Rational design of an “all-in-one” phototheranostic

We report here porphodilactol derivatives and their corresponding metal complexes. These systems show promise as “all-in-one” phototheranostics and are predicated on a design strategy that involves controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation. The requisite balance was achieved by tuning the aromaticity of these porphyrinoid derivatives and forming complexes with one of two lanthanide cations, namely Gd³⁺ and Lu³⁺. The net result led to a metalloporphodilactol system, Gd-trans-2, with seemingly optimal ISC efficiency, photothermal conversion efficiency and fluorescence properties, as well as good chemical stability. Encapsulation of Gd-trans-2 within mesoporous silica nanoparticles (MSN) allowed its evaluation for tumour diagnosis and therapy. It was found to be effective as an “all-in-one” phototheranostic that allowed for NIR fluorescence/photoacoustic dual-modal imaging while providing an excellent combined PTT/PDT therapeutic efficacy in vitro and in vivo in 4T1-tumour-bearing mice.

We report here porphodilactol derivatives and their corresponding metal complexes as “all-in-one” phototheranostics by controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation.     

Regulation of redox balance using a biocompatible nanoplatform enhances phototherapy efficacy and suppresses tumor metastasis

Many cancer treatments including photodynamic therapy (PDT) utilize reactive oxygen species (ROS) to kill tumor cells. However, elevated antioxidant defense systems in cancer cells result in resistance to the therapy involving ROS. Here we describe a highly effective phototherapy through regulation of redox homeostasis with a biocompatible and versatile nanotherapeutic to inhibit tumor growth and metastasis. We systematically explore and exploit methylene blue adsorbed polydopamine nanoparticles as a targeted and precise nanocarrier, oxidative stress amplifier, photodynamic/photothermal agent, and multimodal probe for fluorescence, photothermal and photoacoustic imaging to enhance anti-tumor efficacy. Remarkably, following the glutathione-stimulated photosensitizer release to generate exogenous ROS, polydopamine eliminates the endogenous ROS scavenging system through depleting the primary antioxidant, thus amplifying the phototherapy and effectively suppressing tumor growth in vitro and in vivo. Furthermore, this approach enables a robust inhibition against breast cancer metastasis, as oxidative stress is a vital impediment to distant metastasis in tumor cells. Innovative, safe and effective nanotherapeutics via regulation of redox balance may provide a clinically relevant approach for cancer treatment.

Amplified oxidative stress achieved by modulating redox homeostasis with PDA–MB for highly effective synergistic phototherapy to inhibit primary tumors and metastases.     

Recent advances of AIE light-up probes for photodynamic therapy

As a new non-invasive treatment method, photodynamic therapy (PDT) has attracted great attention in biomedical applications. The advantages of possessing fluorescence for photosensitizers have made it possible to combine imaging and diagnosis together with PDT. The unique features of aggregation-induced emission (AIE) fluorogens provide new opportunities for facile design of light-up probes with high signal-to-noise ratios and improved theranostic accuracy and efficacy for image-guided PDT. In this review, we summarize the recent advances of AIE light-up probes for PDT. The strategies and principles to design AIE photosensitizers and light-up probes are firstly introduced. The application of AIE light-up probes in photodynamic antitumor and antibacterial applications is further elaborated in detail, from binding/targeting-mediated, reaction-mediated, and external stimuli-mediated light-up aspects. The challenges and future perspectives of AIE light-up probes in the PDT field are also presented with the hope to encourage more promising developments of AIE materials for phototheranostic applications and translational research.

AIE fluorogens provide new opportunities for the development of light-up probes for photodynamic therapy.     

Supramolecular agents for combination of photodynamic therapy and other treatments

Photodynamic therapy (PDT) is a promising treatment for cancers such as superficial skin cancers, esophageal cancer, and cervical cancer. Unfortunately, PDT often does not have sufficient therapeutic benefits due to its intrinsic oxygen dependence and the limited permeability of irradiating light. Side effects from “always on” photosensitizers (PSs) can be problematic, and PDT cannot treat tumor metastases or recurrences. In recent years, supramolecular approaches using non-covalent interactions have attracted attention due to their potential in PS development. A supramolecular PS assembly could be built to maximize photodynamic effects and minimize side effects. A combination of two or more therapies can effectively address shortcomings while maximizing the benefits of each treatment regimen. Using the supramolecular assembly, it is possible to design a multifunctional supramolecular PS to exert synergistic effects by combining PDT with other treatment methods. This review provides a summary of important research progress on supramolecular systems that can be used to combine PDT with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT, and it provides an overview of the prospects for future cancer treatment advances and clinical applications.

This review provides a summary of important research progress on supramolecular systems that can be used to combine photodynamic therapy (PDT) with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT.     

A plasmon-enhanced theranostic nanoplatform for synergistic chemo-phototherapy of hypoxic tumors in the NIR-II window

Development of simple and effective synergistic therapy by combination of different therapeutic modalities within one single nanostructure is of great importance for cancer treatment. In this study, by integrating the anticancer drug DOX and plasmonic bimetal heterostructures into zeolitic imidazolate framework-8 (ZIF-8), a stimuli-responsive multifunctional nanoplatform, DOX-Pt-tipped Au@ZIF-8, has been successfully fabricated. Pt nanocrystals with catalase-like activity were selectively grown on the ends of the Au nanorods to form Pt-tipped Au NR heterostructures. Under single 1064 nm laser irradiation, compared with Au NRs and Pt-covered Au NRs, the Pt-tipped Au nanorods exhibit outstanding photothermal and photodynamic properties owing to more efficient plasmon-induced electron–hole separation. The heat generated by laser irradiation can enhance the catalytic activity of Pt and improve the O₂ level to relieve tumor hypoxia. Meanwhile, the strong absorption in the NIR-II region and high-Z elements (Au, Pt) of the DOX-Pt-tipped Au@ZIF-8 provide the possibility for photothermal (PT) and computed tomography (CT) imaging. Both in vitro and in vivo experimental results illustrated that the DOX-Pt-tipped Au@ZIF-8 exhibits remarkably synergistic plasmon-enhanced chemo-phototherapy (PTT/PDT) and successfully inhibited tumor growth. Taken together, this work contributes to designing a rational theranostic nanoplatform for PT/CT imaging-guided synergistic chemo-phototherapy under single laser activation.

A plasmon-enhanced theranostic nanoplatform for synergistic chemo-phototherapy (PTT/PDT) of hypoxic tumors in the NIR-II window.     

Coupling molecular rigidity and flexibility on fused backbones for NIR-II photothermal conversion

Great attention is being increasingly paid to photothermal conversion in the near-infrared (NIR)-II window (1000–1350 nm), where deeper tissue penetration is favored. To date, only a limited number of organic photothermal polymers and relevant theory have been exploited to direct the molecular design of polymers with highly efficient photothermal conversion, specifically in the NIR-II window. This work proposes a fused backbone structure locked via an intramolecular hydrogen bonding interaction and double bond, which favors molecular planarity and rigidity in the ground state and molecular flexibility in the excited state. Following this proposal, a particular class of NIR-II photothermal polymers are prepared. Their remarkable photothermal conversion efficiency is in good agreement with our strategy of coupling polymeric rigidity and flexibility, which accounts for the improved light absorption on going from the ground state to the excited state and nonradiative emission on going from the excited state to the ground state. It is envisioned that such a concept of coupling polymeric rigidity and flexibility will offer great inspiration for developing NIR-II photothermal polymers with the use of other chromophores.

Low bandgap and large deformation generally conflict each other. This work couples molecular rigidity and flexibility by intramolecular hydrogen bonds and double bonds to achieve NIR-II light absorption and reinforced internal conversion at the same time.     

A pH-responsive ultrathin Cu-based nanoplatform for specific photothermal and chemodynamic synergistic therapy

Noninvasive tumor therapy requires a new generation of bionanomaterials towards sensitive response to the unique tumor microenvironment to achieve accurate and effective treatment. Herein, we have developed a tumor therapy nanoplatform by immobilizing natural glucose oxidase (GOD) onto Cu-based layered double hydroxide (CuFe-LDH) nanosheets, which for the first time integrates acid-enhanced photothermal therapy (PTT), and pH-responsive and heat-facilitated chemodynamic therapy (CDT) simultaneously. As demonstrated by EXAFS and HRTEM, CuFe-LDH nanosheets possess a considerable number of defects caused by different acid conditions, resulting in a significantly acid-enhanced photothermal conversion efficiency (83.2% at pH 5.4 vs. 46.0% at pH 7.4). Moreover, GOD/CuFe-LDH nanosheets can convert a cascade of glucose into hydroxyl radicals (˙OH) under tumor acid conditions, which is validated by a high maximum velocity (V_max = 2.00 × 10⁻⁷ M) and low Michaelis–Menten constant (K_M = 12.01 mM). With the combination of PTT and CDT, the tumor tissue in vivo is almost eliminated with low-dose drug injection (1 mg kg⁻¹). Therefore, this novel pH-responsive Cu-based nanoplatform holds great promise in tumor-specific CDT/PTT synergistic therapy.

A pH-responsive multifunctional nanosystem was synthesized by loading glucose oxidase (GOD) onto CuFe-layered double hydroxide (LDH) nanosheets, which exhibited synchronous acid-enhanced/responsive photothermal and chemodynamic synergistic therapy.     

Precision photothermal therapy and photoacoustic imaging by in situ activatable thermoplasmonics

Phototherapy holds great promise for disease treatment; however, traditional “always-on” photoagents have been restricted to clinical translation due to their nonspecific response and side effects on normal tissues. Here, we show a tumor microenvironment activated photothermal and photoacoustic agent as an activatable prodrug and probe that allows precise cancer diagnosis and treatment. Such an in situ revitalized therapeutic and contrast agent is achieved via controllable plasmonic heating for thermoplasmonic activation. This enables monitoring of signal molecule dynamics, real-time photothermal and photoacoustic imaging of tumors and lymph node metastasis, and targeted photothermal therapy without unwanted phototoxicity to normal tissues. Our study provides a practical solution to the non-specificity problem in phototherapy and offers precision cancer therapeutic and theranostic strategies. This work may advance the development of ultrasensitive disease diagnosis and precision medicine.

A tumor microenvironment-activated photoagent is reported for precise photothermal therapy and photoacoustic imaging via controllable thermoplasmonics. The agent can sensitively image tumors and lymph node metastasis and specifically ablate tumors.     

Rational design of iridium–porphyrin conjugates for novel synergistic photodynamic and photothermal therapy anticancer agents

Near-infrared (NIR) emitters are important probes for biomedical applications. Nanoparticles (NPs) incorporating mono- and tetranuclear iridium(iii) complexes attached to a porphyrin core have been synthesized. They possess deep-red absorbance, long-wavelength excitation (635 nm) and NIR emission (720 nm). TD-DFT calculations demonstrate that the iridium–porphyrin conjugates herein combine the respective advantages of small organic molecules and transition metal complexes as photosensitizers (PSs): (i) the conjugates retain the long-wavelength excitation and NIR emission of porphyrin itself; (ii) the conjugates possess highly effective intersystem crossing (ISC) to obtain a considerably more long-lived triplet photoexcited state. These photoexcited states do not have the usual radiative behavior of phosphorescent Ir(iii) complexes, and they play a very important role in promoting the singlet oxygen (¹O₂) and heat generation required for photodynamic therapy (PDT) and photothermal therapy (PTT). The tetranuclear 4-Ir NPs exhibit high ¹O₂ generation ability, outstanding photothermal conversion efficiency (49.5%), good biocompatibility, low half-maximal inhibitory concentration (IC₅₀) (0.057 μM), excellent photothermal imaging and synergistic PDT and PTT under 635 nm laser irradiation. To our knowledge this is the first example of iridium–porphyrin conjugates as PSs for photothermal imaging-guided synergistic PDT and PTT treatment in vivo.

Iridium–porphyrin conjugates assembled in nanoparticles are photosensitizers that exhibit excellent photothermal imaging and synergistic PDT and PTT in vivo.     

A hierarchical assembly strategy for near-infrared photothermal conversion: unconventional heterogeneous metalla[2]catenanes

Herein, we report a hierarchical assembly strategy for constructing heterogeneous half-sandwich organometallic D–A (D = π-donor, A = π-acceptor) interlocked structures, and their application in near-infrared (NIR) photothermal conversion. Thienothiophene and diketopyrrolopyrrole groups were selected as the D and A units, leading to two homogeneous metalla[2]catenanes with D–D–D–D and A–A–A–A stacks, respectively. By the ordered secondary assembly of homogeneous metalla[2]catenanes, two unprecedented heterogeneous D–A metalla[2]catenanes comprising an unusual mixed D–A–D–D and unconventional D–A–A–A stacks were realized by the combination of multiple noncovalent interactions, as all demonstrated by a detailed X-ray crystallographic study. Benefiting from the mixed D–A stacking modes, NIR absorption of heterogeneous D–A metalla[2]catenanes is significantly enhanced in contrast to homogeneous metalla[2]catenanes. Thanks to the enhanced NIR absorption and the fluorescence quenching effect from half-sandwich organometallic fragments, heterogeneous D–A metalla[2]catenanes displayed high-performance NIR photothermal conversion properties (η = 27.3%).

Herein, we report a hierarchical assembly strategy for constructing heterogeneous half-sandwich organometallic D–A (D = π-donor, A = π-acceptor) interlocked structures, and their application in near-infrared (NIR) photothermal conversion.     

A Single-wavelength NIR-triggered Polymer for in situ Generation of Peroxynitrite(ONOO~–) to Enhance Phototherapeutic Efficacy

Phototherapies including photodynamic therapy(PDT) and photothermal therapy(PTT) are the most promising and non-invasive cancer treatments. However, the efficacy of mono-therapy of PDT or PTT is often limited by the phototherapeutic defects such as low light penetration depth of photosensitizers and insufficiency of photothermal agents. Peroxynitrite(ONOO~-) has been proved to be an efficient oxidizing and nitrating agent that involves in various physiological and pathological processes. Therefore, ONOO~-produced in tumor site could be an effective treatment in cancer therapy. Herein, a novel cyanine dye-based(Cy7) polymer nanoplatform is developed for enhanced phototherapy by in situ producing ONOO~-. The Cy7 units in the nanoparticles can not only be served as the photosensitizer to produce reactive oxygen species(ROS) including singlet oxygen and superoxide anion for PDT, but also be used as a heat source for PTT and the release of NO gas from N-nitrosated napthalimide(NORM) at the same time. Since NO can react quickly with superoxide anion to generate ONOO~-, the enhanced phototherapy could be achieved by in situ ONOO~-produced by PCy7-NO upon exposure to the near infrared(NIR) light. Therefore, the NIRtriggered Cy7-based nanoplatform for ONOO~--enhanced phototherapy may provide a new perspective in cancer therapy.     

Dual-targeted photothermal agents for enhanced cancer therapy

Photothermal therapy, in which light is converted into heat and triggers local hyperthermia to ablate tumors, presents an inherently specific and noninvasive treatment for tumor tissues. In this area, the development of efficient photothermal agents (PTAs) has always been a central topic. Although many efforts have been made on the investigation of novel molecular architectures and photothermal materials over the past decades, PTAs can cause severe damage to normal tissues because of the poor tumor aggregate ability and high irradiation density. Recently, dual-targeted photothermal agents (DTPTAs) provide an attractive strategy to overcome these problems and enhance cancer therapy. DTPTAs are functionalized with two classes of targeting units, including tumor environment targeting sites, tumor targeting sites and organelle targeting sites. In this perspective, typical targeted ligands and representative examples of photothermal therapeutic agents with dual-targeted properties are systematically summarized and recent advances using DTPTAs in tumor therapy are highlighted.

In this perspective, the design, applications and potential directions of photothermal therapeutic agents with dual-targeted properties are systematically described.     

AIE-active luminogens as highly efficient free-radical ROS photogenerator for image-guided photodynamic therapy

Image-guided photodynamic therapy (PDT) can realize highly precise and effective therapy via the integration of imaging and therapy, and has created high requirements for photosensitizers. However, the PDT modality usually utilizes conventional type II photosensitizers, resulting in unsatisfactory imaging and therapeutic outcomes due to aggregation-caused quenching (ACQ), “always on” fluorescence and strong oxygen dependence. Herein, we report the type I-based aggregation-induced emission (AIE) photosensitizer TCM-CPS with low oxygen dependence, near-infrared (NIR) emission and “off–on” fluorescence; in particular, it produces more reactive oxygen species (ROS) than commercially available Chlorin e6 and Rose Bengal. In the rational design of the AIE-based photosensitizer TCM-CPS, the strongly electron-donating carbazole unit and π-thiophene bridge distinctly extend the emission wavelength and decrease the autofluorescence interference in bio-imaging, and the hydrophilic pyridinium salt group guarantees good molecular dispersion and maintains the fluorescence-off state in the aqueous system to decrease the initial fluorescence background. Moreover, the strong donor–π–acceptor (D–π–A) character in TCM-CPS greatly separates the HOMO–LUMO distribution, enhancing the ROS generation, and TCM-CPS was constructed as a type I photosensitizer with the assistance of strong intramolecular charge transfer in the electron-rich anion–π⁺ structure. Based on its favorable hydrophilicity and photosensitivity, TCM-CPS was found to be a highly efficient free-radical ROS photogenerator for both visualizing cells using light-up NIR fluorescence and efficiently killing cancer cells upon light irradiation. The positively charged TCM-CPS could quickly bind to bacteria via electrostatic interactions to provide a light-up signal and kill bacteria at a low concentration. In the PDT treatment of bacteria-infected mice, the mice exhibited accelerated wound healing with low wound infection. Thus, the AIE-based type I photosensitizer TCM-CPS has great potential to replace commercially available photosensitizers in the image-guided PDT modality for the treatment of cancer and bacterial infection.

The AIE-based type I photosensitizer TCM-CPS exhibits high free radical generation and light-up fluorescence characteristics, giving it great potential in the image-guided PDT modality for the treatment of cancer and bacterial infections.     

New directions of activity-based sensing for in vivo NIR imaging

In vivo imaging is a powerful approach to study biological processes. Beyond cellular methods, in vivo studies allow for biological stimuli (small molecules or proteins) to be studied in their native environment. This has the potential to aid in the discovery of new biology and guide the development of diagnostics and therapies for diseases. To ensure selectivity and an observable readout, the probe development field is shifting towards activity-based sensing (ABS) approaches and near-infrared (NIR) imaging modalities. This perspective will highlight recent in vivo ABS applications that utilize NIR imaging platforms.

In vivo imaging is a powerful approach to study biological processes.     

Development of photo- and chemo-stable near-infrared-emitting dyes: linear-shape benzo-rosol and its derivatives as unique ratiometric bioimaging platforms

Microscopic imaging aided with fluorescent probes has revolutionized our understanding of biological systems. Organic fluorophores and probes thus continue to evolve for bioimaging applications. Fluorophores such as cyanines and hemicyanines emit in the near-infrared (NIR) region and thus allow deeper imaging with minimal autofluorescence; however, they show limited photo- and chemo-stability, demanding new robust NIR fluorophores. Such photo- and chemo-stable NIR fluorophores, linear-shape π-extended rosol and rosamine analogues, are disclosed here which provide bright fluorescence images in cells as well as in tissues by confocal laser-scanning microscopy. Furthermore, they offer unique ratiometric imaging platforms for activatable probes with dual excitation and dual emission capability, as demonstrated with a 2,4-dinitrophenyl ether derivative of benzo-rosol.

NIR-emitting benzo-rosol and -rosamine dyes offer novel ratiometric imaging platforms with high pohoto- and chemo-stability.     

Near-infrared absorbing Ru(ii) complexes act as immunoprotective photodynamic therapy (PDT) agents against aggressive melanoma

Mounting evidence over the past 20 years suggests that photodynamic therapy (PDT), an anticancer modality known mostly as a local treatment, has the capacity to invoke a systemic antitumor immune response, leading to protection against tumor recurrence. For aggressive cancers such as melanoma, where chemotherapy and radiotherapy are ineffective, immunomodulating PDT as an adjuvant to surgery is of interest. Towards the development of specialized photosensitizers (PSs) for treating pigmented melanomas, nine new near-infrared (NIR) absorbing PSs based on a Ru(ii) tris-heteroleptic scaffold [Ru(NNN)(NN)(L)]Cl_n, were explored. Compounds 2, 6, and 9 exhibited high potency toward melanoma cells, with visible EC₅₀ values as low as 0.292–0.602 μM and PIs as high as 156–360. Single-micromolar phototoxicity was obtained with NIR-light (733 nm) with PIs up to 71. The common feature of these lead NIR PSs was an accessible low-energy triplet intraligand (³IL) excited state for high singlet oxygen (¹O₂) quantum yields (69–93%), which was only possible when the photosensitizing ³IL states were lower in energy than the lowest triplet metal-to-ligand charge transfer (³MLCT) excited states that typically govern Ru(ii) polypyridyl photophysics. PDT treatment with 2 elicited a pro-inflammatory response alongside immunogenic cell death in mouse B16F10 melanoma cells and proved safe for in vivo administration (maximum tolerated dose = 50 mg kg⁻¹). Female and male mice vaccinated with B16F10 cells that were PDT-treated with 2 and challenged with live B16F10 cells exhibited 80 and 55% protection from tumor growth, respectively, leading to significantly improved survival and excellent hazard ratios of ≤0.2.

Ru(ii) photosensitizers (PSs) destroy aggressive melanoma cells, triggering an immune response that leads to protection against tumor challenge and mouse survival.     

An azo dye for photodynamic therapy that is activated selectively by two-photon excitation

Two-photon photodynamic therapy (TP-PDT) is a promising approach for the treatment of cancer because of its better penetration depth and superior spatial selectivity. Here, we describe an azo group containing cyclized-cyanine derivatives (ACC1 and ACC2) as a two-photon activated, type I based photosensitizer (PS). These small-molecule and heavy atom-free organic dyes showed marked reactive oxygen species (ROS)-generating ability under physiological conditions, as well as fast loading ability into the cells and negligible dark toxicity. Live cell analyses with one- and two-photon microscopy revealed that these dyes showed higher ROS generation ability upon two-photon excitation than upon one-photon excitation via the type I process. The PSs have superior PDT properties compared to conventional Visudyne and 5-ALA under mild conditions. These characteristics allowed for precise PDT at the target region in mimic tumor spheroids, demonstrating that the developed TP PS could be useful in efficient PDT applications and in designing various PSs.

Azo containing dyes as a two-photon selective and type I based photosensitizers (PSs) were developed that exhibit excellent photodynamic therapy properties under mild condition.     

Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy

Photosensitizing agents are essential for precise and efficient photodynamic therapy (PDT). However, most of the conventional photosensitizers still suffer from limitations such as aggregation-caused quenching (ACQ) in physiological environments and toxic side-effects on normal tissues during treatment, leading to reduced therapeutic efficacy. Thus, integrating excellent photophysical properties and accurate carcinoma selectivity in a photosensitizer system remains highly desired. Herein, a “dual lock-and-key” supramolecular photosensitizer BIBCl–PAE NPs for specific and enhanced cancer therapy is reported. BIBCl–PAE NPs are constructed by encapsulating a rationally designed glutathione (GSH)-activatable photosensitizer BIBCl in a pH-responsive diblock copolymer. In normal tissues, BIBCl is “locked” in the hydrophobic core of the polymeric micelles due to ACQ. Under the “dual key” activation of low pH and high levels of GSH in a tumor microenvironment, the disassembly of micelles facilitates the reaction of BIBCl with GSH to release water-soluble BIBSG with ideal biocompatibility, enabling the highly efficient PDT. Moreover, benefiting from the Förster resonance energy transfer effect of BIBSG, improved light harvesting ability and ¹O₂ production are achieved. In vitro and vivo experiments have demonstrated that BIBCl–PAE NPs are effective in targeting and inhibiting carcinoma. BIBCl–PAE NPs show superior anticancer efficiency relative to non-activatable controls.

The “dual lock-and-key” supramolecular photosensitizers enable specific and enhanced photodynamic therapy (PDT).     

NIR nanoprobe-facilitated cross-referencing manifestation of local disease biology for dynamic therapeutic response assessment

Pharmacological interventions for effective treatment require opportune, dynamic and accurate manifestation of pathological status. Traditional clinical techniques relying on biopsy-based histological examinations and blood tests are dramatically restricted due to their invasiveness, unsatisfactory precision, non-real-time reporting and risk of complications. Although current strategies through molecular imaging enable non-invasive and spatiotemporal mapping of pathological changes in intact organisms, environment-activatable, sensitive and quantitative sensing platforms, especially for dynamic feedback of the therapeutic response, are still urgently desired in practice. Herein, we innovatively integrate deep-tissue penetrable multispectral optoacoustic tomography (MSOT) and near-infrared (NIR) optical imaging based technology by tailoring a free radical-responsive chromophore with photon-upconverting nanocrystals. During the therapeutic process, the specific reactions between the drug-stimulated reactive oxygen species (ROS) and radical-sensitive probes result in an absorption shift, which can be captured by MSOT. Meanwhile, the radical-triggered reaction also induces multispectral upconversion luminescence (UCL) responses that exhibit the opposite trend in comparison to MSOT. Such reversed-ratiometric dual-modal imaging outcomes provide an ideal cross-referencing system that guarantees the maximum sensing specificity and sensitivity, thus enabling precise disease biology evaluation and treatment assessments in vivo.

NIR photoacoustic and upconversion luminescent nanoprobe-facilitated cross-referencing manifestation of oxidative stress-induced liver pathophysiology for dynamic therapeutic response assessment.     

Polyethylene glycol phospholipids encapsulated silicon 2,3-naphthalocyanine dihydroxide nanoparticles (SiNcOH-DSPEPEG(NH2) NPs) for single NIR laser induced cancer combination therapy

Currently, the combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a powerful technique for cancer treatment. However, most examples of combined PTT and PDT reported use multi-component nanocomposites under excitation of separate wavelength, resulting in complex treatment process. In this work, a novel theranostic nanoplatform (SiNcOH-DSPE-PEG(NH₂) NPs) has been successfully developed by coating silicon 2,3-naphthalocyanine dihydroxide (SiNcOH) with DSPE-PEG and DSPE-PEG-NH₂ for photoacoustic (PA) imaging-guided PTT and PDT tumor ablation for the first time. The as-prepared single-agent SiNcOH-DSPE-PEG(NH₂) NPs not only have good water solubility and biocompatibility, but also exhibit high photothermal conversion efficiency and singlet oxygen generation capability upon 808 nm NIR laser irradiation. In addition, owing to their high absorption at NIR region, the SiNcOH-DSPE-PEG(NH₂) NPs can also be employed as an effective diagnostic nanoagent for photoacoustic (PA) imaging. In vitro and in vivo experimental results clearly indicated that the simultaneously combined PTT and PDT under the guidance of PA imaging with single NIR laser excitation can effectively kill cancer cells or eradicate tumor tissues. Taking facile synthesis and high efficiency in cancer treatment by SiNcOH-DSPE-PEG(NH₂) NPs into consideration, our study provides a promising strategy to realize molecular imaging-guided combination therapy.