy.

Because therapeutic cancer vaccines can, in theory, eliminate tumor cells specifically with relatively low toxicity, they have long been considered for application in repressing cancer progression. Traditional cancer vaccines containing a single or a few discrete tumor epitopes have failed in the clinic, possibly due to challenges in epitope selection, target downregulation, cancer cell heterogeneity, tumor microenvironment immunosuppression, or a lack of vaccine immunogenicity. Whole cancer cell or cancer membrane vaccines, which provide a rich source of antigens, are emerging as viable alternatives.

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.

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.

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.

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.

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.

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 CuSO·5HO 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 Cu ions not only promoted the self-assembly of the carboxy phthalocyanine through metal complexation, but also catalyzed the transformation of HO 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.

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.

Assessing the therapeutic impact of resveratrol in ALS SOD1-G93A mice with electrical impedance myography.

To aid in the identification of new treatments for amyotrophic lateral sclerosis (ALS), convenient biomarkers are needed to effectively and uniformly measure drug efficacy. To this end, we assessed the effects of the nutraceutical resveratrol (RSV) on disease onset and overall survival in SOD1-G93A (ALS) mice and compared several standard biomarkers including body mass, motor score (MS), paw grip endurance (PGE), and compound motor action potential (CMAP) amplitude, with the technique of electrical impedance myography (EIM) to follow disease progression. Eighteen ALS mice (nine females, nine males) received RSV in the chow (dose: 120 mg/kg/day) starting at 8 weeks of age; 19 ALS mice (nine females, 10 males) received normal chow; 10 wild type (WT) littermates (five females, five males) fed standard chow served as controls.

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.

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).

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.

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.

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.

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.

Bioorthogonal Conjugation-Assisted Purification Method for Profiling Cell Surface Proteome.

Surface biotinylation has been widely adapted in profiling the cellular proteome associated with the plasma membrane. However, the workflow is subject to interference from the cytoplasmic biotin-associated proteins that compete for streptavidin-binding during purification. Here we established a bioorthogonal conjugation-assisted purification (BCAP) workflow that utilizes the Staudinger chemoselective ligation to label and isolate surface-associated proteins while minimizing the binding of endogenous biotin-associated proteins.

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.

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.

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.

Self-Assembled Nanophotosensitizing Systems with Zinc(II) Phthalocyanine-Peptide Conjugates as Building Blocks for Targeted Chemo-Photodynamic Therapy.

Two zinc(II) phthalocyanines (ZnPcs) substituted with a short peptide (Gly-Gly-Lys) with either a carboxyl or a carbamoyl group at the C-terminus and an appended biotin moiety were prepared and characterized. They could self-assemble into spherical nanoparticles, namely ZnPc-GGK(B)-COOH NP and ZnPc-GGK(B)-CONH NP, through noncovalent interactions, which encapsulated the hydrophobic ZnPc units in the core and exposed the biotin moieties on the surface. The zeta potential of ZnPc-GGK(B)-COOH NP in water was found to be -28 mV, whereas that of ZnPc-GGK(B)-CONH NP was in opposite sign (+15 mV), reflecting the different functionality at the C-terminus, which also greatly affected the stability of the self-assembled nanoparticles.

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.

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 Fe -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 Fe -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.

Synthesis and In Vitro Photodynamic Activity of Cationic Boron Dipyrromethene-Based Photosensitizers against Methicillin-Resistant .

A series of cationic boron dipyrromethene (BODIPY) derivatives were synthesized and characterized with various spectroscopic methods. Having the ability to generate singlet oxygen upon irradiation, these compounds could potentially serve as photosensitizers for antimicrobial photodynamic therapy. Of the five BODIPYs being examined, the dicationic aza-BODIPY analogue (compound ) demonstrated the highest potency against a broad spectrum of clinically relevant methicillin-resistant (MRSA), including four ATCC-type strains (ATCC 43300, ATCC BAA-42, ATCC BAA-43, and ATCC BAA-44), two strains carrying specific antibiotic resistance mechanisms [-AAC(6')-APH(2") and RN4220/pUL5054], and ten non-duplicate clinical strains from hospital- and community-associated MRSAs of the important clonal types ST239, ST30, and ST59, which have previously been documented to be prevalent in Hong Kong and its neighboring countries.

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.