Self-Amplified pH/ROS Dual-Responsive Co-Delivery Nano-System with Chemo-Photodynamic Combination Therapy in Hepatic Carcinoma Treatment.

Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.

Biodegradable pyroptosis inducer with multienzyme-mimic activity kicks up reactive oxygen species storm for sensitizing immunotherapy.

Triggering pyroptosis is a major new weathervane for activating tumor immune response. However, biodegradable pyroptosis inducers for the safe and efficient treatment of tumors are still scarce. Herein, a novel tumor microenvironment (TME)-responsive activation nanoneedle for pyroptosis induction, copper-tannic acid (CuTA), was synthesized and combined with the sonosensitizer Chlorin e6 (Ce6) to form a pyroptosis amplifier (CuTA-Ce6) for dual activation and amplification of pyroptosis by exogenous ultrasound (US) and TME. It was demonstrated that Ce6-triggered sonodynamic therapy (SDT) further enhanced the cellular pyroptosis caused by CuTA, activating the body to develop a powerful anti-tumor immune response. Concretely, CuTA nanoneedles with quadruple mimetic enzyme activity could be activated to an "active" state in the TME, destroying the antioxidant defense system of the tumor cells through self-destructive degradation, breaking the "immunosilent" TME, and thus realizing the pyroptosis-mediated immunotherapy with fewer systemic side effects. Considering the outstanding oxygen-producing capacity of CuTA and the distinctive advantages of US, the sonosensitizer Ce6 was attached to CuTA via an amide reaction, which further amplified the pyroptosis and sensitized pyroptosis-induced immunotherapy with the two-pronged strategy of CuTA enzyme-catalyzed cascade and US-driven SDT pathway to generate a "reactive oxygen species (ROS) storm". Conclusively, this work provided a representative paradigm for achieving safe, reliable and efficient pyroptosis, which was further enhanced by SDT for more robust immunotherapy.

Glutathione-Responsive Polymersome with Continuous Glutathione Depletion for Enhanced Photodynamic Therapy and Hypoxia-Activated Chemotherapy.

The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.

Cold-Responsive Hyaluronated Upconversion Nanoplatform for Transdermal Cryo-Photodynamic Cancer Therapy.

Cryotherapy leverages controlled freezing temperature interventions to engender a cascade of tumor-suppressing effects. However, its bottleneck lies in the standalone ineffectiveness. A promising strategy is using nanoparticle therapeutics to augment the efficacy of cryotherapy. Here, a cold-responsive nanoplatform composed of upconversion nanoparticles coated with silica - chlorin e6 - hyaluronic acid (UCNPs@SiO2-Ce6-HA) is designed. This nanoplatform is employed to integrate cryotherapy with photodynamic therapy (PDT) in order to improve skin cancer treatment efficacy in a synergistic manner. The cryotherapy appeared to enhance the upconversion brightness by suppressing the thermal quenching. The low-temperature treatment afforded a 2.45-fold enhancement in the luminescence of UCNPs and a 3.15-fold increase in the photodynamic efficacy of UCNPs@SiO2-Ce6-HA nanoplatforms. Ex vivo tests with porcine skins and the subsequent validation in mouse tumor tissues revealed the effective HA-mediated transdermal delivery of designed nanoplatforms to deep tumor tissues. After transdermal delivery, in vivo photodynamic therapy using the UCNPs@SiO2-Ce6-HA nanoplatforms resulted in the optimized efficacy of 79% in combination with cryotherapy. These findings underscore the Cryo-PDT as a truly promising integrated treatment paradigm and warrant further exploring the synergistic interplay between cryotherapy and PDT with bright upconversion to unlock their full potential in cancer therapy.

Spatiotemporally-controlled hydrophobic drug delivery via photosensitizer-driven assembly-disassembly for enhanced triple-negative breast cancer treatment.

Therapeutic approaches for triple-negative breast cancer (TNBC) have been continuously advancing, but inadequate control over release behavior, insufficient tumor selectivity, and limited drug availability continue to impede therapeutic outcomes in nanodrug systems. In this study, we propose a general hydrophobic antineoplastic delivery system, termed spatiotemporally-controlled hydrophobic antineoplastic delivery system (SCHADS) for enhanced TNBC treatment. The key feature of SCHADS is the formation of metastable photosensitive-antineoplastic complexes (PACs) through the self-assembly of hydrophobic drugs driven by photosensitive molecules. With the further decoration of tumor-targeting peptides coupled with the EPR effect, the PACs tend to accumulate in the tumor site tremendously, promoting drug delivery efficiency. Meanwhile, the disassembly behavior of the metastable PACs could be driven by light on demand to achieve in situ drug release, thus promoting chemotherapeutics availability. Furthermore, the abundant ROS generated by the photosensitizer could effectively kill tumor cells, ultimately realizing an effective combination of photodynamic and chemotherapeutic therapy. As an exemplary presentation, chlorin e6 has been chosen to drive the formation of PACs with the system xc- inhibitor sorafenib. Compared with pure drug treatment, the PACs with the above-described preponderances exhibit superior therapeutic effects both in vitro and in vivo and circumvent the side effects due to off-target. By manipulating the laser irradiation, the PACs-treated cell death mechanism could be dynamically regulated, thus providing the potential to remedy intrinsic/acquired resistance of tumor. Collectively, this SCHADS achieves spatio-temporal control of the drug that greatly enhances the availability of anticarcinogen and realizes synergistic antitumor effect in TNBC treatment, even ultimately being extended to the treatment of other types of tumors.

Comparison of photodynamic therapy with two different parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization.

BACKGROUND: To the best of our knowledge, no studies have been performed to determine the optimal parameters of photodynamic therapy (PDT) combined with subconjunctival injection of bevacizumab for corneal neovascularization. This study aimed to compare the effect of photodynamic therapy with two different sets of parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization. METHODS: Patients with stable corneal neovascularization (CNV) unresponsive to conventional treatment (topical steroid) were included in this study. Patients were divided into two groups, receiving PDT with two different sets of parameters (group 1 receiving fluence of 50 J/cm2 at 15 min after intravenous injection of verteporfin with, group 2 receiving fluence of 150 J/cm2 at 60 min after intravenous injection of verteporfin with). Subconjunctival injection of bevacizumab was performed immediately after PDT. All patients were followed for 6 months. Best-corrected visual acuity and intraocular pressure were evaluated, and slit-lamp biomicroscopy as well as digital photography were performed. Average diameter and cumulative length of corneal neovascular were measured to evaluate the corneal neovascularization. RESULTS: Seventeen patients (20 eyes) were included in this study. At the last visit, the vision was improved in 12 eyes (60 %), steady in 4 eyes (20 %) and worsen in 4 eyes (20 %). The intraocular pressure (IOP) of all patients remained in normal range. A significant decrease in corneal neovascularization was showed in all the eyes after treatment. At 6 months after the combined treatment, the average diameter and cumulative length of vessels significantly decreased to 0.041 ± 0.023 mm (P < 0.05) and 18.78 ± 17.73 mm (P < 0.05), respectively, compared with the pretreatment data (0.062 ± 0.015 mm, 31.48 ± 18.21 mm). The reduction was more remarkable in group 2 compared to group 1.In group 1, the average diameter was 0.062 ± 0.013mm before and 0.056 ± 0.017mm after, the cumulative length of vessels was 38.66 ± 22.55mm before and 31.21 ± 17.30 after. In group 2, the date were 0.061 ± 0.016mm before and 0.029 ± 0.020mm after, 25.60 ± 8.95 mm before and 8.61 ± 8.26 mm. The reported complications included epithelial defect in four eyes, small white filaments in two eyes and corneal epithelial erosion in two eyes. CONCLUSION: The PDT combined with subconjunctival injection of bevacizumab was effective for the chronic corneal neovascularization. A more promising treatment outcome was observed when PDT was performed at 60 min after intravenous injection of verteporfin with fluence of 150 J/cm2. No serious complications or systemic events were observed throughout the follow-up period.

Photomedicine based on heme-derived compounds.

Photoimaging and phototherapy have become major platforms for the diagnosis and treatment of various health complications. These applications require a photosensitizer (PS) that is capable of absorbing light from a source and converting it into other energy forms for detection and therapy. While synthetic inorganic materials such as quantum dots and gold nanorods have been widely explored for their medical diagnosis and photodynamic (PDT) and photothermal (PTT) therapy capabilities, translation of these technologies has lagged, primarily owing to potential cytotoxicity and immunogenicity issues. Of the various photoreactive molecules, the naturally occurring endogenous compound heme, a constituent of red blood cells, and its derivatives, porphyrin, biliverdin and bilirubin, have shown immense potential as noteworthy candidates for clinically translatable photoreactive agents, as evidenced by previous reports. While porphyrin-based photomedicines have attracted significant attention and are well documented, research on photomedicines based on two other heme-derived compounds, biliverdin and bilirubin, has been relatively lacking. In this review, we summarize the unique photoproperties of heme-derived compounds and outline recent efforts to use them in biomedical imaging and phototherapy applications.

meso-Tetra-(4-pyridyl)porphyrin/palladium(II) complexes as anticancer agents.

This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P-P)]4}(PF6)4, where P-P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1'-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1H and 31P{1H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)]4}(PF6)4 (in an excess of NaBF4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P21/a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π-π stacking and electrostatic interactions.

Cationic Polyporphyrins as siRNA Delivery Vectors for Photodynamic and Gene Synergistic Anticancer Therapy.

Successful gene therapy is highly dependent on the efficiency of gene delivery, which is mostly achieved by the carrier. Current gene carriers are generally nontherapeutic and take over most of the proportion in the delivery systems. Therefore, a library of polymerized and cationic photosensitive drugs (polyphotosensitizers, pPSs) with HIF-1α siRNA delivery capability is constructed to realize using "drug" to deliver "gene". The pPS component acts as both a therapeutic carrier for intracellular HIF-1α siRNA delivery and a photosensitive drug with photodynamic therapy (PDT). A reactive oxygen species (ROS)-cleavable linker is used to polymerize PS, allowing the successful segregation of PS monomers in space, avoiding the undesired aggregation-caused quenching (ACQ) effect and enhancing the in vitro and in vivo PDT effect. The complexes formed by pPSs and HIF-1α siRNA exhibited desired siRNA condensation and serum stability at the optimal conditions (pPSs with guanidines/siRNA weight ratio of 15), efficient intracellular internalization, and gene-silencing efficiency (60%) compared with commercial available transfection reagents (40%), as well as synergistic in vitro and in vivo phototoxicity for the combination PDT-gene therapy toward cancer treatment. This study provides a promising paradigm for the design of both the gene delivery carrier and the photosensitizer, as well as for broad utilities in the combination therapy toward cancer treatment.

Light-assisted anticancer photodynamic therapy using porphyrin-doped nanoencapsulates.

Light activatable porphyrinic photosensitizers (PSs) are essential components of anticancer and antimicrobial therapy and diagnostic imaging. However, their biological applications are quite challenging due to the lack of hydrophilicity and biocompatibility. To overcome such drawbacks, photosensitizers can be doped into a biocompatible polymer such as gelatin and further can be used for biomedical applications. Herein, first, a novel A4 type porphyrin PS [5,10,15,20-tetrakis(4-pyridylamidephenyl)porphyrin; TPyAPP] was synthesized via a rational route with good yield. Further, this porphyrin was encapsulated into the gelatin nanoparticles (GNPs) to develop hydrophilic phototherapeutic nanoagents (PTNAs, A4por-GNPs). Notably, the synthesis of such porphyrin-doped GNPs avoids the use of any toxic chemicals or solvents. The nanoprobes have also shown good fluorescence quantum yield demonstrating their applicability in bioimaging. Further, the mechanistic aspects of the anticancer and antimicrobial efficacy of the developed A4por-GNPs were evaluated via singlet oxygen generation studies. Overall, our results indicated porphyrin-doped biodegradable polymeric nanoparticles act as effective phototherapeutic agents against a broad range of cancer cell lines and microbes upon activation by the low-cost LED light.

H2O2 enhances the anticancer activity of TMPyP4 by ROS-mediated mitochondrial dysfunction and DNA damage.

Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide. High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this influences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in H2O2. The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and H2O2 exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells, but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and H2O2 activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and H2O2 combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that H2O2 enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.

Photodynamic effect of TPP encapsulated in polystyrene nanoparticles toward multi-resistant pathogenic bacterial strains: AFM evaluation.

Photodynamic inactivation (PDI) is a promising approach for the efficient killing of pathogenic microbes. In this study, the photodynamic effect of sulfonated polystyrene nanoparticles with encapsulated hydrophobic 5,10,15,20-tetraphenylporphyrin (TPP-NP) photosensitizers on Gram-positive (including multi-resistant) and Gram-negative bacterial strains was investigated. The cell viability was determined by the colony forming unit method. The results showed no dark cytotoxicity but high phototoxicity within the tested conditions. Gram-positive bacteria were more sensitive to TPP-NPs than Gram-negative bacteria. Atomic force microscopy was used to detect changes in the morphological properties of bacteria before and after the PDI treatment.

Characterization of radical types, penetration profile and distribution pattern of the topically applied photosensitizer THPTS in porcine skin ex vivo.

The topical photodynamic therapy (PDT) is mainly used in the treatment of dermato-oncological diseases. The distribution and functionality of the photosensitizer Tetrahydroporphyrin-Tetratosylat (THPTS) was investigated using microscopic and spectroscopic methods after topical application to excised porcine skin followed by irradiation. The distribution of THPTS was determined by two-photon tomography combined with fluorescence lifetime imaging (TPT/FLIM) and confocal Raman microspectroscopy (CRM). The radicals were quantified and characterized by electron paramagnetic resonance (EPR) spectroscopy. Results show a penetration depth of THPTS into the skin down to around 12 ± 5 µm. A penetration of THPTS through the stratum corneum was not clearly observable after 1 h penetration time, but cannot be excluded. The irradiation within the phototherapeutic window (spectral range of visible and near infrared light in the range ≈ 650-850 nm) is needed to activate THPTS. An incubation time of 10 min showed the highest radical production. A longer incubation time affected the functionality of THPTS, whereby significant less radicals were detectable. During PDT mainly reactive oxygen species (ROS) and lipid oxygen species (LOS) are produced. Overall, the irradiation dose per se influences the radical types formed in skin. While ROS are always prominent at low doses, LOS increase at high doses, independent of previous skin treatment and the irradiation wavelength used.

Bioorthogonal Pretargeting Strategy for Anchoring Activatable Photosensitizers on Plasma Membranes for Effective Photodynamic Therapy.

Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate in tumor tissue and disassemble upon protonation of their tertiary amines in response to the acidic tumor environment, exposing the contained DBCO and Ce6. The selective, highly specific click reactions between DBCO and azide groups enable Ce6 to be anchored on the tumor cell surface. Upon laser irradiation, the cell membrane is severely damaged by the cytotoxic reactive oxygen species, resulting in remarkable cellular apoptosis. Taken together, the membrane-localized PDT by our bioorthogonal pretargeting strategy to anchor activatable photosensitizers on the plasma membrane provides a simple but effective method for enhancing the therapeutic efficacy of photosensitizers in anticancer therapy.

Multifunctional nanoparticle PEG­Ce6­Gd for MRI­guided photodynamic therapy.

Gliomas are one of the most common types of primary brain tumors. Despite recent advances in the combination of surgery, radiotherapy, systemic therapy (chemotherapy, targeted therapy) and supportive therapy in the multimodal treatment of gliomas, the overall prognosis remains poor and the long­term survival rate is low. Thus, it is crucial to develop a novel glioma management method. Due to its relatively non­invasive, selective and repeatable characteristics, photodynamic therapy (PDT) has been investigated for glioma therapy in the past decade, exhibiting higher selectivity and lower side effects compared with those of conventional therapy. However, most of the photosensitizers (PSs) are highly hydrophobic, leading to poor water solubility, rapid degradation with clearance in blood circulation and ultimately, low bioavailability. In the present study, hydrophilic polyethylene glycol (PEG)­chlorin e6 (Ce6) chelated gadolinium ion (Gd3+) nanoparticles (PEG­Ce6­Gd NPs) were synthesized via a chelation and self­assembly process. Initially, the cell cytotoxicity of PEG­Ce6­Gd NPs was evaluated with or without laser irradiation. The in vitro study demonstrated the lack of toxicity of PEG­Ce6­Gd NPs to tumor cells in the absence of laser irradiation. However, its toxicity was enhanced under laser irradiation. Moreover, the size and weight of brain tumors were significantly decreased in mice with glioma xenografts, which was further confirmed via histological analysis. Subsequently, the results indicated that the PEG­Ce6­Gd NPs had a favorable T1­weighted contrast performance (0.43 mg ml­1 s­1) and were observed to have significant contrast enhancement at the tumor site from 0.25 to 1 h post­injection in vivo. The favorable MRI, as well as the synergetic photodynamic antitumor effect and antineoplastic ability of PEG­Ce6­Gd NPs was identified. It was suggested that PEG­Ce6­Gd NPs had great potential in the diagnosis and PDT treatment of gliomas, and possibly other cancer types, with prospects of clinical application in the near future.

Combination of talaporfin photodynamic therapy and Poly (ADP-Ribose) polymerase (PARP) inhibitor in gastric cancer.

Photodynamic therapy (PDT) utilizes photochemical reactions induced by a photosensitizer and light in the target tissue and is used to treat various cancers. There is a high degree of anticipation of success regarding the application of PDT with talaporfin (photosensitizer) for gastric cancer. Olaparib is an oral inhibitor of Poly (ADP-Ribose) polymerase (PARP) and has demonstrated optimal efficacy and clinical activity in trials. Therefore, the aim of the present study was to investigate the efficacy of talaporfin PDT combined with olaparib for gastric cancer. MKN45, a gastric cancer cell line, was incubated with talaporfin, followed by irradiation, in the presence/absence of olaparib. Talaporfin PDT and olaparib exhibited excellent synergistic action in a concentration-dependent manner. PARP-DNA complexes were characterized based on bound chromatin using Western blot analyses. The combination of talaporfin PDT and olaparib enhanced PARP1 accumulation (the entrapment of PARP1-DNA complexes) in bound chromatin. The combination of talaporfin PDT and olaparib induced DNA double-strand breaks, which was confirmed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established, and antitumor effects were analyzed. In vivo, tumor growth was significantly suppressed following PDT with talaporfin and olaparib. Our results demonstrated that olaparib enhances the efficacy of talaporfin PDT by inducing the formation of PARP-DNA complexes. Therefore, our results suggest that the combination of talaporfin PDT and olaparib is a potential antitumor therapy for gastric cancer.

Self-assembly supramolecular drug delivery system for combination of photodynamic therapy and chemotherapy.

AIMS: To construct a self-assembly supramolecular drug delivery system (DDS) to co-deliver chlorin e6 (Ce6) and tripeptide tyroseroleutide (YSL) and evaluate the anti-tumour effects. METHODS: A supramolecular DDS was constructed via self-assembly of Ce6 and YSL based on π-π stacking and hydrogen-bond interaction. The size, morphology, stability, in vitro drug release, cellular uptake, cytotoxicity, pharmacokinetics analysis and pharmacodynamics analysis were respectively studied. RESULTS: Ce6-YSL nanoparticles with a uniform size of 75 ± 3.5 nm (PDI = 0.128) and monodispersed spherical morphology were constructed. The nanoparticles exhibited good stability with zeta potential -21.2 ± 1.73 mV. Under the weak acidic conditions, the accumulative drug release was 82.8% (w/w) (pH = 6.0) and 91.5% (w/w) (pH = 5.0), respectively, indicating that nanoparticles performed smart responsive properties and achieved controlled release characteristics in acidic tumour microenvironment. In addition, nanoparticles could easily enter the tumour cells and induce ROS production and inhibit cell proliferation in SMMCC-7721 cells with IC50 value 3.4 ± 0.023 µg/mL under laser irradiation. Furthermore, the nanoparticles could retain a much higher blood concentration in vivo and displayed excellent antitumor effect in tumour-bearing mice, showing no influence on body weight. CONCLUSIONS: This self-assembly supramolecular DDS can be used for combination of photodynamic therapy and chemotherapy in future research.

Comparison of the Photodynamic Action of Porphyrin, Chlorin, and Isobacteriochlorin Derivatives toward a Melanotic Cell Line.

Melanoma is the most dangerous form of skin cancer, with an abrupt growth of its incidence over the last years. It is extremely resistant to traditional treatments such as chemotherapy and radiotherapy, but therapies for this cancer are gaining attention. Photodynamic therapy (PDT) is considered an effective modality to treat several types of skin cancers and can offer the possibility to treat one of the most aggressive ones: melanoma. In this work, the effect of PDT on a melanotic cell line (B16F10 cells) was assessed by exposing cultured cells to 5,10,15-tris(pentafluorophenyl)-20-(4-pyridyl)porphyrin (PS1) and to its chlorin (PS2) and isobacteriochlorin (PS3) corresponding derivatives and red LED light (λ = 660 ± 20 nm). The PDT effect in the cells' viability was measured using the MTT assay. The cell apoptosis was quantified by flow cytometry, and the subcellular localization of the photosensitizer was determined by fluorescence microscopy. In addition, the ability of PS2 to generate superoxide radicals was qualitatively assessed by tyrosine nitration. The results show that the efficiency of the PDT process is dependent on the structure of the PS and on their ability to produce singlet oxygen. Besides that, the photoactivation efficiency is highly dependent on the cellular sublocalization of the PS and on its cellular uptake and singlet oxygen production. We also found that the resistant cell line B16F10 has distinctive chlorin, isobacteriochlorin, or porphyrin-specific resistance profiles. Furthermore, it is shown that the highly fluorescent chlorin derivative PS2 can also be considered in imaging diagnostics.

Structural requirement of G-quadruplex/aptamer-combined DNA macromolecule serving as efficient drug carrier for cancer-targeted drug delivery.

Photodynamic therapy (PDT) as a clinical cancer treatment method has been used to treat carcinomas in different organs, and G-quadruplex-based DNA nanocompartments serving as the carriers of cationic porphyrin photosensitizers, especially combined with cell-targeting aptamers, is considered to offer new opportunities for future cancer treatment. However, the structural features of G-quadruplex/aptamer complexes suitable for the capsulation of photosensitizers and target cell recognition is unexplored so far. In this study, unimolecular (UM), bimolecular (BM) and tetramolecular (TM) G-quadruplex structures were used as the drug loading compartments and grafted onto tumor cell-targeting aptamer Sgc8, constructing several targeting drug delivery vehicles (T-GMVs). Besides the binding affinity of resulting DNA architectures for target cells and cell recognition specificity were explored in a comparative fashion, the drug loading capability and cancer therapy efficacy were evaluated using TMPyP4 as the model porphyrin-based drug. The experimental results show that only TM G-quadruplex structure is suitable to combine with Sgc8 for the development of drug delivery vehicle and the as-prepared T-GMV- TMPyP4 complexes display the desirable cancer therapy efficacy, holding the potential application in the future cancer therapy. More importantly, T-GMV- TMPyP4 is expected to lay the scientific groundwork for the successful development of G-quadruplex-based photosensitizer drug delivery carriers for the targeted cancer therapy.

In Vitro Photodynamic Effects of the Inclusion Nanocomplexes of Glucan and Chlorin e6 on Atherogenic Foam Cells.

Macrophage-derived foam cells play critical roles in the initiation and progression of atherosclerosis. Activated macrophages and foam cells are important biomarkers for targeted imaging and inflammatory disease therapy. Macrophages also express the dectin-1 receptor, which specifically recognizes ß-glucan (Glu). Here, we prepared photoactivatable nanoagents (termed Glu/Ce6 nanocomplexes) by encapsulating hydrophobic chlorin e6 (Ce6) within the triple-helix structure of Glu in aqueous condition. Glu/Ce6 nanocomplexes generate singlet oxygen upon laser irradiation. The Glu/Ce6 nanocomplexes were internalized into foam cells and delivered Ce6 molecules into the cytoplasm of foam cells. Upon laser irradiation, they induced significant membrane damage and apoptosis of foam cells. These results suggest that Glu/Ce6 nanocomplexes can be a photoactivatable material for treating atherogenic foam cells.