A Self‐Delivery Chimeric Peptide for Photodynamic Therapy Amplified Immunotherapy

In this paper, a self‐delivery chimeric peptide PpIX‐PEG₈‐KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self‐assembly into nanoparticles (designated as PPMA), this self‐delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti‐tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti‐tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti‐tumor immune response. This self‐delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.     

The Course of Immune Stimulation by Photodynamic Therapy: Bridging Fundamentals of Photochemically Induced Immunogenic Cell Death to the Enrichment of T‐Cell Repertoire

Photodynamic therapy (PDT) is a potentially immunogenic and FDA‐approved antitumor treatment modality that utilizes the spatiotemporal combination of a photosensitizer, light and oftentimes oxygen, to generate therapeutic cytotoxic molecules. Certain photosensitizers under specific conditions, including ones in clinical practice, have been shown to elicit an immune response following photoillumination. When localized within tumor tissue, photogenerated cytotoxic molecules can lead to immunogenic cell death (ICD) of tumor cells, which release damage‐associated molecular patterns and tumor‐specific antigens. Subsequently, the T‐lymphocyte (T cell)–mediated adaptive immune system can become activated. Activated T cells then disseminate into systemic circulation and can eliminate primary and metastatic tumors. In this review, we will detail the multistage cascade of events following PDT of solid tumors that ultimately lead to the activation of an antitumor immune response. More specifically, we connect the fundamentals of photochemically induced ICD with a proposition on potential mechanisms for PDT enhancement of the adaptive antitumor response. We postulate a hypothesis that during the course of the immune stimulation process, PDT also enriches the T‐cell repertoire with tumor‐reactive activated T cells, diversifying their tumor‐specific targets and eliciting a more expansive and rigorous antitumor response. The implications of such a process are likely to impact the outcomes of rational combinations with immune checkpoint blockade, warranting investigations into T‐cell diversity as a previously understudied and potentially transformative paradigm in antitumor photodynamic immunotherapy.     

Exploitation of Immune Response-eliciting Properties of Hypocrellin Photosensitizer SL052-based Photodynamic Therapy for Eradication of Malignant Tumors

A diaminophenyl derivative of hypocrellin B (SL052) has been developed as a photosensitizer for use in photodynamic therapy (PDT) of solid tumors. Testing SL052-PDT on mouse carcinoma and fibrosarcoma models revealed a typical response seen with clinically established photosensitizers featuring initial rapid tumor ablation with ensuing recurrence at rates dependent on photosensitizer/light doses. Elevated numbers of immune cells were found in lymph nodes draining SCCVII mouse squamous cell carcinomas treated by SL052-PDT (in particular T cells), and the accumulation of degranulating cytotoxic T cells was detected at the tumor-treated site. This indicates that a significant contribution to tumor cures is elicited by an antitumor adaptive immune response. Two different immunotherapy agents, γ-interferon and antibody blocking inhibitory FcγRIIB receptor, were both found to be highly effective in potentiating the curative effect of SL052-PDT with SCCVII tumors. Combining SL052-PDT with FcγRIIB-blocking antibody treatment caused a further increase in the number of cells in tumor-draining lymph nodes and in degranulating CD8⁺ cells, suggesting the amplification of the immune response induced by PDT. Vaccines consisting of SCCVII cells treated with SL052-PDT in vitro were effective in reducing growth of established subcutaneous SCCVII tumors. In conclusion, PDT mediated by SL052 is suitable to be integrated with various immunotherapy protocols.     

A Nanoscale Metal–Organic Framework to Mediate Photodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Enhance Antigen Presentation and Cancer Immunotherapy

Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale metal–organic framework, W‐TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear W^VI secondary building units and photosensitizing 5,10,15,20‐tetra(p‐benzoato)porphyrin (TBP) ligands, cationic W‐TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.     

Interaction between photodynamic therapy and BCG immunotherapy responsible for the reduced recurrence of treated mouse tumors

Subcutaneous mouse EMT6 tumors were treated by individual or combined regimens of a single Bacillus Calmette-Guérin (BCG) vaccine administration and photodynamic therapy (PDT). Six clinically relevant photosensitizers characterized by different action mechanisms were used: Photofrin, benzoporphyrin derivative, tetra(m-hydroxyphenyl)chlorin (foscan), mono-L-aspartylchlorin e6, lutetium texaphyrin or zinc phthalocyanine. Irrespective of the type of photosensitizer used, the optimized BCG protocols improved the cure rate of PDT-treated tumors. This indicates that the interaction does not take place during the early phase of tumor ablation but at later events involved in preventing tumor recurrence. Beneficial effects on tumor cure were observed even when the BCG injection was delayed to 7 days after PDT. The accumulation of activated myeloid cells that markedly increases in tumors treated by Photofrin-based PDT was not additionally affected by BCG treatment. However, the incidence of immune memory T cells in tumor-draining lymph nodes that almost doubled at 6 days after Photofrin-PDT further increased close to three-fold with adjuvant BCG. This suggests that BCG immunotherapy amplifies the T-lymphocyte-mediated immune response against PDT-treated tumors. Since both these modalities are established for the treatment of superficial bladder carcinomas, use of their combination for this condition should be clinically tested.     

A Multiresponsive Nanohybrid to Enhance the Lysosomal Delivery of Oxygen and Photosensitizers

Photodynamic therapy (PDT) is a promising cancer ablation method, but its efficiency is easily affected by several factors, such as the insufficient delivery of photosensitizers, low oxygen levels as well as long distance between singlet oxygen and intended organelles. A multifunctional nanohybrid, named MGAB, consisting of gelatin-coated manganese dioxide and albumin-coated gold nanoclusters, was designed to overcome these issues by improving chlorin e6 (Ce6) delivery and stimulating oxygen production in lysosomes. MGAB were quickly degraded in a high hydrogen peroxide, high protease activity, and low pH microenvironment, which is closely associated with tumor growth. The Ce6-loaded MGAB were picked up by tumor cells through endocytosis, degraded within the lysosomes, and released oxygen and photosensitizers. Upon near-infrared light irradiation, the close proximity of oxygen with photosensitizer within lysosomes enabled the production of cytotoxic singlet oxygen, resulting in more effective PDT.     

Innovative Strategies for Hypoxic‐Tumor Photodynamic Therapy

Despite its clinical promise, photodynamic therapy (PDT) suffers from a key drawback associated with its oxygen‐dependent nature, which limits its effective use against hypoxic tumors. Moreover, both PDT‐mediated oxygen consumption and microvascular damage further increase tumor hypoxia and, thus, impede therapeutic outcomes. In recent years, numerous investigations have focused on strategies for overcoming this drawback of PDT. These efforts, which are summarized in this review, have produced many innovative methods to avoid the limits of PDT associated with hypoxia.     

A Nanoscale Metal–Organic Framework to Mediate Photodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Enhance Antigen Presentation and Cancer Immunotherapy

Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale metal–organic framework, W-TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear W^VI secondary building units and photosensitizing 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) ligands, cationic W-TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.     

An Assembled Nanocomplex for Improving both Therapeutic Efficiency and Treatment Depth in Photodynamic Therapy

Photodynamic therapy (PDT) shows unique selectivity and irreversible destruction toward treated tissues or cells, but still has several problems in clinical practice. One is limited therapeutic efficiency, which is attributed to hypoxia in tumor sites. Another is the limited treatment depth because traditional photosensitizes are excited by short wavelength light (<700 nm). An assembled nano‐complex system composed of oxygen donor, two‐photon absorption (TPA) species, and photosensitizer (PS) was synthesized to address both problems. The photosensitizer is excited indirectly by two‐photon laser through intraparticle FRET mechanism for improving treatment depth. The oxygen donor, hemoglobin, can supply extra oxygen into tumor location through targeting effect for enhanced PDT efficiency. The mechanism and PDT effect were verified through both in vitro and in vivo experiments. The simple system is promising to promote two‐photon PDT for clinical applications.     

铁掺杂的聚2-硝基-1,4-苯二胺纳米球的制备及在光热/光动力/化学动力学肿瘤治疗中的应用

肿瘤微环境(TME)的复杂性,使得单一治疗方式很难实现完全治愈。 为此,构建了一种负载吲哚菁绿(ICG)的铁掺杂的聚2-硝基-1,4-苯二胺多功能纳米球Fe-PNPD-ICG(FPIs),用于光热(PTT)/光动力(PDT)/化学动力学(CDT)的联合治疗。 在808 nm激光器照射下,ICG作为光敏剂可以产生单线态氧,铁掺杂的聚2-硝基-1,4-苯二胺纳米球作为光热剂具有36.65%的光热转换效率。 FPIs一旦内化到肿瘤内,由Fe³⁺/Fe²⁺转化引发Fenton反应产生·OH实现化学动力学治疗,反应过程中可以清除TME中过表达的谷胱甘肽(GSH),从而降低肿瘤中的抗氧化能力。 同时,产生的氧气可以改善TME中乏氧情况,增强PDT的治疗效果。 因此,FPIs是PTT/PDT/CDT联合治疗的一种理想材料,在肿瘤治疗中具有潜在的应用前景。     

A mini review of nanomaterials on photodynamic therapy

In this account, the reactive oxygen species (ROS) in photodynamic therapy (PDT) were deliberately reviewed. First, the specific definition of ROS and PDT were readily clarified. Afterward, this review focuses on the fundamental principles and applications of PDT. Due to strong oxidation ability of radicals (e.g., •OH and O₂^•-) and non-radical (e.g., ¹O₂ and H₂O₂), these ROS would attack the in vitro and in vivo tumor cells, thus achieving the goal of cancer treatment. Then, ROS in PDT for cancer treatment was thoroughly reviewed, including the mechanism and photosensitizer (PS) selection (i.e., nanomaterials). Ultimately, emphasis was made on the challenges, research gap, and prospects of ROS in cancer treatment and critically discussed. Hopefully, this review can offer detailed theoretical guidance for the researchers who participate in the study regarding ROS in PDT.     

Boosting the photodynamic therapy efficiency with a mitochondria-targeted nanophotosensitizer

A nanophotosensitizer with outstanding mitochondrion-targeting ability was developed and the enhanced photodynamic therapy efficiency both in cancer cells and xenograft tumor models was successfully realized.     

Recent Progress in Boosted PDT Induced Immunogenic Cell Death for Tumor Immunotherapy

With the rapid development of materials science,photosensitive materials have been widely used in the field of immunogenic cell death(ICD),which was on account of the reactive oxygen species(ROS)generation by photosensitizer under light irradiation inducing cellular oxidative stress during the dying of cells.Considerable researches related to photodynamic therapy(PDT)induced ICD were conducted and exhibited brilliant performance in cancer immunotherapy.Herein,a variety of different strategies for PDT induced ICD have been summarized and discussed to provide researchers more inspiration for cancer immunotherapy.     

A Bifunctional Photosensitizer for Enhanced Fractional Photodynamic Therapy: Singlet Oxygen Generation in the Presence and Absence of Light

The photosensitized generation of singlet oxygen within tumor tissues during photodynamic therapy (PDT) is self‐limiting, as the already low oxygen concentrations within tumors is further diminished during the process. In certain applications, to minimize photoinduced hypoxia the light is introduced intermittently (fractional PDT) to allow time for the replenishment of cellular oxygen. This condition extends the time required for effective therapy. Herein, we demonstrated that a photosensitizer with an additional 2‐pyridone module for trapping singlet oxygen would be useful in fractional PDT. Thus, in the light cycle, the endoperoxide of 2‐pyridone is generated along with singlet oxygen. In the dark cycle, the endoperoxide undergoes thermal cycloreversion to produce singlet oxygen, regenerating the 2‐pyridone module. As a result, the photodynamic process can continue in the dark as well as in the light cycles. Cell‐culture studies validated this working principle in vitro.     

Targeted and Oxygen-Enriched Nanoplatform for Enhanced Photodynamic Therapy: In Vitro 2D Cell and 3D Spheroid Model Evaluation

Hypoxic microenvironment and limited penetration of photosensitizers within solid tumors are two crucial factors that restrict photodynamic therapy (PDT) efficacy. Herein, a new fluorinated mixed micelle ( M60@PFC-Ce6 ) is developed as a tumor-penetrating and oxygen-enriching nanoplatform, which consists of chlorin e6 (Ce6) and perfluorocarbons (PFCs) co-loaded into fluorinated micelles to relieve hypoxia conditions as well as folate as targeting ligand that facilitates the selective biodistribution within tumor solids. The incorporation of fluorinated copolymers into mixed micelles exhibits not only a great increase in the oxygen-loading capacity, but also improves the stability of liquid PFCs emulsion within micelles without leakage. M60@PFC-Ce6 shows excellent oxygen delivery capability, good intracellular reactive oxygen species (ROS) generation, and superior phototoxicity in vitro for both 2D monolayer of cells and 3D multicellular spheroid model. These results indicate the enriched oxygen delivery and increased cellular uptake resulting from folate-targeted ability to enhance ROS production and PDT efficacy. The penetration study of M60@PFC-Ce6 into a 3D spheroid confirms that small micellar size and folate-conjugation are beneficial for micelles to penetrate and accumulate within spheroids. Thus, a new nanoplatform with enriched oxygen-carrying amounts, better drug penetration, and stable micellar properties that relieve tumor hypoxia and improve PDT efficacy is provided.     

Luminescent,Oxygen‐Supplying,Hemoglobin‐Linked Conjugated Polymer Nanoparticles for Photodynamic Therapy

Photodynamic therapy (PDT) is a promising method for cancer treatment. Two parameters that influence the efficacy of PDT are the light source and oxygen supply. Herein, we prepared a system for PDT using hemoglobin (Hb)‐linked conjugated polymer nanoparticles (CPNs), which can luminesce and supply oxygen. Hb catalyzes the activation of luminol, the conjugated polymer poly[2‐methoxy‐5‐(2‐ethylhexyloxy)‐1,4‐phenylenevinylene] (MEH–PPV) nanoparticles can absorb the chemiluminescence of luminol through chemiluminescence resonance energy transfer (CRET) and then sensitize the oxygen supplied by Hb to produce reactive oxygen species that kill cancer cells. This system could be used for the controlled release of an anticancer prodrug. The system does not need an external light source and circumvents the insufficient level molecular oxygen under hypoxia. This work provides a proof‐of‐concept to explore smart and multifunctional nanoplatforms for phototherapy.     

Functional organic nanoparticles for photodynamic therapy

In recent years, cancer has been one of the leading causes of death in the world. Much effort has been devoted to developing cancer treatments. Photodynamic therapy (PDT) is a noninvasive therapeutic modality by combining the light of a specific wavelength, a photosensitizer (PS) and oxygen, which has been widely applied for the treatment of cancers. However, the application of PDT in clinic is greatly limited due to lack of tumor selectivity and often causing skin photosensitivity. The use of organic nanoparticles (NPs) as an advanced technology in the field of PDT shows a great promise to overcome these shortcomings. Therefore, in this review, we summarize several functional organic NPs as PS carriers that have been developed to enhance the efficacy of PDT against cancers.     

Highly Charged Ruthenium(II) Polypyridyl Complexes as Lysosome‐Localized Photosensitizers for Two‐Photon Photodynamic Therapy

Photodynamic therapy (PDT) is a noninvasive medical technique that has received increasing attention over the last years and been applied for the treatment of certain types of cancer. However, the currently clinically used PDT agents have several limitations, such as low water solubility, poor photostability, and limited selectivity towards cancer cells, aside from having very low two‐photon cross‐sections around 800 nm, which limits their potential use in TP‐PDT. To tackle these drawbacks, three highly positively charged ruthenium(II) polypyridyl complexes were synthesized. These complexes selectively localize in the lysosomes, an ideal localization for PDT purposes. One of these complexes showed an impressive phototoxicity index upon irradiation at 800 nm in 3D HeLa multicellular tumor spheroids and thus holds great promise for applications in two‐photon photodynamic therapy.     

Bioluminescence imaging of the response of rat gliosarcoma to ALA-PpIX-mediated photodynamic therapy

Photodynamic therapy (PDT) is a promising modality for the treatment of solid tumors that combines a photosensitizing agent and light to produce cytotoxic reactive oxygen species that lead to tumor cell death. The recent introduction of bioluminescence imaging (BLI), involving the use of the luciferase gene (luc) transferred into target tumor cells, followed by systemic administration of luciferin and detection of the emitted visible chemiluminescence photons, offers the potential for longitudinal imaging of tumor growth and therapeutic response in single animals. We demonstrate in this study the first results of the use of BLI to assess the response of an intracranial brain tumor model (9L rat gliosarcoma) to aminolevulinic acid (ALA)-mediated PDT. Complementary in vitro experiments with the luciferase-transfected 9L cells show that the decrease in the luminescent signal after PDT correlates with cell kill. In vivo imaging shows a decrease in the BLI signal from the tumor after ALA-PDT treatment, followed by tumor regrowth. Furthermore, preliminary studies using cells transfected with a hypoxia-responsive vector show an increase in bioluminescence within 4 h after Photofrin-mediated PDT, demonstrating the ability to observe stress-gene responses. These results suggest that BLI can be used to provide spatiotemporal information of intracranial brain tumor responses after PDT and may serve as a valuable response-endpoint measure.     

Endoperoxides Compounds for Highly Efficient Cancer Treatment under Hypoxia

Photodynamic therapy (PDT) for cancer treatment has garnered tremendous attention with its promising non-invasiveness, low side effects, and spatiotemporal selectivity. However, the hypoxic microenvironment in solid tumours remains a serious resistant factor to reducing the effects of PDT. Endoperoxides are successfully utilized as the chemical storage or supplier of singlet oxygen (¹O₂), the active substance for PDT in materials and other domains. Recent reports indicated that this type of compound could remarkably enhance the therapeutic effects of PDT under hypoxia. This concept mainly introduces a few representative endoperoxides and the outlook of their potent application for treating hypoxic cancer cells.