Photothermal Theranostics Research Articles

Combing NIR-II molecular dye with magnetic nanoparticles for enhanced photothermal theranostics with a 95.6% photothermal conversion efficiency

Photoheranostics have emerged as a promising tool for cancer theranostics owing to their real-time feedback on treatment and their precise diagnosis. Among them, how to improve the photothermal conversion efficiency (PCE) of phototheranostic agents (PTAs) is the key factor for phototheranostic systems. Herein, we provided an efficient method to improve PCE and constructed a biocompatible nano-material ICR-Qu@NH2-Fe3O4@PEG (QNFP) by combing near-infrared second region (NIR-II) molecular dye ICR-Qu and amino-modified magnetic nanoparticles and then encapsulated by DSPE-mPEG2000. QNFP exhibited excellent performance for photothermal therapy with a high PCE of 95.6%. Both in vitro and in vivo experiments indicated that QNFP could inhibit the growth of tumors under laser irradiation with low toxicity and realized real-time NIR-II fluorescent imaging of tumors. In general, we realized a simple but efficient method to improve the PCE of NIR-II molecular dye without reduce its quantum yield, which is an ideal choice for cancer diagnosis and treatment.

Chalcogen Atom-Modulated Croconaine for Efficient NIR-II Photothermal Theranostics.

Organic dye-based agents with near-infrared (NIR)-II absorption have great potential for cancer theranostics because of the deeper tissue penetration and good biocompatibility. However, proper design is required to develop NIR-II-absorbing dyes with good optical properties. We proposed to construct chalcogen atom-modulated croconaine for NIR-II light-triggered photothermal theranostics. By introducing different chalcogen atoms (O, S, Se, or Te) into the structure of croconaine, the light absorption of croconaine can be precisely regulated from the NIR-I to the NIR-II range due to the heavy-atom effect. Especially, Te-substituted croconaine (CRTe) and its nanoformulations exhibit superior NIR-II responsiveness, a high photothermal conversion efficiency (70.6%), and good photostability. With their favorable tumor accumulation, CRTe-NPs from tumor regions can be visualized by NIR-II optoacoustic systems with high resolution and high contrast; meanwhile, their superior photothermal performance also contributes to efficient cell killing and tumor elimination upon 1064 nm laser irradiation. Therefore, this work provides an efficient strategy for the molecular design of NIR-II organic photothermal agents.

Synchronously manipulating absorption and nonradiative transition of croconaine via donor engineering for efficient NIR-II photothermal theranostics

Organic molecules with strong absorption in the near-infrared (NIR)-II region are highly desired for cancer photothermal theranostics. However, it remains challenges to construct NIR-II photothermal agents with desired optical properties. This study reports a donor engineering approach to simultaneously manipulate the absorption and nonradiative transitions of croconaine dyes. By introducing different donor units with increasing electron donating ability to the backbone, the absorption of the synthesized croconaines were gradually red-shifted to NIR-II region, especially the benzo[c,d]indolium conjugated croconaine (CR1045). The extensive conjugation of CR1045 had a narrower HOMO-LUMO energy gap and strong NIR-II light responsiveness. Importantly, the steric repulsion between this large planar donor and croconate acceptor of CR1045 promotes the formation of a twisted intramolecular charge transfer (TICT) state, making it more prone to direct the absorbed energy towards heat-producing non-radiative decay rather than other dissipative pathways. And the nanoformulated CR1045 exhibits excellent optoacoustic generation capability and ultrahigh photothermal conversion efficiency (∼84%). In vitro and in vivo investigations confirm good optoacoustic imaging and effective photothermal treatment of tumors. Therefore, this work offers insights into donor regulation for the future development of efficient NIR-II photothermal agents.

Tantalum Nitride-Based Theranostic Agent for Photoacoustic Imaging-Guided Photothermal Therapy in the Second NIR Window.

Metal nitrides show excellent photothermal stability and conversion properties, which have the potential for photothermal therapy (PTT) for cancer. Photoacoustic imaging (PAI) is a new non-invasive and non-ionizing biomedical imaging method that can provide real-time guidance for precise cancer treatment. In this work, we develop polyvinylpyrrolidone-functionalized tantalum nitride nanoparticles (defined as TaN-PVP NPs) for PAI-guided PTT of cancer in the second near-infrared (NIR-II) window. The TaN-PVP NPs are obtained by ultrasonic crushing of massive tantalum nitride and further modification by PVP to obtain good dispersion in water. Due to their good absorbance in the NIR-II window, TaN-PVP NPs with good biocompatibility have obvious photothermal conversion performance, realizing efficient tumor elimination by PTT in the NIR-II window. Meanwhile, the excellent PAI and photothermal imaging (PTI) capabilities of TaN-PVP NPs are able to provide monitoring and guidance for the treatment process. These results indicate that TaN-PVP NPs are qualified for cancer photothermal theranostics.

Synchronously Manipulating Absorption and Extinction Coefficient of Semiconducting Polymers via Precise Dual-Acceptor Engineering for NIR-II Excited Photothermal Theranostics.

Integrating the ultralong excitation wavelength, high extinction coefficient, and prominent photothermal conversion ability into a single photothermal agent is an appealing yet significantly challenging task. Herein, a precise dual-acceptor engineering strategy is exploited for this attempt based on donor-acceptor (D-A) type semiconductor polymers by subtly regulating the molar proportions of the two employed electron acceptor moieties featuring different electronic affinity and π-conjugation degrees, and making full use of the active intramolecular motion-induced photothermal effect. The optimal polymer SP4 synchronously shows desirable second near-infrared (NIR-II) absorption, an extremely high extinction coefficient, and satisfactory photothermal conversion behavior. Consequently, the unprecedented performance of SP4 NPs on 1064 nm laser-excited photoacoustic imaging (PAI)-guided photothermal therapy (PTT) is demonstrated by the precise tumor diagnosis and complete tumor elimination.

Synchronously Manipulating Absorption and Extinction Coefficient of Semiconducting Polymers via Precise Dual‐Acceptor Engineering for NIR‐II Excited Photothermal Theranostics

AbstractIntegrating the ultralong excitation wavelength, high extinction coefficient, and prominent photothermal conversion ability into a single photothermal agent is an appealing yet significantly challenging task. Herein, a precise dual‐acceptor engineering strategy is exploited for this attempt based on donor‐acceptor (D‐A) type semiconductor polymers by subtly regulating the molar proportions of the two employed electron acceptor moieties featuring different electronic affinity and π‐conjugation degrees, and making full use of the active intramolecular motion‐induced photothermal effect. The optimal polymer SP4 synchronously shows desirable second near‐infrared (NIR‐II) absorption, an extremely high extinction coefficient, and satisfactory photothermal conversion behavior. Consequently, the unprecedented performance of SP4 NPs on 1064 nm laser‐excited photoacoustic imaging (PAI)‐guided photothermal therapy (PTT) is demonstrated by the precise tumor diagnosis and complete tumor elimination.

HDAC6 inhibitor loaded bimetallene nanosheets with antagonizing thermoresistance for augmented mild photothermal therapy

Photothermal therapy (PTT) induces thermoresistance through cellular heat shock response, which impairs the therapeutic efficacy of the PTT. To resolve this problem, we developed a photothermal theranostics (denoted as PMH), which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6 (HDAC6) selected inhibitor (ACY-1215), showing the synergistic antitumor effect both in vitro and in vivo. Mechanistically, under the photoacoustic imaging (PA) navigation, the released ACY-1215 triggered by NIR laser irradiation decrease the heat shock proteins (HSPs) expression and weaken the HDAC6-regulated HSP90 deacetylation, thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway. Moreover, mild photothermal therapy (mPTT) treatment compromised the autophagy, which induced by HDAC6 inhibition, leading to mPTT-induced misfolded or unfold proteins further accumulation. Given that inhibition of HDAC6 plus mPTT contribute to tumor eradication. This study develops a promising combination strategy based on mPTT for future cancer treatment.

Photothermal theranostics with glutathione depletion and enhanced reactive oxygen species generation for efficient antibacterial treatment.

Drug-resistant bacteria caused by the abuse of antibiotics have brought great challenges to antimicrobial therapy. Herein an antibiotic-free polydopamine (PDA) modified metal-organic framework (PDA-FDM-23) with photothermal-enhanced chemodynamic effect was developed for synergistic antibacterial treatment. The PDA-FDM-23 antibacterial agent exhibited high peroxidase-like activity. Moreover, the process was significantly accelerated by consuming glutathione (GSH) to generate more efficient oxidizing Cu+. In addition, the photothermal therapy (PTT) derived from PDA improved the chemodynamic therapy (CDT) activity triggering a reactive oxygen species explosion. This PTT-enhanced CDT strategy illustrated 100% antibacterial efficiency against both Staphylococcus aureus and Escherichia coli. Cytotoxicity and hemolysis analyses fully demonstrated the excellent biocompatibility of PDA-FDM-23. Overall, our work highlighted the strong peroxidase catalytic activity, excellent GSH consumption and photothermal performance of PDA-FDM-23, providing a new strategy for antibiotic-free reactive oxygen species (ROS) synergistic sterilization.

Lighting up Self-Quenching Nanoaggregates with Protein Corona for Simultaneous Intraoperative Imaging and Photothermal Theranostics of Metastatic Cancer

Near-infrared (NIR) photothermal transduction agents (PTAs) with large rigid π-extended and planar structures are prone to aggregate in a physiological environment where their emission is often quenched due to the strong intermolecular dipole-dipole or π-π interactions. This aggregation-caused quenching effect greatly impedes their applications in image-guided photothermal theranostics. Herein, we made an interesting finding that engineering a bioinspired protein corona (PC), once thermodynamically stabilized in preferred orientations on PTA nanoaggregates, can produce brilliant NIR fluorescence with a high quantum yield (∼6.2%) without compromising their photothermal properties. Both experimental data and computational modeling suggest that the mechanism of fluorescence enhancement is due to the high-affinity binding of nano-sized PTA to albumin, which regulates the molecular conformation and aggregation state of PTA. High spatial and temporal resolution imaging of albumin PC-coated PTA aggregates enables image-guided photothermal therapy for cancer cells in sentinel lymph nodes to remarkably inhibit pulmonary metastasis. Such a treatment combined with the surgical removal of the primary tumor can prolong animal survival, which is a promising candidate for clinical applications in the treatment of advanced metastatic cancers.

Boost photothermal theranostics via self‐assembly‐induced crystallization (SAIC)

AbstractOwing to the intrinsic advantages of spatiotemporal selectivity, photothermal theranostics have become the advancing edge of precision medicine for cancer. Developing photothermal transduction agents (PTAs) with near‐infrared (NIR) absorption, high photothermal conversion efficiency, robust photothermal stability, and good accumulation in tumors, is particularly valuable. Herein, we report a new concept, self‐assembly‐induced crystallization (SAIC), which can serve as a mechanism that dramatically boosts photothermal behaviors of PTA in NIR region. As a proof of concept, three heptamethine cyanine molecules with internal degrees of freedom (geometry and intramolecular interaction) are designed to fine‐tune their crystallinity. Notably, Cy7‐TCF‐EMBI molecules with rigid and planar skeletons self‐assemble into a crystalline state to maximize their packing density and improve the charge transfer, both of which contribute to nonradiative decay for energy dissipation as heat. The high packing density also renders an ideal scaffold for controlling intermolecular interactions to exhibit better photothermal stability, and endows an anisotropic three‐dimensional architecture for passive tumor targeting. This “SAIC” strategy may offer a conceptually novel, practically simple but effective approach to unveil the structure–property relationship that could provide some general rules in rational design of PTAs, and paves the way for a next generation of supramolecular medicine for photothermal theranostics.

Boosting Photothermal Theranostics via TICT and Molecular Motions for Photohyperthermia Therapy of Muscle‐Invasive Bladder Cancer (Adv. Healthcare Mater. 24/2021)

Photothermal Therapies In article number 2101063 by Qian Liu, Guangxue Feng, Dan Ding, and co-workers, a small photothermal molecule with active intramolecular motions and a dark state twisted intramolecular charge transfer feature is designed to boost the photothermal conversion ability. Such a design strategy enables the effective low-temperature photo-hyperthermia treatment of muscle-invasive bladder cancers at low drug and laser dosages with minimal side effects.

Carrier‐Free Delivery of Ultrasmall π‐Conjugated Oligomer Nanoparticles with Photothermal Conversion over 80% for Cancer Theranostics

High-performance photothermal theranostics is urgently desired for cancer therapy because of their good controllability and noninvasive features. The relatively low photothermal conversion efficiency is still at the drawbacks because of the absence of efficient extraneous carriers. Herein, a carrier-free nanomedicine is developed to in vivo self-deliver organic photothermal agents for efficient cancer phototheranostics. By a facile self-assembly strategy, the near-infrared (NIR)-absorbing conjugated oligomer IDIC-4F is fabricated into a carrier-free nanoparticle (DCF-P), showing ultrasmall size of nearly 4.0nm with a nearly 100% of drug loading capacity. Notably, DCF-P achieves a superhigh photothermal conversion efficiency of 80.5% that is far greater than that of IDIC-4F-loaded nanomicelle DCF-M (57.3%). With the guidance of NIR fluorescence and photoacoustic dual-imaging, it is verified that DCF-P could well achieve tumor-preferential accumulation and retention at 4 h postinjection, and meanwhile shows highly efficient in vivo tumor elimination with good biosafety. This study thus contributes a novel concept for designing ultrasmall nanoparticle characteristics of preferential accumulation in tumors, and also provides a strategy for creating high-performance carrier-free nanomedicine via highly ordered molecular stacking.

Boosting Photothermal Theranostics via TICT and Molecular Motions for Photohyperthermia Therapy of Muscle-Invasive Bladder Cancer.

The development of photothermal agents with high photothermal conversion efficiency (PCE) can help to reduce drug and laser dosage, but still remains a big challenge. Herein, a novel approach is reported to design photothermal agents with high PCE values by promoting nonradiative heat generation processes through the cooperation of twisted intramolecular charge transfer (TICT) and molecular motions. Within the designed molecule 2DMTT-BBTD, the tetraphenylethenes act as molecular rotors, the long alkyl chain grafted thiophene helps to twist the molecular geometry to facilitate TICT state formation and preserve molecular motions in aggregate, while the strong electron-withdrawing BBTD unit enhances TICT effect. 2DMTT-BBTD exhibits NIR-absorption and a high PCE value of 74.8% under 808nm laser irradiation. Gambogic acid (GA) which surmounts tumor cell thermotolerance by inhibiting heat shock protein 90 (HSP90) expression is coloaded into the nanoparticles, RGD peptide is further introduced to the nanoparticle surface to improve tumor accumulation. The resultant nanoparticles facilitate the effective low-temperature hyperthermia therapy of muscle-invasive bladder cancer (MIBC) with minimal damage to surrounding heathy tissues. This work delivers a new design concept for development of highly efficient photothermal agents, which also provides a safer approach for noninvasive treatment of MIBC and other malignant tumors.

Fabrication of gold nanohybrids modified with antibody and functional dendrimers for targeted photothermal theranostics

AbstractTargeted theranostics can improve benefits of therapeutics or imaging probes by minimizing the dose and by selective delivery to a target site. For this study, a gold nanorod (AuNR)‐based nanohybrid was designed for efficient cancer treatment and diagnosis. The AuNR was functionalized with polyamidoamine dendrimers having poly(ethylene glycol) and Gd‐DOTA residues to provide biocompatibility and magnetic resonance (MR) imaging properties. Furthermore, trastuzumab was conjugated to the obtained nanohybrids to enhance the delivery performance to HER2‐expressing tumor cells. Fabricated nanohybrids possessed uniform hydrodynamic diameter and showed typical surface plasmon absorption, which is useful to convert light energy to heat for photothermal therapy. Nanohybrids exhibited T1‐weighted relaxation and comparable MR imaging property to that of commercially available MR contrast reagent. In vitro experiments demonstrated that photothermal effects of nanohybrid under near infrared (NIR) irradiation were sufficient to kill 80%–90% of cancer cells. The combination of the targeted nanohybrid and NIR laser irradiation strongly suppressed tumor growth and extended the survival of HER2‐positive SKOV3 tumor‐bearing nude mice. Therefore, fabricated nanohybrids are promising for targeted photothermal therapy and imaging.

Rational Design of Conjugated Small Molecules for Superior Photothermal Theranostics in the NIR-II Biowindow.

Extensive recent progress has been made on the design and applications of organic photothermal agents for biomedical applications because of their excellent biocompatibility comparing with inorganic materials. One major hurdle for the further development and applications of organic photothermal agents is the rarity of high-performance materials in the second near-infrared (NIR-II) window, which allows deep tissue penetration and causes minimized side effects. Up till now, there have been few reported NIR-II-active photothermal agents and their photothermal conversion efficiencies are relatively low. Herein, optical absorption of π-conjugated small molecules from the first NIR window to the NIR-II window is precisely regulated by molecular surgery of substituting an individual atom. With this technique, the first demonstration of a conjugated oligomer (IR-SS) with an absorption peak beyond 1000nm is presented, and its nanoparticle achieves a record-high photothermal conversion efficiency of 77% under 1064nm excitation. The nanoparticles show a good photoacoustic response, photothermal therapeutic efficacy, and biocompatibility in vitro and in vivo. This work develops a strategy to boost the light-harvesting efficiency in the NIR-II window for cancer theranostics, offering an important step forward in advancing the design and application of NIR-II photothermal agents.

Molecular Motion in Aggregates: Manipulating TICT for Boosting Photothermal Theranostics.

Planar donor and acceptor (D-A) conjugated structures are generally believed to be the standard for architecting highly efficient photothermal theranostic agents, in order to restrict intramolecular motions in aggregates (nanoparticles). However, other channels of extra nonradiative decay may be blocked. Now this challenge is addressed by proposing an "abnormal" strategy based on molecular motion in aggregates. Molecular rotors and bulky alkyl chains are grafted to the central D-A core to lower intermolecular interaction. The enhanced molecular motion favors the formation of a dark twisted intramolecular charge transfer state, whose nonradiative decay enhances the photothermal properties. Result shows that small-molecule NIRb14 with long alkyl chains branched at the second carbon exhibits enhanced photothermal properties compared with NIRb6, with short branched chains, and much higher than NIR6, with short linear chains, and the commercial gold nanorods. Both in vitro and in vivo experiments demonstrate that NIRb14 nanoparticles can be used as nanoagents for photoacoustic imaging-guided photothermal therapy. Moreover, charge reversal poly(β-amino ester) makes NIRb14 specifically accumulate at tumor sites. This study thus provides an excited molecular motion approach toward efficient phototheranostic agents.

Near-Infrared Fluorescent Dye-Decorated Nanocages to Form Grenade-like Nanoparticles with Dual Control Release for Photothermal Theranostics and Chemotherapy.

Recently, nanoparticles (NPs) have been widely investigated for delivery of anticancer drugs. Here, a dual control drug-release modality was developed that uses naturally occurring protein apoferritin loaded with doxorubicin (DOX) and ADS-780 near-infrared (NIR) fluorescent dye-decorated NPs (ADNIR NPs). ADNIR NPs act as a grenade to detonate the targeted tumor site following laser irradiation (photothermal therapy, PTT) and explode into cluster warheads (apoferritin-loaded DOX nanocages, AF-DOX NCs) that further destroy the tumor cells (chemotherapy). Light was shown to disrupt the grenade-like structure of NPs to release AF-DOX NCs as well as DOX from NCs in low-pH intercellular environments. In vitro and in vivo studies showed that the structure of AF-DOX NCs was disassembled to release DOX, which then killed the cancer cells in organelles with acidic environments. In vivo studies showed that the ADNIR NP-decorated with NIR dye facilitated tracking of the accumulated NPs at the tumor site using an IVIS imaging system. Overall, targeted ADNIR NPs with dual-release mechanisms were developed for use in photothermal theranostic and chemotherapy. This modality has high potential for application in cancer treatment and clinical translation for drug delivery and imaging.

Degradable rhenium trioxide nanocubes with high localized surface plasmon resonance absorbance like gold for photothermal theranostics

The applications of inorganic theranostic agents in clinical trials are generally limited to their innate non-biodegradability and potential long-term biotoxicity. To address this problem, herein via a straightforward and tailored space-confined on-substrate route, we obtained rhenium trioxide (ReO3) nanocubes (NCs) that display a good biocompatibility and biosafety. Importantly, their aqueous dispersion has high localized surface plasmon resonance (LSPR) absorbance in near-infrared (NIR) region different from previous report, which possibly associates with the charge transfer and structural distortion in hydrogen rhenium bronze (HxReO3), as well as ReO3's cubic shape. Such a high LSPR absorbance in the NIR region endows them with photoacoustic (PA)/infrared (IR) thermal imaging, and high photothermal conversion efficiency (∼57.0%) for efficient ablation of cancer cells. Also, ReO3 NCs show X-ray computed tomography (CT) imaging derived from the high-Z element Re. More attractively, those ReO3 NCs, with pH-dependent oxidized degradation behaviors, are revealed to be relatively stable in hypoxic and weakly acidic microenvironment of tumor for imaging and treatment whilst degradable in normal physiological environments of organs to enable effective clearance. In spite of their degradability, ReO3 NCs still possess tumor targeting capabilities. We thus develop a simple but powerful, safe and biodegradable inorganic theranostic platform to achieve PA/CT/IR imaging-guided cancer photothermal therapy (PTT) for improved therapeutic efficacy and decreased toxic side effects.

Dopamine-mediated photothermal theranostics combined with up-conversion platform under near infrared light

An organic-inorganic hybrid core-shell nanostructure, based on mesoporous silica coated upconversion core-shell nanoparticles (NaGdF4:Yb,Er@NaGdF4:Yb@mSiO2-Dopa abbreviated here as UCNP@mSiO2-Dopa) that stably incorporates dopamine (Dopa) in the silica layer was introduced as a theranostic nanoplatform for optical imaging guided photothermal therapy (PTT) using NIR excitation. Silica-attaching polyethylenimine make the Dopa transforms into an active form (transferred Dopa) that strongly absorbs light under single 980 nm irradiation. We show that the activated UCNP@mSiO2-Dopa nanoplatform is able to produce a pronounced photothermal effect, that elevates water temperature from room temperature to 41.8 °C within 2 minutes, while concurrently emitting strong upconverted luminescence (UCL) for visualized guidance under 980 nm laser. In addition, we demonstrate the application of the same UCNP@mSiO2-Dopa nanoplatform for magnetic resonance imaging (MRI) and x-ray computed tomography (CT) enabled by the gadolinium (Gd) element contained in the UCNP. Importantly, the in vitro and in vivo anti-cancer therapeutic effects have been shown efficacious, implying the use of the described nanoplatform as an effective multi-modal imaging enabled PTT agent. Results from the in vivo biodistribution of UCNPs@mSiO2, cellular live/dead assay, and histologic analysis of main organs of treated mice, reveal that the UCNP@mSiO2-Dopa agents are bio-compatible with low toxicity.

Advances on the Use of Biodegradable Proteins/Peptides in Photothermal Theranostics

Recently, photothermal therapy (PTT) which employs light-induced heating to destroy cancer tissues/cells has received tremendous attention due to its improved selectivity and minimal invasion to surrounding healthy tissues. A variety of photothermal conversion agents (PTCAs) with high near-infrared (NIR) light absorbance have been widely explored for NIR light-induced PTT. However, many of them cannot be used directlyin vivoowing to their nonbiodegradability, immunogenicity, poor pharmacokinetics, or potential long-term toxicity. Proteins and peptides with inherent biocompatibility and biodegradability have been used as delivery vehicles for PTCAs or used as biotemplates to direct the synthesis of PTCAs. In this review, we will summarize recent advances in the development of protein/peptide-based photothermal cancer theranostics. The perspectives and challenges of these nanoplatforms will also be discussed.