Antitumor Photodynamic Therapy Research Articles

Fabrication of Multitargeting and pH-Regulated Nanocomposites for Antitumor Photodynamic Therapy Based on Triphenylphosphine and Graphene Oxide.

Targeted delivery of photosensitizer for antitumor photodynamic therapy has received much attention recently. In this research, a multitargeting graphene oxide (GO) nanosystem (GFFP-TPPa) was fabricated based on the magnetically targeted nano-Fe3O4, active targeted folic acid (FA), and mitochondria-targeted triphenylphosphine, aiming to provide an effective drug delivery system of photosensitizer for improved photodynamic therapy against human tumor. The effective photosensitizer release from GFFP-TPPa under mild acidic pH condition (such as tumor microenvironment) suggested our designed nanosystem could reduce cutaneous phototoxicity of nanoparticles (NPs) in normal cells environment, which was further verified by the observation that the fluorescence of GFFP-TPPa was significantly quenched compared with free PPa. Research of cellular morphological variation, uptaking test, and intracellular single oxygen detection has validated the effectiveness of GFFP-TPPa NPs against tumor cells and potential fluorescence imaging function. Moreover, GFFP-TPPa NPs have excellent superparamagnetic properties and FA-targeted property of NPs, which was verified by the tumor cellular uptake of GFFP-TPPa. Finally, the precise deliver of photosensitizer to mitochondria has been proved by Mito-Tracker Green organelle localization. Our research indicated that the fabricated nanosystem could be applied conveniently for PDT based on multitargetability.

Bystander Effects of Nitric Oxide in Cellular Models of Anti-tumor Photodynamic Therapy

Bystander Effects of Nitric Oxide in Cellular Models of Anti-tumor Photodynamic Therapy

Nitric Oxide-Mediated Resistance to Antitumor Photodynamic Therapy.

As an antitumor modality based on sensitizer photoexcitation by tumor-directed light, photodynamic therapy (PDT) has the advantage of being site-specific compared with conventional chemotherapy or radiotherapy. Like these other therapies, however, PDT is often limited by pre-existing or acquired resistance. One type of resistance, discovered in the author's laboratory, involves nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) in tumor cells. Using human breast, prostate and brain cancer cell lines, we have shown that iNOS is dramatically upregulated after a moderate PDT challenge sensitized by 5-aminolevulinic acid-induced protoporphyrin IX. The elevated NO not only elicited a greater resistance to cell photokilling, but also an increase in the growth and migration/invasion rate of surviving cells. Greater iNOS/NO-based resistance was also demonstrated at the in vivo level using a breast tumor xenograft model. More recent studies have shown that NO from PDT-targeted cells can stimulate a progrowth/promigration response in non-targeted bystander cells. These novel effects of NO, their negative impact on PDT efficacy and possible mitigation thereof by anti-iNOS/NO pharmacologic agents will be discussed.

Nanoscale Covalent Organic Framework for Combinatorial Antitumor Photodynamic and Photothermal Therapy.

Despite the excellent photodynamic and photothermal properties of organic molecular photosensitizers (PSs) and photothermal agents (PTAs), such as porphyrin and naphthalocyanine, their poor water solubility severely impedes their biological applications. Covalent organic frameworks (COFs), as an emerging class of organic crystalline porous materials, possess free active end groups (bonding defects) and large inner pores, which make them an ideal type of nanocarriers for loading hydrophobic organic molecular PSs and PTAs by both bonding defect functionalization (BDF) and guest encapsulation approaches to obtain multifunctional nanomedicines for PDT/PTT combination therapy. In this work, we report a nanoscale COF (NCOF) prepared via a facile synthetic approach under ambient conditions. Furthermore, a dual-modal PDT/PTT therapeutic nanoagent, VONc@COF-Por (3), is successfully fabricated by stepwise BDF and guest encapsulation processes. The covalently grafted porphyrinic PS (Por) and the noncovalently loaded naphthalocyanine PTA (VONc) are independently responsible for the PDT and PTT functionalities of the nanoagent. Upon visible (red LED) and NIR (808 nm laser) irradiation, VONc@COF-Por (3) displayed high 1O2 generation and photothermal conversion ability (55.9%), consequently providing an excellent combined PDT/PTT therapeutic effect on inhibiting MCF-7 tumor cell proliferation and metastasis, which was well evidenced by in vitro and in vivo experiments. We believe that the results obtained herein can significantly promote the development of NCOF-based multifunctional nanomedicines for biomedical applications.

Bystander Effects of Nitric Oxide in Cellular Models of Anti-Tumor Photodynamic Therapy.

Tumor cells exposed to stress-inducing radiotherapy or chemotherapy can send signals to non- or minimally exposed bystander cells. Bystander effects of ionizing radiation are well established, but little is known about such effects in non-ionizing photodynamic therapy (PDT). Our previous studies revealed that several cancer cell types upregulate inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after a moderate 5-aminolevulinic acid (ALA)-based PDT challenge. The NO signaled for cell resistance to photokilling as well as greater growth, migration and invasion of surviving cells. Based on this work, we hypothesized that diffusible NO produced by PDT-targeted cells in a tumor might elicit pro-growth/migration responses in non-targeted bystander cells. In the present study, we tested this using a novel approach, in which ALA-PDT-targeted human cancer cells on culture dishes (prostate PC3, breast MDA-MB-231, glioma U87, or melanoma BLM) were initially segregated from non-targeted bystanders via impermeable silicone-rimmed rings. Several hours after LED irradiation, rings were removed, and both cell populations analyzed for various post-hν responses. For a moderate and uniform level of targeted cell killing by PDT (~25%), bystander proliferation and migration were both enhanced. Enhancement correlated with iNOS/NO upregulation in surviving targeted cells in the following order: PC3 > MDA-MB-231 > U87 > BLM. If occurring in an actual tumor PDT setting and not suppressed (e.g., by iNOS activity or transcription inhibitors), then such effects could compromise treatment efficacy or even stimulate disease progression if PDT’s anti-tumor potency is not great enough.

Triggered All-Active Metal Organic Framework: Ferroptosis Machinery Contributes to the Apoptotic Photodynamic Antitumor Therapy.

Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide-thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior in vivo antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.

Zinc(II) phthalocyanines as photosensitizers for antitumor photodynamic therapy.

Photodynamic therapy (PDT) is a highly specific and clinically approved method for cancer treatment in which a nontoxic drug known as photosensitizer (PS) is administered to a patient. After selective tumor irradiation, an almost complete eradication of the tumor can be reached as a consequence of reactive oxygen species (ROS) generation, which not only damage tumor cells, but also lead to tumor-associated vasculature occlusion and the induction of an immune response. Despite exhaustive investigation and encouraging results, zinc(II) phthalocyanines (ZnPcs) have not been approved as PSs for clinical use yet. This review presents an overview on the physicochemical properties of ZnPcs and biological results obtained both in vitro and in more complex models, such as 3D cell cultures, chicken chorioallantoic membranes and tumor-bearing mice. Cell death pathways induced after PDT treatment with ZnPcs are discussed in each case. Finally, combined therapeutic strategies including ZnPcs and the currently available clinical trials are mentioned.

Simple and Multifunctional Natural Self-Assembled Sterols with Anticancer Activity-Mediated Supramolecular Photosensitizers for Enhanced Antitumor Photodynamic Therapy.

Supramolecular photosensitizers based on nanosized drug delivery or combination therapy have been proposed as a promising strategy for cancer treatment. Herein, we screen and develop a series of multifunctional single-component, carrier-based, natural small-molecule sterols (ergosterol, β-sitosterol, and stigmasterol) that simultaneously possess self-assembly ability, anticancer activity, and better biocompatibility and biodegradability to deliver photosensitizer chlorin e6 (Ce6) for significantly combined and safe antitumor photodynamic therapy. The resultant ergosterol-Ce6 nanodrugs (Ergo-Ce6 NPs) have enhanced reactive oxygen species (ROS) generation by promoting type I photoreactions, while Ce6 mainly exists in the monomer state in assembled Ergo-Ce6 NPs via intermolecular π-π stacking and hydrophobic interactions. In addition, with the improved water solubility and stability and higher intercellular ROS generation, Ergo-Ce6 NPs show remarkably in vitro phototoxicity with approximately 73% and 92% cell inhibition ratios to 4T1 and MCF-7 cancer cells at a rather low dosage of Ce6 (1 μg/mL), respectively. Moreover, the excellent tumor targeting ability of Ergo NPs and prolonged blood circulation ensure a quick tumor accumulation of Ergo-Ce6 NPs, resulting in a significantly enhanced in vivo anticancer efficiency of 86.4%, higher than that of the anticancer ability of Ergo NPs (51.0%) or Ce6 PDT alone (59.5%). Furthermore, the resulting nanodrugs have better biocompatibility and biodegradability and low in vivo toxicity, and all of which ensure a safe tumor therapy. This study provides a promising perspective to develop more natural self-assembled biological small-molecule nanomaterials for the fabrication of novel medicinal photosensitizers for clinical application in the future.

Corrole‐based photodynamic antitumor therapy

AbstractStudy of photodynamic therapy (PDT) based on corroles has become one of the most important topics in corrole chemistry. Advances in synthetic methodology have made it possible for the preparation of structurally diverse corrole photosensitizers. This review covers the recent progress in the study of corrole as a photosensitizer in the photodynamic antitumor therapy. The content is organized in three sections: cellular uptaking and localization of corrole in tumor cells; morphological changes and cytotoxicity after corrole PDT treatment; and the animal level corrole PDT test. The possible mechanism of corrole‐based PDT antitumor activity is also summarized.

A Mesoporous Nanoenzyme Derived from Metal-Organic Frameworks with Endogenous Oxygen Generation to Alleviate Tumor Hypoxia for Significantly Enhanced Photodynamic Therapy.

Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen (1 O2 ). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal-organic frameworks (MOFs) is presented for in situ generation of endogenous O2 to enhance the PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese-based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post-modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O2 generation through the catalytic reaction between the catalytic amount NE and the endogenous H2 O2 , the hypoxic tumor microenvironment is relieved. Thus, Ce6-loaded NE serves as a H2 O2 -activated oxygen supplier to increase the local O2 concentration for significantly enhanced antitumor PDT efficacy in vitro and in vivo. In addition, the NE also shows T2 -weighted magnetic resonance imaging ability for its in vivo tracking. This work presents an interesting biomedical use of MOF-derived mesoporous NE as a multifunctional theranostic agent in cancer therapy.

The effect of curcumin in antitumor photodynamic therapy: In vitro experiments with Caco-2 and PC-3 cancer lines.

Photodynamic Therapy (PDT) is a promising antitumor and anti-bacterial treatment method for its high selectivity, non-invasiveness, and minimal side effects. However, cellular mechanisms may lead to PDT resistance and thus effect efficacy. The aim of this study is to test whether Curcumin, which is a non-toxic natural compound that has antitumor characteristics, can increase PDT efficacy by overcoming the resistance of cancer cells. 5-ALA mediated PDT was tested on two cell lines, PC-3 and Caco-2. Curcumin toxicity was evaluated at different concentrations. The determined PDT doses were applied to the cell lines together with two different Curcumin concentrations. Cell viability was evaluated by MTT assay, 24 hs after the treatments. Results were evaluated using One-Way ANOVA followed by post-hoc tests. Using non-toxic doses of Curcumin resulted in a significant decrease in PDT resistance in Caco-2 cells and thus increased the efficacy of 5-ALA mediated PDT, but not on PC-3. Adding Curcumin to 5-ALA mediated PDT led to more effective results on Caco-2 with a 62.4% decrease in cell viability. On the other hand, adding Curcumin to 5-ALA mediated PDT on PC-3 cells didn't produce statistically significant increase in efficacy with a 36% decrease in cell viability. 5-ALA mediated PDT combined with Curcumin synergistically enhanced antitumor PDT efficacy on Caco-2, which is considered a highly resistive cancer cell line.

Development of glyco‐conjugated chlorin e6 for photodynamic therapy

PDT (photodynamic therapy) has much attracted as less invasive method for treating cancer.1 To increase the antitumor effects and shorten the light shielding duration, we developed third‐generation photosensitizers for PDT. We have focused much attention to the glyco‐conjugation of chlorin derivatives mainly for the purpose of improving their biocompatibility and tumor selectivity. Generally, cancer cells uptake higher level of glucose than normal cells in a phenomenon known as Warburg's effect, which is also utilized in positron emission tomography (19FDG‐PET‐CT). We developed a number of glyco‐conjugated chlorins resulting finally in Glc‐chlorin e6, which showed the strongest antitumor effects in PDT ever reported for synthesized glyco‐conjugated chlorins.2 Furthermore, Glc‐chlorin e6 is discharged very fast from the body. We also confirmed extremely promising antitumor effects of 40% CR in vivo under conditions that killed all mice in the comparable TS (talaporfin sodium) PDT group. We have also already synthesized 14C‐labeled Glc‐chlorin e6 and examined its pharmacokinetics in rat to reveal a plasma half‐life of 42.65 h, which is shorted than that of TS. In rat, 14C‐labeled Glc‐chlorin e6 was mainly discharged in bile and faster than TS. Single time toxicity test of Glc‐chlorin e6 in mouse also showed the lowest published lethal dose of 250 mg/kg. From these findings, we consider that Glc‐chlorin e6 is the ideal sugar for conjugating to chlorin, evidenced by the remarkable antitumor PDT effects, rapid excretion, and low toxicity demonstrated herein. Glc‐chlorin e6 is considered to be the best candidate PS thus far for third‐generation PDT and we plan to continue with our investigatory studies with the ultimate aim of clinical trials. We examined the efficacy of PDT with Glc‐chlorin e6 for tumor‐bearing dogs.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The behavior of monocationic chlorin in water and aqueous solutions of non-ionic surfactant Tween 80 and potassium iodide

We have studied the behavior of monocationic chlorin (compound 1) which is considered as an appropriate agent for both antimicrobial and antitumor photodynamic therapy in water, aqueous solutions of KI and non-ionic surfactant Tween 80 with the dynamic light scattering (DLS), UV–Vis and fluorescence spectroscopy techniques. Our results do indicate that the solute reveals a tendency to form aggregates both in diluted (~10−5 mol/kg) and rather concentrated aqueous solutions (~10−3 mol/kg). For diluted aqueous solutions UV–Vis spectra appear to show the appearance of small associates, so-called H-aggregates, whereas for more concentrated solutions the DLS study reveals formation of large aggregates containing both chlorin and water molecules. The addition of surfactants or polymers such as Tween 80 or polyvinylpyrrolidone (PVP) leads to monomerisation of a potential drug for all cases. The spectrophotometric titration of aqueous solutions of compound 1 with Tween 80 demonstrates the strong interaction between surfactant and chlorin molecules, the binding constants and stoichiometry of complex formation being dependent of a solute concentration. The comparison of fluorescence quenching by KI in water and surfactant solutions indicates that solute molecules mainly occupy intermediate positions within Tween 80 micelles nearby the hydrophilic head groups of the surfactant.

Modulation of Intracellular Oxygen Pressure by Dual‐Drug Nanoparticles to Enhance Photodynamic Therapy

AbstractOxygen plays an essential role in the photodynamic therapy (PDT) of cancer. However, hypoxia inside tumors severely attenuates the therapeutic effect of PDT. To address this issue, a novel strategy is reported for cutting off the oxygen consumption pathway by using sub‐50 nm dual‐drug nanoparticles (NPs) to attenuate the hypoxia‐induced resistance to PDT and to enhance PDT efficiency. Specifically, dual‐drug NPs that encapsulate photosensitizer (PS) verteporfin (VER) and oxygen‐regulator atovaquone (ATO) with sub‐50 nm diameters can penetrate deep into the interior regions of tumors and effectively deliver dual‐drug into tumor tissues. Then, ATO released from NPs efficiently reduce in advance cellular oxygen consumption by inhibition of mitochondria respiratory chain and further heighten VER to generate greater amounts of 1O2 in hypoxic tumor. As a result, accompanied with the upregulated oxygen content in tumor cells and laser irradiation, the dual‐drug NPs exhibit powerful and overall antitumor PDT effects both in vitro and in vivo, and even tumor elimination. This study presents a potential appealing clinical strategy in photodynamic eradication of tumors.

A series of photosensitizers with incremental positive electric charges for photodynamic antitumor therapy.

In recent years, photodynamic therapy (PDT) studies have gained considerable attention as a non-invasive method used to fight cancer. In this study, a series of structurally similar photosensitizers (PSs) with incremental positive electric charges (ZnPc-4, 8 and 12) was investigated via in vitro and in vivo experiments. Photodynamic antitumor studies of these PSs, including phototoxicities, cellular uptake, the production of reactive oxygen species (ROSs) and the process of apoptosis, were conducted in the murine breast carcinoma cell line 4T1. The results indicated that the amount of positive electric charges in PSs is a key factor in influencing the efficacy of PDT. Furthermore, we established a hepatocellular carcinoma (H22) tumor-bearing mouse model to detect the antitumor activities of three PSs. ZnPc-4, 8 and 12 demonstrated significant antitumor effects and no obvious systemic damages in vivo (PDT effects: ZnPc-4 > ZnPc-8 > ZnPc-12), suggesting that the amount of positive electric charges was important to PSs, as well as the PDT effects. Our study not only indicates that ZnPc-4, 8 and 12 were highly potent anticancer PSs, but also suggests that adjusting the amount of positive electric charges is able to promote the PDT effects in cancer therapy.

Near-Infrared Activatable Phthalocyanine-Poly-L-Glutamic Acid Conjugate: Enhanced in Vivo Safety and Antitumor Efficacy toward an Effective Photodynamic Cancer Therapy.

We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.

Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery.

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

P-365 - Beneficial effects of inhibiting iNOS activity versus iNOS transcription in anti-tumor photodynamic therapy

We have shown that various cancer cells can exploit endogenous nitric oxide (NO) to resist elimination by photodynamic therapy (PDT) or cisplatin treatment. Inducible NO synthase (iNOS) was rapidly and persistently upregulated after treatment and the resulting NO signaled not only for greater resistance, but greater growth, migration, and invasion aggressiveness of surviving cells. NO-mediated hyper-aggressiveness has been also observed in non-targeted bystander cells. In the present study involving human glioblastoma U87 cells, we compared the pro-PDT effectiveness of inhibiting iNOS activity, using 1400 W, with inhibiting NF-κB-mediated iNOS transcription, using a BET bromodomain inhibitor (JQ1). iNOS was upregulated 2–3-fold in PDT-treated U87 cells and Bay11–7082 inhibition of NF-κB-activating kinase IKK prevented this response. JQ1 strongly suppressed basal as well as post-PDT iNOS induction. JQ1 synergized with PDT in enhancing either apoptotic cell killing or suppressing hyper-invasiveness of PDT-surviving cells. This is the first evidence for JQ1's superior effectiveness in suppressing iNOS antagonism to an anticancer therapy. Since several BET bromodomain inhibitors are now in clinical trials for various cancers, the translational potential of our findings are clear.

Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity.

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO3-PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity.

Platelet membrane coating coupled with solar irradiation endows a photodynamic nanosystem with both improved antitumor efficacy and undetectable skin damage

The therapeutic efficacy of tumor photodynamic therapy (PDT) is hindered by the following three challenges. The extremely short lifetime of reactive oxygen species (ROS, the cytotoxic factor of PDT) limits the radius of their action to tens-of-nanometer scale; functionalizing a photodynamic nanosystem with active targeting moieties helps bring the target cells into reach of ROS but requires extra research efforts. Current photodynamic systems are in general excited by light on the short end of near-infrared (NIR) region; deep tissue penetration necessitates the development of those excitable by longer NIR light. Reducing irradiation dose is necessary for avoiding skin damages but impacts the therapeutic outcome; how to resolve this delimma remains a challenge. We herein show that platelet membrane-coating over a photodynamic nanoparticle coupled with solar irradiation may simultaneously resolve all challenges above. Platelet membrane-coating provides both long circulation and active targeting, leading to preferential internalization by tumor over fibroblast cells in vitro and higher tumor uptake than the red blood cell (RBC) membrane-coated counterpart. Preloading a photodynamic sensitizer into a synthetic nanocarrier shifts its absorption peak to longer wavelength, which favors deep tissue penetration. Upon irradiation with NIR light from a solar simulator at extremely low output power density, the platelet membrane-coated photodynamic-nanoparticle outperforms its RBC membrane-coated counterpart and effectively ablates tumor without causing skin damages, which underscores the importance of active targeting in tumor PDT. We anticipate that platelet membrane coating may facilitate the in vivo applications of antitumor photodynamic therapy.