A Mitochondria-Targeted NIR-II Molecule Fluorophore for Precise Cancer Phototheranostics.

Subcellular organelle mitochondria are becoming a key player and a driver of cancer. Mitochondrial targeting phototheranostics has attracted increasing attention for precise cancer therapy. However, those phototheranostic systems still face great challenges, including complex and multiple components, light scattering, and insufficient therapeutic efficacy. Herein, a molecular fluorophore IR-TPP-1100 was tactfully designed by molecular engineering for mitochondria-targeted fluorescence imaging-guided phototherapy in the second near-infrared window (NIR-II). IR-TPP-1100 not only exhibited prominent photophysical properties and high photothermal conversion efficiency but also achieved excellent mitochondria-targeting ability. The mitochondria-targeting IR-TPP-1100 enabled NIR-II fluorescence and photoacoustic dual-modality imaging of mitochondria at the organism level. Moreover, it integrated photothermal and photodynamic therapy, obtaining remarkable tumor therapeutic efficacy by inducing mitochondrial apoptosis. These results indicate that IR-TPP-1100 has great potential for precise cancer therapy and provides a promising strategy for developing mitochondria-targeting NIR-II phototheranostic agents.

A biomimetic cuproptosis amplifier for targeted NIR-II fluorescence/photoacoustic imaging-guided synergistic NIR-II photothermal immunotherapy.

The therapeutic efficacy of cuproptosis combined with phototheranostics is still hindered by easy copper efflux, nonspecific accumulation and limited light penetration depth. Here, a high-performance NIR-II semiconductor polymer was first synthesized through dual-donor engineering. Then a biomimetic cuproptosis amplifier (PCD@CM) was prepared by Cu(II)-mediated coordinative self-assembly of NIR-II ultrasmall polymer dots and the chemotherapeutic drug DOX, followed by camouflaging of tumor cell membranes. After homologous targeting delivery to tumor cells, overexpressed GSH in the tumor microenvironment (TME) triggers the disassembly of the amplifier and the release of therapeutic components through the reduction of Cu(II) to Cu(I), which enable NIR-II fluorescence/photoacoustic imaging-guided NIR-II photothermal therapy (PTT) and chemotherapy. The released Cu(I) induces the aggregation of lipoylated mitochondrial proteins accompanied by the loss of iron-sulfur proteins, leading to severe proteotoxic stress and eventually cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis sensitization provokes significant immune surveillance, triggering the immunogenic cell death (ICD) to promote cytotoxic T lymphocyte infiltration together with aPD-L1-mediated immune checkpoint blockade. This work proposes a new strategy to develop cuproptosis sensitization systems enhanced by NIR-II phototheranostics with homologous targeting and anti-tumor immune response capabilities.

Phenylboronic Acid-Modified Near-Infrared Region II Excitation Donor-Acceptor-Donor Molecule for 2-Deoxy-d-Glucose Improved Starvation/Chemo/Photothermal Combination Therapy.

Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side effects. However, the chemo/PTT combination therapy suffers from limited penetration depth, thermoresistance performance of tumor cells, and low drug bioavailability. Herein, multifunctional nanoparticles (BTP/DOX/2DG NPs) coloaded with near-infrared region II (NIR-II) light excitation donor-acceptor-donor (D-A-D) small molecules, doxorubicin (DOX), and 2-deoxy-d-glucose (2-DG) are developed for reinforced starvation/chemo/NIR-II PTT combination therapy. The synthesized phenylboronic acid (PBA)-modified water-soluble D-A-D molecule (BBT-TF-PBA) not only exhibits high binding ability to DOX and 2-DG through donor-acceptor coordination interactions PBA-diol bonds but also serves as a photoactive agent for NIR-II fluorescence imaging, NIR-II photoacoustic imaging, and NIR-II PTT. Under the acidic and oxidizing conditions in the tumor microenvironment, donor-acceptor coordination interactions and PBA-diol bond are decomposed, simultaneously releasing DOX and 2-DG from BTP/DOX/2DG NPs to achieve effective chemotherapy and starvation therapy. 2-DG also effectively inhibits the expression of heat shock protein and further enhances NIR-II PTT and chemotherapy efficiency. In vitro and in vivo experiments demonstrate the combination effect of BTP/DOX/2DG NPs for chemotherapy, NIR-II PTT, and starvation therapy.

Self-delivery of metal-coordinated NIR-II nanoadjuvants for multimodal imaging-guided photothermal-chemodynamic amplified immunotherapy.

The effectiveness of phototheranostics induced immunotherapy is still hampered by limited light penetration depth, the complex immunosuppressive tumor microenvironment (TME) and the low efficiency of immunomodulator drug delivery. Herein, self-delivery and TME responsive NIR-II phototheranostic nanoadjuvants (NAs) were fabricated to suppress the growth and metastasis of melanoma through the integration of photothermal-chemodynamic therapy (PTT-CDT) and immune remodeling. The NAs were constructed by the self-assembly of ultrasmall NIR-II semiconducting polymer dots and the toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. Under acidic TME, the NAs responsively disintegrated and released therapeutic components, which enable NIR-II fluorescence/photoacoustic/magnetic resonance imaging-guided tumor PTT-CDT. Moreover, the synergistic treatment of PTT-CDT could induce significant tumor immunogenic cell death and evoke highly efficacious cancer immunosurveillance. The released R848 stimulated the maturation of dendritic cells, which both amplified the antitumor immune response by modulating and remodeling the TME. The NAs present a promising integration strategy of polymer dot-metal ion coordination and immune adjuvants for precise diagnosis and amplified anti-tumor immunotherapy against deep-seated tumors. STATEMENT OF SIGNIFICANCE: The efficiency of phototheranostics induced immunotherapy is still limited by insufficient light penetration depth, low immune response and the complex immunosuppressive tumor microenvironment (TME). In order to improve the efficacy of immunotherapy, self-delivery NIR-II phototheranostic nanoadjuvants (PMR NAs) were successfully fabricated via the facile coordination self-assembly of ultra-small NIR-II semiconducting polymer dots and toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. PMR NAs not only enable TME responsive cargo release and NIR-II fluorescence/photoacoustic/magnetic resonance imaging mediated precise localization of tumors, but also achieve synergistic photothermal-chemodynamic therapy, evoking an effective anti-tumor immune response by ICD effect. The responsively released R848 could further amplify the efficiency of immunotherapy by reversing and remodeling the immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor growth and lung metastasis.

Molecular Oligomerization and Donor Engineering Strategies for Achieving Superior NIR-II Fluorescence Imaging and Thermotherapy under 1064 nm Laser Irradiation.

An enormous challenge still exists for designing molecules with the second near-infrared (NIR-II, 1000-1700 nm) window absorption, NIR-II fluorescence emission, and batch-to-batch reproducibility, which is the premise for high-performance NIR-II phototheranostics. Although organic small molecules and polymers have been largely explored for phototheranostics, it is difficult to satisfy the above three elements simultaneously. In this work, molecular oligomerization (the general structure is S-D-A-D'-A-D-S) and donor engineering (changing the donor linker D') strategies are applied to design phototheranostic agents. Such strategies are proved to be efficient in adjusting molecular configuration and energy level, affecting the optical and thermal properties. Three oligomers (O-T, O-DT, and O-Q) are further prepared into water-soluble nanoparticles (NPs). Particularly, the O-T NPs exhibit a higher molar extinction coefficient at 1064 nm (≈4.3-fold of O-DT NPs and ≈4.8-fold of O-Q NPs). Furthermore, the O-T NPs show the highest NIR-II fluorescence brightness and heating capacity (PCE = 73%) among the three NPs under 1064 nm laser irradiation and served as agents for NIR-II imaging guided in vivo photothermal therapy. Overall, by using molecular oligomerization and donor engineering strategies, a powerful example of constructing high-performance NIR-II phototheranostics for clinical translation is given.

NIR-II Excitation Phototheranostic Platform for Synergistic Photothermal Therapy/Chemotherapy/Chemodynamic Therapy of Breast Cancer Bone Metastases.

To improve bone metastases treatment efficacy, current strategies are focused on the integration of chemotherapy with phototheranostic. However, the success of phototheranostic approaches is hampered by the limited tissue penetration depth of near-infrared-I (NIR-I) light (700-900 nm). In this study, a NIR-II (1000-1700 nm) excitation phototheranostic (BTZ/Fe2+ @BTF/ALD) is presented for NIR-II fluorescence imaging and NIR-II photoacoustic imaging-guided NIR-II photothermal therapy (PTT), chemotherapy, and chemodynamic therapy (CDT) of breast cancer bone metastases. This phototheranostic is developed by integrating a dopamine-modified NIR-II absorbing donor-acceptor-donor small molecule (BBT-FT-DA), the boronate anticancer drug bortezomib (BTZ), and Fe2+ ions, as CDT catalysts, into an amphiphilic PEGylated phospholipid modified with the bone-targeting ligand alendronate. In acidic and hydrogen peroxide (H2 O2 ) over expression tumor microenvironment, the boronate-catechol linkage is cleaved and BTZ and Fe2+ ions are released to initiate the Fenton reaction, that is, chemotherapy and CDT, respectively, are initialized. It is confirmed using the murine 4T1 bone metastasis model that BTZ/Fe2+ @BTF/ALD significantly suppresses the progression of tumor cells in the bone tissue via a synergistic NIR-II PTT/chemotherapy/CDT effect. Overall, this work provides fresh insights to guide the development of NIR-II phototheranostics for breast cancer bone metastases.

Anisotropic plasmonic Pd-tipped Au nanorods for near-infrared light-activated photoacoustic imaging guided photothermal-photodynamic cancer therapy.

The integration of photothermal therapy (PTT) and photodynamic therapy (PDT) has become a promising cancer treatment method. Herein, anisotropic metal hetero-nanostructure Pd-tipped Au nanorods (PTA NRs) were fabricated, which exhibit plasmon-enhanced photothermal performance under near-infrared laser irradiation. Due to their anisotropic nanostructure, PTA NRs promote the generation of energetic hot electrons and prolong the separation time of electrons and holes. The hot electrons could generate heat energy through the electron-phonon relaxation process and produce reactive oxygen species through energy and electron transformation processes. Because of their high NIR absorption cross-section, as well as good photostability, PTA NRs can be used for NIR-activated photoacoustic imaging-guided PTT-PDT combination cancer therapy. Experiments in tumor-bearing mice proved that PTA NRs exhibit excellent anti-tumor effects, with little side effects on normal organs, making them promising for NIR cancer phototherapy.

Near-infrared-II light excitation thermosensitive liposomes for photoacoustic imaging-guided enhanced photothermal-chemo synergistic tumor therapy.

Despite the great success of photothermal therapy (PTT), it still suffers from many obstacles, such as the limited penetration depth of light, thermoresistance of tumors, and limitations of mono-therapeutic modalities. Herein, second near-infrared (NIR-II, 1064 nm) light excitation thermosensitive liposomes (DG@TLs) were fabricated for photoacoustic imaging (PAI) guided enhanced PTT-chemotherapy. DG@TLs were constructed by encapsulating NIR-II light excitation semiconducting polymers into liposomes composed of phase change materials (PCMs), along with gambogic acid (GA) with chemotherapeutic and heat shock protein inhibition effects. Under 1064 nm laser irradiation, DG@TLs exhibited superior NIR-II PAI and PTT performances with deep tissue penetration while triggering the thermoresponsive release of GA based on the phase transition of PCMs from solid to liquid. The released GA could enhance the NIR-II PTT efficacy by inhibiting the activity of HSP90, reducing the thermoresistance of tumors, exhibiting significant chemotherapeutic effects, and achieving synergistic anti-tumor efficiency. This work provides a new strategy for achieving on-demand drug release and effective theranostics in deep-seated tumor regions.

NIR-II Excitation Phototheranostic Nanomedicine for Fluorescence/Photoacoustic Tumor Imaging and Targeted Photothermal-Photonic Thermodynamic Therapy.

The success of phototheranostics is hampered by some intrinsic defects, such as limited light penetration depth, heat resistance of tumor cells to photothermal therapy (PTT) induced by heat shock protein (HSP) and stress resistance against photodynamic therapy (PDT) caused by hypoxia microenvironment of tumor. Herein, a second near infrared (NIR-II) light excitation phototheranostic nanomedicine has been fabricated by integrating the semiconducting polymer, azo compound, and HSP inhibitor into a thermosensitive liposome, followed by modification with targeting aptamer, forming Lip(PTQ/GA/AIPH) for multimodal phototheranostics of triple-negative breast cancer (TNBC). The phototheranostic nanomedicine provides tumor targeting NIR-II fluorescence and photoacoustic dual-modal imaging, as well as NIR-II PTT. The released HSP inhibitor can effectively inhibit the activity of HSP for enhanced NIR-II PTT. Moreover, azo compound can be decomposed by the NIR-II photothermal activation, generating cytotoxic free radicals and realizing oxygen-irrelevant photonic thermodynamic therapy (PTDT) effects. Under the NIR-II laser irradiation, NIR-II fluorescence/photoacoustic dual-modal imaging guided enhanced NIR-II PTT and PTDT by Lip(PTQ/GA/AIPH), can achieve precise diagnosis and effective suppression of deep-seated TNBC with negligible side effects. This work develops a promising NIR-II excitation phototheranostic nanomedicine for spatiotemporally specific diagnosis and combination therapy of TNBC.

NIR-II fluorescence imaging guided tumor-specific NIR-II photothermal therapy enhanced by starvation mediated thermal sensitization strategy.

Photothermal therapy (PTT) is hampered by limited light penetration depth and cell thermoresistance induced by over-expressed heat shock proteins (HSPs). Herein, we proposed a tumor-specific enhanced NIR-II PTT through the starvation mediated thermal sensitization strategy. A semiconducting polymer with superior NIR-II fluorescence imaging (FI) performance and NIR-II PTT efficacy was synthesized and encapsulated into folate modified liposomes, together with a glycolysis inhibitor, 2-deoxy-d-glucose (2DG). Upon specifically targeting folate receptors and guidance of NIR-II FI, spatiotemporal 2DG release could be achieved by the trigger of NIR-II photothermal effect. The released 2DG could not only deplete the energy supply of tumor cells by inhibiting tumor anaerobic glycolysis, but also decrease the ATP levels and hamper the production of HSPs, ultimately enhancing the tumor thermal sensitivity toward PTT. Owing to the sensitization effect of 2DG, tumor cells with overexpressed folate receptors could be significantly damaged by NIR-II PTT with an enhanced therapeutic efficiency. The work provided a promising strategy for specific starvation/NIR-II PTT synergistic therapy towards tumors.

Injectable and Thermosensitive Liposomal Hydrogels for NIR-II Light-Triggered Photothermal-Chemo Therapy of Pancreatic Cancer.

An injectable hydrogel sustained drug release system could be a promising technique for in situ treatment. Herein, an injectable hydrogel was prepared for photothermal-chemo therapy of cancer based on the thermosensitive liposomal hydrogel (Lip-Gel). The Lip-Gel system was fabricated by encapsulation of the NIR-II photothermal agent (DPP-BTz) and chemotherapy drugs (GEM) in thermosensitive liposomes and then combined with hydrogel precursor solution. The hydrogel precursor was used as an injectable flowing solution at room temperature and transferred into a cross-linked gel structure at physiological temperature. After being injected into the tumor, DPP-BTz in the Lip-Gel system can generate heat under irradiation of 1064 nm laser, breaking the thermosensitive liposomes and releasing GEM to kill tumor cells. From the treatment results, the Lip-Gel system showed a significant antitumor effect through chemo-/photothermal therapy combination therapy triggered by the NIR-II laser. This work provides a useful scheme for the development of drug delivery and drug treatment directions for local cancer therapy.

High performance one-for-all phototheranostics: NIR-II fluorescence imaging guided mitochondria-targeting phototherapy with a single-dose injection and 808 nm laser irradiation.

Current phototheranostics is still encountering various impediments, which causes complicated and prolonged therapy, and increases unnecessary side effects and systemic toxicity to patients. Herein, mitochondria-targeting one-for-all phototheranostic nanoparticles based on single-component organic molecule were designed and fabricated. After being irradiated with a single 808 nm laser, outstanding second near-infrared (NIR-II) fluorescence signals (with a high fluorescence quantum yield of 2.2% in water) were obtained for NIR-II fluorescence imaging, which could efficiently locate tumor and real-time monitor the therapeutic process. Moreover, such nanoparticles also presented superb photothermal conversion efficiency (39.6%) and singlet oxygen yield (2.3%, almost 12 times higher than clinical NIR dye indocyanine green) under 808 nm laser illumination, which could produce both potent hyperthermia and abundant singlet oxygen, resultantly leading to the mitochondrial dysfunction and further cell apoptosis. Both in vitro and in vivo investigations demonstrated that such nanoagents displayed significantly tumor theranostic efficacy, resulting from single 808 nm laser triggered high performance NIR-II fluorescence imaging guided mitochondria-targeting phototherapy. It was noteworthy that only a single-dose injection and 808 nm laser irradiation were employed during in vivo treatment. We believe that the phototheranostic nanoparticles developed in this work will open up a new dimension in cancer theranostics.

Endogenous oxygen generating multifunctional theranostic nanoplatform for enhanced photodynamic-photothermal therapy and multimodal imaging.

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered as a noninvasive option for cancer therapy. However, insufficient penetration depth, tumor hypoxia, and a single treatment method severely limit the effectiveness of treatment. Methods: In this study, a multifunctional theranostic nanoplatform has been fabricated based on Au/Ag-MnO2 hollow nanospheres (AAM HNSs). The Au/Ag alloy HNSs were first synthesized by galvanic replacement reaction and then the MnO2 nanoparticles were deposited on the Au/Ag alloy HNSs by the reaction between Ag and permanganate (KMnO4), finally obtained the AAM HNSs. Then, SH-PEG was modified on the surface of AAM HNSs by the interaction of sulfhydryl and Au/Ag alloy, which improved the dispersibility and biocompatibility of the HNS. Next, the PDT photosensitizer Ce6 was loaded into AAM HNSs, benefiting from the hollow interior of the structure, and the AAM-Ce6 HNSs were obtained. Results: The AAM HNSs exhibit broad absorption at the near infrared (NIR) biological window and remarkable photothermal conversion ability in the NIR-II window. The MnO2 nanoparticles can catalyze endogenous H2O2 to generate O2 and enhance the therapeutic effect of PDT on tumor tissue. Simultaneously, MnO2 nanoparticles intelligently respond to the tumor microenvironment and degrade to release massive Mn2+ ions, which introduce magnetic resonance imaging (MRI) properties. When AAM-Ce6 HNSs are loaded with Ce6, the AAM-Ce6 HNSs can be used for triple-modal imaging (fluorescence/photoacoustic/magnetic resonance imaging, FL/PAI/MRI) guided combination tumor phototherapy (PTT/PDT). Conclusion: This multifunctional nanoplatform shows synergistic therapeutic efficacy better than any single therapy by achieving multimodal imaging guided cancer combination phototherapy, which are promising for the diagnosis and treatment of cancer.

Multifunctional Thermosensitive Liposomes Based on Natural Phase-Change Material: Near-Infrared Light-Triggered Drug Release and Multimodal Imaging-Guided Cancer Combination Therapy.

Multifunctional theranostic nanoplatforms (NPs) in response to environment stimulations for on-demand drug release are highly desirable. Herein, the near-infrared (NIR)-absorbing dye, indocyanine green (ICG), and the antitumor drug, doxorubicin (DOX), were efficiently coencapsulated into the thermosensitive liposomes based on natural phase-change material. Folate and conjugated gadolinium (Gd) chelate-modified liposome shells enhance active targeting and magnetic resonance performance of the NPs while maintaining the size of the NPs. The ICG/DOX-loaded and gadolinium chelate conjugated temperature-sensitive liposome nanoplatforms (ID@TSL-Gd NPs) exhibited NIR-triggered drug release and prominent chemo-, photothermal, and photodynamic therapy properties. With the coencapsulated ICG, DOX, and the conjugated gadolinium chelates, the ID@TSL-Gd NPs can be used for triple-modal imaging (fluorescence/photoacoustic/magnetic resonance imaging)-guided combination tumor therapy (chemotherapy, photothermotherapy, and photodynamic therapy). After tail vein injection, the ID@TSL-Gd NPs accumulated effectively in subcutaneous HeLa tumor of mice. The tumor was effectively suppressed by accurate imaging-guided NIR-triggered phototherapy and chemotherapy, and no tumor regression and side effects were observed. In summary, the prepared ID@TSL-Gd NPs achieved multimodal imaging-guided cancer combination therapy, providing a promising platform for improving diagnosis and treatment of cancer.

A perylene diimide zwitterionic polymer for photoacoustic imaging guided photothermal/photodynamic synergistic therapy with single near-infrared irradiation.

Phototherapy has great promise for precise cancer diagnosis and effective therapy, but the development of one multifunctional nanoplatform for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) at a single excitation wavelength remains a challenge. In this work, a perylene diimide zwitterionic polymer PDS-PDI was synthesized via atom transfer radical polymerization (ATRP). This polymer was designed for photoacoustic imaging (PAI) guided synergistic PDT and PTT with single 660 nm near-infrared (NIR) light irradiation. The prepared PDS-PDI polymer presents high photothermal conversion efficiency (η≈ 40%) and efficient singlet oxygen quantum yield (ΦΔ≈ 16.7%) under 660 nm laser irradiation. Polymer PDS-PDI also acts as a contrast agent for PAI, offering real-time monitoring in tumor sites. Additionally, in vitro and in vivo assays indicate that polymer PDS-PDI has good biocompatibility and effective tumor destruction ability under 660 nm laser irradiation. In brief, polymer PDS-PDI prepared in this study could be applied as a dual-mode phototherapeutic agent under single laser irradiation.