Phototherapeutic Agents Research Articles

The ‘click’ synthesis of new cytotoxic conjugate based on meso-arylporphyrin and Erlotinib

New phototherapeutic agents based on synthetic porphyrin- type tetrapyrroles and small-molecule-targeted tyrosine kinase inhibitor Erlotinib have been synthesized based on the scheme involving ‘click’ reaction between bis(4- azidophenyl)-containing zinc porphyrinate derivative and N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)- quinazoline. The final compound and its precursors were tested as potential photosensitizers for targeted photo- dynamic therapy (PDT), the conjugate having shown photoinduced cytotoxicity IC50 for NKE cells 0.86 ± 0.017 μm and for A431 cells 0.54 ± 0.011 μm.

BOPHY Derivatives as Phototherapeutic Agents for the Photodynamic Inactivation of Microorganisms

AbstractThe improvement of photodynamic inactivation (PDI) significantly depends on the development of new families of photosensitizers (PSs). In this sense, three BOPHY derivatives (BP, BP‐Br and BP‐I) were synthetized, studied, and compared to assess their antimicrobial photodynamic properties. BP is an interesting fluorescent probe for cell imaging, while the halogenated analogs (BP‐Br and BP‐I) are excellent oxygen photosensitizing agents. BP compound presented a fluorescence quantum yield close unity and showed no reactive oxygen species (ROS) production. In contrast, BP‐I did not show emission properties but exhibited a high production of ROS through both photodynamic mechanisms, generating singlet oxygen (type II) and superoxide radical anion (type I) under aerobic light irradiation. BP‐Br presented an adequate balance between ROS production and emission properties. The photokilling action and the binding to bacterial cells of these macrocycles were evaluated in vitro against methicillin‐resistant Staphylococcus aureus (MRSA) and Escherichia coli bacteria. Our results demonstrated that the halogenated BOPHY derivatives were effective PSs in inactivating MRSA using shorter irradiation periods. In addition, the antimicrobial action sensitized by these BOPHYs was potentiated by adding KI. The combination of halogenated BOPHY and KI led to a complete elimination of both Gram‐positive and Gram‐negative bacteria. Hence, BP‐Br and BP‐I prove to be potent broad‐spectrum antimicrobial PSs. To the best of our knowledge, this is the first time that BOPHY derivatives have been applied to photokill pathogenic microorganisms.

Tumor microenvironment ameliorative and adaptive nanoparticles with photothermal-to-photodynamic switch for cancer phototherapy

The notorious tumor microenvironment (TME) usually becomes more deteriorative during phototherapeutic progress that hampers the antitumor efficacy. To overcome this issue, we herein report the ameliorative and adaptive nanoparticles (TPASIC-PFH@PLGA NPs) that simultaneously reverse hypoxia TME and switch photoactivities from photothermal-dominated state to photodynamic-dominated state to maximize phototherapeutic effect. TPASIC-PFH@PLGA NPs are designed by incorporating oxygen-rich liquid perfluorohexane (PFH) into the intraparticle microenvironment to regulate the intramolecular motions of AIE photosensitizer TPASIC. TPASIC exhibits a unique aggregation-enhanced reactive oxygen species (ROS) generation feature. PFH incorporation affords TPASIC the initially dispersed state, thus promoting active intramolecular motions and photothermal conversion efficiency. While PFH volatilization leads to nanoparticle collapse and the formation of tight TPASIC aggregates with largely enhanced ROS generation efficiency. As a consequence, PFH incorporation not only currently promotes both photothermal and photodynamic efficacies of TPASIC and increases the intratumoral oxygen level, but also enables the smart photothermal-to-photodynamic switch to maximize the phototherapeutic performance. The integration of PFH and AIE photosensitizer eventually delivers more excellent antitumor effect over conventional phototherapeutic agents with fixed photothermal and photodynamic efficacies. This study proposes a new nanoengineering strategy to ameliorate TME and adapt the treatment modality to fit the changed TME for advanced antitumor applications.

Dual Photoreactive Ternary Ruthenium(II) Terpyridyl Complexes: A Comparative Study on Visible-Light-Induced Single-Step Dissociation of Bidentate Ligands and Generation of Singlet Oxygen.

The versatile and tunable ligand-exchange dynamics in ruthenium(II)-polypyridyl complexes imposed by the modulation of the steric and electronic effects of the coordinated ligands provide an unlimited scope for developing phototherapeutic agents. The photorelease of a bidentate ligand from the Ru-center is better suited for potent Ru(II)-based photocytotoxic agents with two available labile sites for cross-linking with biological targets augmented with possible phototriggered 1O2 generation. Herein, we introduced a phenyl-terpyridine (ptpy) ligand in the octahedral Ru(II) core of [Ru(ptpy)(L-L)Cl]+ to induce structural distortion for the possible photorelease of electronically distinct bidentate ligands (L-L). For a systematic study, we designed four Ru(II) polypyridyl complexes: [Ru(ptpy)(L-L)Cl](PF6), ([1]-[4]), where L-L = 1,2-bis(phenylthio)ethane (SPH) [1], N,N,N',N'-tetramethylethylenediamine (TMEN) [2], N1,N2-diphenylethane-1,2-diimine (BPEDI) [3], and bis[2-(diphenylphosphino)phenyl]ether (DPE-Phos) [4]. The detailed photochemical studies suggest a single-step dissociation of L-L from the bis-thioether (SPH) complex [1] and diamine (TMEN) complex [2], while no photosubstitution was observed for [3] and [4]. Complex [1] and [2] demonstrated a dual role, involving both photosubstitution and 1O2 generation, while [3] and [4] solely exhibited poor to moderate 1O2 production. The interplay of excited states leading to these behaviors was rationalized from the lifetimes of the 3MLCT excited states by using transient absorption spectroscopy, suggesting intricate relaxation dynamics and 1O2 generation upon excitation. Therefore, the photolabile complexes [1] and [2] could potentially act as dual photoreactive agents via the phototriggered release of L-L (PACT) and/or 1O2-mediated PDT mechanisms, while [4] primarily can be utilized as a PDT agent.

Harnessing Dual Phototherapy and Immune Activation for Cancer Treatment: The Development and Application of BODIPY@F127 Nanoparticles.

Conventional phototherapeutic agents are typically used in either photodynamic therapy (PDT) or photothermal therapy (PTT). However, efficacy is often hindered by hypoxia and elevated levels of heat shock proteins in the tumor microenvironment (TME). To address these limitations, a formylated, near-infrared (NIR)-absorbing and heavy-atom-free Aza-BODIPY dye is presented that exhibits both type-I and type-II PDT actions with a high yield of reactive oxygen species (ROS) and manifests efficient photothermal conversion by precise adjustments to the conjugate structure and electron distribution, leading to a large amount of ROS production even under severe hypoxia. To improve biosafety and water solubility, the dye with an amphiphilic triblock copolymer (Pluronic F-127), yielding BDP-6@F127 nanoparticles (NPs) is coated. Furthermore, inspired by the fact that phototherapy triggers the release of tumor-associated antigens, a strategy that leverages potential immune activation by combining PDT/PTT with immune checkpoint blockade (ICB) therapy to amplify the systemic immune response and achieve the much-desired abscopal effect is developed. In conclusion, this study presents a promising molecular design strategy that integrates multimodal therapeutics for a precise and effective approach to cancer therapy.

"Rigid-Flexible" Dual-Ferrocene Chimeric Nanonetwork for Simultaneous Tumor-Targeted Tracing and Photothermal/Photodynamic Therapy.

There is an urgent need to develop phototherapeutic agents with imaging capabilities to assess the treatment process and efficacy in real-time during cancer phototherapy for precision cancer therapy. The safe near-infrared (NIR) fluorescent dyes have garnered significant attention and are desirable for theranostics agents. However, until now, achieving excellent photostability and fluorescence (FL) imaging capability in aggregation-caused quenching (ACQ) dyes remains a big challenge. Here, for the only FDA-approved NIR dye, indocyanine green (ICG), we developed a dual-ferrocene (Fc) chimeric nanonetwork ICG@HFFC based on the rigid-flexible strategy through one-step self-assembly, which uses rigid Fc-modified hyaluronic acid (HA) copolymer (HA-Fc) and flexible octadecylamine (ODA) bonded Fc (Fc-C18) as the delivery system. HA-Fc reserved the ability of HA to target the CD44 receptor of the tumor cell surface, and the dual-Fc region provided a rigid space for securely binding ICG through metal-ligand interaction and π-π conjugation, ensuring excellent photostability. Additionally, the alkyl chain provided flexible confinement for the remaining ICG through hydrophobic forces, preserving its FL. Thereby, a balance is achieved between outstanding photostability and FL imaging capability. In vitro studies showed improved photobleaching resistance, enhanced FL stability, and increased singlet oxygen (1O2) production efficiency in ICG@HFFC. Further in vivo results display that ICG@HFFC had good tumor tracing ability and significant tumor inhibition which also exhibited good biocompatibility.. Therefore, ICG@HFFC provides an encouraging strategy to realize simultaneous enhanced tumor tracing and photothermal/photodynamic therapy (PTT/PDT) and offers a novel approach to address the limitations of ACQ dyes.

Applications of nanomedicine-integrated phototherapeutic agents in cancer theranostics: A comprehensive review of the current state of research

Abstract Innovative approaches such as photodynamic therapy (PDT) and photothermal therapy (PTT) have made nanomedicines a promising frontier in cancer theranostics. The combination of nanocarriers with photothermal agents and photosensitizers (PSs) has shown excellent promise for the diagnosis and the treatment of cancer, primarily at the cellular, vascular, and tumor microenvironment level. Using nanocarriers in PDT has revolutionized precision and efficacy, allowing the drug to reach cancer cells faster and offering high enhancing PS accumulation. These agents are activated by light of specific wavelengths, leading to localized cytotoxicity, offering highly selective cancer therapy. Nanomaterials such as gold and silver nanoparticles have enabled remarkable progress in cancer hyperthermia using PTT. The unique optical properties of these nanoparticle-based nanomedicines make them ideal candidates for converting light energy into heat, selectively ablating the cancer cells. In this review, nanomedicine-integrated phototherapeutic agents are discussed and the most important recent developments in PDT and PTT are examined, as well as how nanoparticle-based formulations improve diagnosis and treatment. In addition, nanocarriers used in cancer phototherapy and their mode of action are discussed. Nanocarriers are useful for drug delivery as well as for imaging and diagnostic purposes during cancer treatment. In this review, we explore the role of nanoparticles in improving phototherapy precision and selectivity while minimizing collateral tissue damage. It specifies a comprehensive impression of the current research on cancer therapy, underscoring its potential to revolutionize the treatment paradigm by highlighting the current state of research.

Magnetic graphene oxide functionalized alginate-g-poly(2-hydroxypropylmethacrylamide) nanoplatform for near-infrared light/pH/magnetic field-sensitive drug release and chemo/phototherapy

Multifunctional nanoplatforms developed from natural polymers and graphene oxide (GO) with enhanced biological/physicochemical features have recently attracted attention in the biomedical field. Herein, a new multifunctional near-infrared (NIR) light-, pH- and magnetic field-sensitive hybrid nanoplatform (mGO@AL-g-PHPM@ICG/EP) is developed by combining iron oxide decorated graphene oxide nanosheets (mGO) and poly(2-hydroxypropylmethacrylamide) grafted alginate (AL-g-PHPM) copolymer loaded with indocyanine green (ICG) and etoposide (EP) for chemo/phototherapy. The functional groups, specific crystal structure, size, morphology, and thermal stability of the nanoplatform were fully characterized by XRD, UV, FTIR, AFM/TEM/FE-SEM, VSM, DSC/TG, and BET analyses. In this platform, the mGO and ICG, as phototherapeutic agents, demonstrate excellent thermal effects and singlet oxygen production under NIR-light (808 nm) irradiation. The XRD and DSC analysis confirmed the amorphous state of the ICG/EP in the nanoparticles. In vitro photothermal tests proved that the mGO@AL-g-PHPM@ICG/EP nanoparticles had outstanding light stability and photothermal conversion ability. The in vitro release profiles presented NIR light-, pH- and magnetic field-controlled EP/ICG release behaviors. In vitro experiments demonstrated the excellent antitumor activity of the mGO@AL-g-PHPM@ICG/EP against H1299 tumor cells under NIR laser. Benefiting from its low-cost, facile preparation, and good dual-modal therapy, the mGO@AL-g-PHPM@ICG/EP nanoplatform holds great promise in multi-stimuli-sensitive drug delivery and chemo/phototherapy.

Photoactivated theranostic nanomaterials based on aggregation‐induced emission luminogens for cancer photoimmunotherapy

AbstractIn this study, a series of high liposoluble near‐infrared emissive aggregation‐induced emission luminogens with triphenylamine derivatives as donor units and 1‐indanone as electron acceptor units are developed. Specifically, MTTOI has promising lipid droplets targeting ability and viscosity‐response characteristics, and it can monitor the viscosity fluctuations in living cells in real time. It is found that MTTOI is able to fulfill the activation of the apoptosis‐related signaling pathways under white light, and it can also activate the ferroptosis to synergize apoptosis resulting in tumor elimination. Interestingly, the occurrence of ferroptosis is positively related to the enhancement of immunogenic cell‐death effect, thus boosting the tumor infiltration of CD8+ T cells and reducing the proportion of regulatory T cells by cooperating with dendritic cells, which can not only carry out primary antitumor treatment, but also prevent tumor metastasis through strong immunological memory effect. Moreover, in vivo experimental results confirm that MTTOI successfully effectuates fatty liver tissue imaging. MTTOI fluorescence signals can be captured at the tumor site after 3 days of administration due to its high fat‐solubility and ease of fusion with tumors. This classic example could promote the further development of phototherapeutic agents in preclinical research and clinical applications.

Multimodal phototherapy agents target lipid droplets for near-infrared imaging-guided type I photodynamic/photothermal therapy

The construction and optimization of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy (PDT), and photothermal therapy (PTT) functions remain challenging. In this study, we aimed to design and synthesize four donor–acceptor (D-A) type aggregation-induced emission molecules: PSI, TPSI, PSSI, and TPSSI. We employed phenothiazine as an electron donor and 1,3-bis(dicyanomethylidene)indan as a strong electron acceptor in the synthesis process. Among them, TPSSI exhibited efficient type I reactive oxygen species generation, high photothermal conversion efficiency (45.44 %), and near-infrared emission. These observations can be attributed to the introduction of a triphenylamine electron donor group and a thiophene unit, which resulted in increased D–A strengths, a reduced singlet-triplet energy gap, and increased free intramolecular motion. TPSSI was loaded into bovine serum albumin to prepare biocompatible TPSSI nanoparticles (NPs). Our results have indicated that TPSSI NPs can target lipid droplets with negligible dark toxicity and can efficiently generate O2•− in hypoxic tumor environments. Moreover, TPSSI NPs selectively targeted 4T1 tumor tissues and exhibited a good PDT-PTT synergistic effect in vitro and in vivo. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technologies. Statement of SignificanceThe construction of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy, and photothermal therapy functions, and its optimization remain challenging. In this study, we construct four donor–acceptor aggregation-induced emission molecules using phenothiazine as an electron donor and 1,3-Bis(dicyanomethylidene)indan as a strong electron acceptor. By optimizing the molecular structure, an integrated phototherapy agent with fluorescence imaging ability and high photodynamic / photothermal therapy performance was prepared. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technology.

Modulation of the skin microbiome in cutaneous T-cell lymphoma delays tumour growth and increases survival in the murine EL4 model.

Cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders of skin-homing T cells causing chronic inflammation. These disorders cause impairment of the immune environment, which leads to severe infections and/or sepsis due to dysbiosis. In this study, we elucidated the host-microbial interaction in CTCL that occurs during the phototherapeutic treatment regime and determined whether modulation of the skin microbiota could beneficially affect the course of CTCL. EL4 T-cell lymphoma cells were intradermally grafted on the back of C57BL/6 mice. Animals were treated with conventional therapeutics such as psoralen + UVA (PUVA) or UVB in the presence or absence of topical antibiotic treatment (neomycin, bacitracin, and polymyxin B sulphate) as an adjuvant. Microbial colonisation of the skin was assessed to correlate with disease severity and tumour growth. Triple antibiotic treatment significantly delayed tumour occurrence (p = 0.026), which prolonged the survival of the mice (p = 0.033). Allocation to phototherapeutic agents PUVA, UVB, or none of these, along with antibiotic intervention, reduced the tumour growth significantly (p = 0.0327, p ≤ 0.0001, p ≤ 0.0001 respectively). The beta diversity indices calculated using the Bray-Curtis model showed that the microbial population significantly differed after antibiotic treatment (p = 0.001). Upon modulating the skin microbiome by antibiotic treatment, we saw an increase in commensal Clostridium species, e.g., Lachnospiraceae sp. (p = 0.0008), Ruminococcaceae sp. (p = 0.0001)., Blautia sp. (p = 0.007) and a significant reduction in facultative pathogens Corynebacterium sp. (p = 0.0009), Pelomonas sp. (p = 0.0306), Streptococcus sp. (p ≥ 0.0001), Pseudomonas sp. (p = 0.0358), and Cutibacterium sp. (p = 0.0237). Intriguingly, we observed a significant decrease in Staphylococcus aureus frequency (p = 0.0001) but an increase in the overall detection frequency of the Staphylococcus genus, indicating that antibiotic treatment helped regain the microbial balance and increased the number of non-pathogenic Staphylococcus populations. These study findings show that modulating microbiota by topical antibiotic treatment helps to restore microbial balance by diminishing the numbers of pathogenic microbes, which, in turn, reduces chronic inflammation, delays tumour growth, and increases survival rates in our CTCL model. These findings support the rationale to modulate the microbial milieu during the disease course of CTCL and indicate its therapeutic potential.

Carbon Dots an Integrative Nanostructure for Fluorescent Bio-imaging, Targeted Delivery of Medication and Phototherapy in Malignancy: A Review

Background: Silent onset and metastasis in tissues make cancer the most devastating illness globally. Monitoring the growth of the tumour and delivering drugs to specific tissues are some of the major issues associated with treatment. However, with an improved understanding of tumour microenvironments and advancements in nanocarriers of drugs, novel nano-targeting pathways that can be utilised by nanocarriers have been developed. Carbon Dots, with their tiny size and outstanding physicochemical features, are an emerging category of carbon nanostructures that have attracted a lot of curiosity. Objective: Multitudinous attempts and extensive studies have been undertaken by many researchers regarding the synthesis of Carbon Dots and their applications in various fields. These studies have explained that the synthesised Carbon Dots have versatile surface functionalities, high luminescence, and excellent biocompatibility. This article focuses on recent developments in synthesis approaches, carbon precursors used, and applications of Carbon Dots, specifically within the biomedical field, with a particular focus on cancer. Results: Carbon dots synthesised from a variety of precursors can act as prominent candidates for bioimaging and drug carriers and are used in cancer phototherapy. In this article, Carbon Dots are summarised based on their bright luminescent properties, distinct structure, drug loading capacity, and near-infrared (NIR) emission. Conclusion: Carbon dots, employed as tumour theranostics, can serve as an alternative to synthetic fluorescent dyes. They fulfil the role of bioimaging agents and facilitate the precise delivery of drugs to cancer cells. Additionally, they exhibit excellence as phototherapeutic agents, featuring high nearinfrared (NIR) emission and minimal side effects.

Photodynamic Therapy with Targeted Release of Boron-Dipyrromethene Dye from Cobalt(III) Prodrugs in Red Light.

Boron-dipyrromethene (BODIPY) dyes are promising photosensitizers for cellular imaging and photodynamic therapy (PDT) owing to their excellent photophysical properties and the synthetically tunable core. Metalation provides a convenient way to overcome the drawbacks arising from their low aqueous solubility. New photo-/redox-responsive Co(III) prodrug chaperones are developed as anticancer PDT agents for efficient cellular delivery of red-light-active BODIPY dyes. The photobiological activity of heteroleptic Co(III) complexes derived from tris(2-pyridylmethyl)amine (TPA) and acetylacetone-conjugated PEGylated distyryl BODIPY (HL1) or its dibromo analogue (HL2), [CoIII(TPA)(L1/L2)](ClO4)2 (1 and 2), are investigated. The Co(III)/Co(II) redox potential is tuned using the Co(III)-TPA scaffold. Complex 1 displays the in vitro release of BODIPY on red light irradiation. Complex 2, having good singlet oxygen quantum yield (ΦΔ ∼ 0.28 in DMSO), demonstrates submicromolar photocytotoxicity to HeLa cancer cells (IC50 ≈ 0.23 μM) while being less toxic to HPL1D normal cells in red light. Cellular imaging using the emissive complex 1 shows mitochondrial localization and significant penetration into the HeLa tumor spheroids. Complex 2 shows supercoiled DNA photocleavage activity and apoptotic cell death through phototriggered generation of reactive oxygen species. The Co(III)-BODIPY prodrug conjugates exemplify new type of phototherapeutic agents with better efficacy than the organic dyes alone in the phototherapeutic window.

Supramolecular phthalocyanine assemblies‐enhanced synergistic photodynamic and photothermal therapy guided by photoacoustic imaging

AbstractPhototherapeutic nanoplatforms that combine photodynamic therapy (PDT) and photothermal therapy (PTT) with the guidance of photoacoustic (PA) imaging are an effective strategy for the treatment of tumors, but establishing a universal method for this strategy has been challenging. In this study, we present a supramolecular assembly strategy based on Förster resonance energy transfer to construct a supramolecular nanostructured phototherapeutic agent (PcDA) via the anion and cation supramolecular interaction between two water‐soluble phthalocyanine ramifications, PcD and PcA. This approach promotes the absorption of energy, thus enhancing the generation of reactive oxygen species (ROS) and heat by PcDA, improving its therapeutic efficacy, and overcoming the low photon utilization efficiency of conventional PSs. Notably, after the intravenous injection of PcDA, neoplastic sites could be clearly visualized using PA imaging, with a PA signal‐to‐liver ratio as high as 11.9. Due to these unique features, PcDA exhibits excellent antitumor efficacy in a preclinical model at a low dose of light irradiation. This study thus offers a general approach for the development of efficient phototherapeutic agents based on the simultaneous effect of PDT and PTT against tumors with the assistance of PA imaging.

SÍNTESE, FOTORREATIVIDADE E INTERAÇÃO COM DNA DE UM NOVO COMPLEXO DE RUTÊNIO PROTÓTIPO PARA O DESENVOLVIMENTO DE AGENTES FOTOQUIMIOTERAPÊUTICOS

SYNTHESIS, PHOTOREACTIVITY AND INTERACTION WITH DNA OF A NEW PROTOTYPE RUTHENIUM COMPLEX FOR THE DEVELOPMENT OF PHOTOCHEMOTHERAPEUTIC AGENTS. A new ruthenium polypyridine complex, cis-[Ru(bpy)2(1- meimN)(4-pyCHO)](PF6)2 (WP1), where 1-meimN and pyCHO are the ligands 1-methylimidazole and 4-pyridinecarboxaldehyde, respectively, was prepared as a prototype for use in phototherapeutic process. This compound was characterized by electronic absorption in UV-Visible, FTIR, 1H and 13C NMR, cyclic voltammetry, besides DFT that supported its molecular structure. The compound WP1 was photoreactive, where blue or green light promoted the release of 4-pyCHO ligand. Additionally, this compound was able to interact with DNA, mainly through electrostatic interactions showing photoinduced nuclease activity. There is also photoproduction of superoxide ions using blue or green light suggesting a route for DNA damage. These promising results opened new opportunities for the potential use of this system and analogues as phototherapeutic agents, which is an ongoing study in our lab.

Boosted photo-immunotherapy via near-infrared light excited phototherapy in tumor sites and photo-activation in sentinel lymph nodes.

Phototherapy is a promising modality that could eradicate tumor and trigger immune responses via immunogenic cell death (ICD) to enhance anti-tumor immunity. However, due to the lack of deep-tissue-excitable phototherapeutic agents and appropriate excitation strategies, the utility of phototherapy for efficient activation of the immune system is challenging. Herein, we report functionalized ICG nanoparticles (NPs) with the capture capability of tumor-associated antigens (TAAs). Under near-infrared (NIR) light excitation, the ICG NPs exhibited high-performance phototherapy, i.e., synergistic photothermal therapy and photodynamic therapy, thereby efficiently eradicating primary solid tumor and inducing ICD and subsequently releasing TAAs. The ICG NPs also captured TAAs and delivered them to sentinel lymph nodes, and then the sentinel lymph nodes were activated with NIR light to trigger efficient T-cell immune responses through activation of dendritic cells with the assistance of ICG NP generated reactive oxygen species, inhibiting residual primary tumor recurrence and controlling distant tumor growth. The strategy of NIR light excited phototherapy in tumor sites and photo-activation in sentinel lymph nodes provides a powerful platform for active immune systems for anti-tumor photo-immunotherapy.

Progress of cell membrane-derived biomimetic nanovesicles for cancer phototherapy.

In recent years, considerable attention has been given to phototherapy, including photothermal and photodynamic therapy to kill tumor cells by producing heat or reactive oxygen species (ROS). It has the high merits of noninvasiveness and limited drug resistance. To fully utilize this therapy, an extraordinary nanovehicle is required to target phototherapeutic agents in the tumor cells. Nanovesicles embody an ideal strategy for drug delivery applications. Cell membrane-derived biomimetic nanovesicles represent a developing type of nanocarrier. Combining this technique with cancer phototherapy could enable a novel strategy. Herein, efforts are made to describe a comprehensive overview of cell membrane-derived biomimetic nanovesicles for cancer phototherapy. The description in this review is mainly based on representative examples of exosome-derived biomimetic nanomedicine research, ranging from their comparison with traditional nanocarriers to extensive applications in cancer phototherapy. Additionally, the challenges and future prospectives for translating these for clinical application are discussed.

Glucose oxidase and ruthenium nanorods-embedded self-healing polyvinyl alcohol/polyethylene imine hydrogel for simultaneous photothermal/photodynamic/starvation therapy and skin reconstruction

Tumor recurrence and wound healing represent significant burdens for tumor patients after the surgical removal of melanomas. Wound dressings with wound healing and anticancer therapeutic abilities could help to solve these issues. Thus, a hybrid hydrogel made of polyvinyl alcohol (PVA) and polyethylene imine (PEI) was prepared by cross-linking imine bond and boronic acid bond. This hydrogel was loaded with ruthenium nanorods (Ru NRs) and glucose oxidase (GOx) and named as nanocomposite hydrogel (Ru/GOx@Hydrogel), exhibiting remarkable photothermal/photodynamic/starvation antitumor therapy and wound repair abilities. Ru NRs are bifunctional phototherapeutic agents that simultaneously exhibit intrinsic photothermal and photodynamic functions. Three-dimensional composite hydrogel loaded with GOx can also consume glucose in the presence of O2 during tumor starvation therapy. Near-infrared (NIR) light-triggered hyperthermia can not only promote the consumption of glucose, but also facilitate the ablation of residual cancer cells. The antitumor effect of the Ru/GOx@Hydrogel resulted in significant improvements, compared to those observed with either phototherapy or starvation therapy alone. Additionally, the postoperative wound was substantially healed after treatment with Ru/GOx@Hydrogel and NIR irradiation. Therefore, the Ru/GOx@Hydrogel can be used as a multi-stimulus-responsive nanoplatform that could facilitate on-demand controlled drug release, and be used as a promising postoperative adjuvant in combination therapy.

The influence of the reducing agent used during the synthesis of gelatin-coated gold nanorods on its thermal properties for photothermal application

The development of Gold nanorods (AuNRs) as phototherapeutic agents (PTAs) has attracted much interest from researchers in recent decades. The majority of their synthetic methods use Hydroquinone (HQ) and Ascorbic acid (AA) as the reducing agent, and these have been shown to affect the properties of AuNRs. However, no study has been conducted on how these two reducing reagents can affect their application, especially after coating. Therefore, we herein report a seed-mediated synthesis of AuNRs using two reducing agents and coating them with gelatin at different volume ratios (1:5, 1:2, 1:1,2:1, and 5:1). The HQ-reduced AuNRs and AA-reduced AuNRs absorbed at TSPR of 512 nm and 514 nm and LSPR of 914 nm and 847 nm, respectively. The gelatin-coated HQ-reduced and AA-reduced AuNRs did not show significant LSPR wavelength changes for all the volume ratios. However, a slight increase in the TSPR and the absorbance at regions below 550 nm was seen for volume ratios 1:1, 2:1, and 5:1. The thermal stability studies at 70 ℃ for the coated materials revealed that AA-reduced AuNRs were more thermally stable than HQ-reduced AuNRs, with the less optical shift. The coated AA-reduced AuNRs were further tested for photothermal responses. The results show that the high gelatin volume during coating affects the photothermal response of the AuNRs. This study indicates volume ratio of 1:5 and 1:2 has good stability while maintaining the good photothermal profiling needed in PTT applications. Hence Gel@AuNRs synthesised with AA is an excellent PTT agent for phototherapy applications.

Antitumor Immunity Mediated by Photodynamic Therapy Using Injectable Chitosan Hydrogels for Intratumoral and Sustained Drug Delivery.

Photodynamic therapy (PDT) is an anticancer therapy with proven efficacy; however, its application is often limited by prolonged skin photosensitivity and solubility issues associated with the phototherapeutic agents. Injectable hydrogels which can effectively provide intratumoral delivery of photosensitizers with sustained release are attracting increased interest for photodynamic cancer therapies. However, most of the hydrogels for PDT applications are based on systems with high complexity, and often, preclinical validation is not provided. Herein, we provide a simple and reliable pH-sensitive hydrogel formulation that presents appropriate rheological properties for intratumoral injection. For this, Temoporfin (m-THPC), which is one of the most potent clinical photosensitizers, was chemically modified to introduce functional groups that act as cross-linkers in the formation of chitosan-based hydrogels. The introduction of -COOH groups resulted in a water-soluble derivative, named PS2, that was the most promising candidate. Although PS2 was not internalized by the target cells, its extracellular activation caused effective damage to the cancer cells, which was likely mediated by lipid peroxidation. The injection of the hydrogel containing PS2 in the tumors was monitored by high-frequency ultrasounds and in vivo fluorescence imaging which confirmed the sustained release of PS2 for at least 72 h. Following local administration, light exposure was conducted one (single irradiation protocol) or three (multiple irradiation protocols) times. The latter delivered the best therapeutic outcomes, which included complete tumor regression and systemic anticancer immune responses. Immunological memory was induced as ∼75% of the mice cured with our strategy rejected a second rechallenge with live cancer cells. Additionally, the failure of PDT to treat immunocompromised mice bearing tumors reinforces the relevance of the host immune system. Finally, our strategy promotes anticancer immune responses that lead to the abscopal protection against distant metastases.