Near-infrared Photothermal Therapy Research Articles

Ginsenoside Rg3 combined with near‐infrared photothermal reversal of multidrug resistance in breast cancer MCF‐7/ADR cells

AbstractAdriamycin (ADR) is a frequently employed chemotherapeutic agent for the management of breast cancer. Nevertheless, multidrug resistance (MDR) can impair its therapeutic efficacy in breast cancer. MDR is characterized by increased expression of the P‐glycoprotein (P‐gp) efflux pump, up‐regulation of anti‐apoptotic proteins, and downregulation of pro‐apoptotic proteins. Consequently, inhibition of ATP‐binding cassette (ABC) transporter proteins has been deemed the most efficacious approach to overcome MDR. In this study, we used MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide), Western blots, flow cytometry, immunofluorescence, and constructed xenograft tumors to investigate whether ginsenoside Rg3‐near‐infrared photothermal (Rg3‐NIR) combination reversed multidrug resistance in MCF‐7/ADR breast cancer. In vivo and in vitro experiments, the results showed that Rg3‐NIR co‐treatment was effective in inducing the apoptosis of MCF‐7/ADR breast cancer cells. This was achieved by reversing the expression of drug resistance‐associated proteins, while also inhibiting cell proliferation, migration, and epithelial–mesenchymal transition (EMT) processes via attenuation of the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway transduction. Ginsenoside Rg3 combined with near‐infrared photothermal therapy (NIR) effectively reverses multidrug resistance in breast cancer MCF‐7/ADR cells, providing a new therapeutic strategy for breast cancer drug resistance.

Chaotropic Effect-Induced Sol-Gel Transition and Radical Stabilization for Bacterially Sensitive Near-Infrared Photothermal Therapy.

Deep-seated bacterial infections (DBIs) are stubborn and deeply penetrate tissues. Eliminating deep-seated bacteria and promoting tissue regeneration remain great challenges. Here, a novel radical-containing hydrogel (SFT-B Gel) cross-linked by a chaotropic effect was designed for the sensing of DBIs and near-infrared photothermal therapy (NIR-II PTT). A silk fibroin solution stained with 4,4',4″-(1,3,5-triazine-2,4,6-triyl)tris(1-methylpyridin-1-ium) (TPT3+) was employed as the backbone, which could be cross-linked by a closo-dodecaborate cluster (B12H122-) through a chaotropic effect to form the SFT-B Gel. More interestingly, the SFT-B Gel exhibited the ability to sense DBIs, which could generate a TPT2+• radical with obvious color changes in the presence of bacteria. The radical-containing SFT-B Gel (SFT-B★ Gel) possessed strong NIR-II absorption and a remarkable photothermal effect, thus demonstrating excellent NIR-II PTT antibacterial activity for the treatment of DBIs. This work provides a new approach for the construction of intelligent hydrogels with unique properties using a chaotropic effect.

Analysis of photothermal coupling of titanium nitride nanorods applied to near-infrared photothermal therapy

Titanium nitride (TiN) serves as an ideal reagent for photothermal therapy due to its cost-effectiveness, stability, and biocompatibility. This study investigates the optical and thermal properties of TiN nanoparticles in the near-infrared (NIR) region. Specifically, we employ the COMSOL Multiphysics software to solve Maxwell's equations using a finite element method, enabling us to investigate the photothermal characteristics of individual TiN nanorods. To ensure accurate photothermal coupling calculations, we utilize the Fourier steady-state heat conduction equation. The results demonstrate that the nanorod photothermal properties exhibit significantly enhanced effects when the incident light is polarized along the long axis of the rod, while the thermal properties of the nanorods are primarily influenced by their optical absorption efficiency. The tunability investigation of the nanorods demonstrates that an increase in aspect ratio (AR) results in a red-shift of the absorption peaks. Concurrently, there is an expansion in the bandwidth corresponding to the absorption peak, accompanied by an augmentation in its peak value. It is evident that at AR = 5, the TiN nanorods exhibit enhanced photothermal properties in the NIR region, resulting in a temperature increase of 43 K in the surrounding medium through efficient heat transfer. Consequently, this accomplishment enables achieving the desired temperature range for effective photothermal therapy. The significance of this study lies in providing a valuable reference and theoretical guidance for exploring the utilization of TiN nanorods in photothermal therapy, with a specific focus on attaining a more precise understanding of temperature elevation and distribution during the treatment process.

Cancer-targeting gold-decorated melanin nanoparticles for in vivo near-infrared photothermal therapy

Melanin-like nanoparticles decorated with gold nanoparticles are presented as cancer-targeting near-infrared (NIR) photothermal agents with excellent photothermal conversion and stability.

A Covalent Organic Framework Derived N-doped Carbon Nanozyme as the All-rounder for Targeted Catalytic Therapy and NIR-II Photothermal Therapy of Cancer.

Nanomaterials with intrinsic enzyme-like activities (nanozymes) have gained significant attention in cancer catalytic therapy; however, developing metal-free nanozymes with multivariant enzyme-like activity as the "all-rounder" for cancer therapy remains challenging. Herein, a covalent organic framework (COF) derived carbon-based nanozyme is rationally devised to achieve synergistic catalytic therapy and second near-infrared (NIR-II) photothermal therapy of cancer. The developed nanozyme possesses multivariant enzyme-like activities, including oxidase (OXD)-like, catalase (CAT)-like, and peroxidase (POD)-like catalytic activities, which enables the nanozyme to produce adequate reactive oxygen species (ROS) for cancer cell killing. Furthermore, the nanozyme showed excellent photothermal converting activity that could kill cancer cells upon NIR-II laser irradiation, owing to the strong NIR-II absorption capacity of carbon-based materials. It is also worth noting that the nanozyme exhibited cytotoxicity specifically in tumor tissue profiting from the discrepant H2O2 level between tumor and normal tissue and the spatiotemporal controllability of laser irradiation. This work may inspire further development of intelligent nanozymes in biological applications across broad therapeutic and biomedical fields.

Biogenic Copper Selenide Nanoparticles for Near-Infrared Photothermal Therapy Application.

Near-infrared (NIR) photothermal therapy (PTT) is attractive for cancer treatment but is currently restricted by limited availability and insufficient NIR-II photoactivity of photothermal agents, for which artificial nanomaterials are usually used. Here, we report the first use of biogenic nanomaterials for PTT application. A fine-controlled extracellular biosynthesis of copper selenide nanoparticles (bio-Cu2-xSe) by Shewanella oneidensis MR-1 was realized. The resulting bio-Cu2-xSe, with fine sizes (∼35.5 nm) and high product purity, exhibited 76.9% photothermal conversion efficiency under 1064 nm laser irradiation, outperforming almost all the existing counterparts. The protein capping also imparted good biocompatibility to bio-Cu2-xSe to favor a safe PTT application. The in vivo PTT with injected bio-Cu2-xSe in mice (without extraction nor further modification) showed 87% tumor ablation without impairing the normal organisms. Our work not only opens a green route to synthesize the NIR-II photothermal nanomaterial but may also lay a basis for the development of bacteria-nanomaterial hybrid therapy technologies.

Insight into the photothermal therapeutic impacts of silica-coated iron oxide nanocomposites

Recently, near-infrared photothermal therapy combined with targeted nano-sensitizer has been used for cancer eradication as it protects the surrounding tissues. Although iron oxide nanoparticles (INPs) are efficient photo-heat conversion agents, they tend to agglomerate, restricting their utility in medical applications. We prepared silica-coated INPs (SCINPs) to overcome this obstacle. The physical properties of INPs and SCINPs were evaluated using transmission electron microscope (TEM), dynamic light scattering (DLS), vibrating sample magnetometer (VSM), atomic force microscope (AFM) and X-RAY diffraction (XRD). The polydispersity index (PDI) value was 0.21 and 0.44 for INPs and SCINPs, respectively. Zeta potential measurements showed that the prepared nanoparticles had negative net surface charges with average values of −28 ± 4.21 and −48 ± 5 mv for INPs and SCINPs, respectively. This is a pioneered study that evaluate the photothermal therapeutic effect of silica coated iron oxide nanoparticles. In addition to evaluate their photothermal therapeutic effect, as nano photothermal agents, using comet assay and oxidative stress parameters. Also, their photothermal therapeutic effect were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Photothermal assessment indicated that SCINPs could improve the photothermal therapy (PTT) because of their reproducible hyper-thermic and hypo-thermic effects with repeated treatment. Compared to INPs, SCINPs significantly improved the photothermal therapeutic behavior in treated cells by around 1.88 folds. SCINPs were more effective photothermal therapeutic agents and had considerable potential as novel therapeutic agents.

Intramolecular charge transfer versus intersystem crossing: The way toward super-high photothermal efficiency by thionation

Development of organic molecules with high photothermal conversion efficiency (PCE) in the near-infrared (NIR) window is a vital yet challenging topic in the field of photothermal therapy. A series of thionated perylenediimides (PDI-4CHA-S) derivatives have been synthesized by replacing carboxylic oxygens in imides with sulfur atoms, providing chances to unravel the effect of thionation on the photophysical properties toward photothermal agents (PTAs) with high PCE. In the presence of the electron-donating substituents at the bay-position, sulfur atoms participate the intramolecular charge transfer (ICT), which induces remarkable redshift in the absorption maximum. Meanwhile, the ICT together with the heavy atoms effect of sulfur atoms promotes the intersystem crossing (ISC), resulting in the generation of the active oxygen species (ROS) upon photoexcitation. Interestingly, the quantum yield of ROS decrease with increasing the number of S-substitutes, which is the resultant of the attenuated ICT in the case of multiple S-substitution. Overall, the promotion in ISC due to thionation is negligible compared to the quenching of the radiation transition and enhancement of the absorption coefficient caused by ICT, hence the energy of the excited PDI-4CHA-S molecules is depleted mainly in the form of heat, leading to the ultrahigh PCE of 88.0% under 808 nm laser irradiation. In particular, the trithionated PDI-4CHA-3S performs surprisingly high PCE in the second near-infrared (NIR-II) window (1064 nm). The superior photothermal effect and excellent photostability of the thionated PDI derivative provide them promising photothermal agents for NIR photothermal therapy.

Afterglow/Photothermal Bifunctional Polymeric Nanoparticles for Precise Postbreast-Conserving Surgery Adjuvant Therapy and Early Recurrence Theranostic.

Adjuvant whole-breast radiotherapy is essential for breast cancer patients who adopted breast-conserving surgery (BCS) to reduce the risk of local recurrences, which however suffer from large-area and highly destructive ionizing radiation-induced adverse events. To tackle this issue, an afterglow/photothermal bifunctional polymeric nanoparticle (APPN) is developed that utilizes nonionizing light for precise afterglow imaging-guided post-BCS adjuvant second near-infrared (NIR-II) photothermal therapy. APPN consists of a tumor cell targeting afterglow agent, which is doped with a NIR dye as an afterglow initiator and a NIR-II light-absorbing semiconducting polymer as a photothermal transducer. Such a design realizes precise afterglow imaging-guided NIR-II photothermal ablation of minimal residual breast tumor foci after BCS, thus achieving complete inhibition of local recurrences. Moreover, APPN enables early diagnosis and treatment of local recurrence after BCS. This study thus provides a nonionizing modality for precision post-BCS adjuvant therapy and early recurrence theranostic.

Bimetallic Hyaluronate-Modified Au@Pt Nanoparticles for Noninvasive Photoacoustic Imaging and Photothermal Therapy of Skin Cancer.

Although spherical gold (Au) nanoparticles have remarkable photothermal conversion efficiency and photostability, their weak absorption in the near-infrared (NIR) region and poor penetration into deep tissues have limited further applications to NIR light-mediated photoacoustic (PA) imaging and noninvasive photothermal cancer therapy. Here, we developed bimetallic hyaluronate-modified Au-platinum (HA-Au@Pt) nanoparticles for noninvasive cancer theranostics by NIR light-mediated PA imaging and photothermal therapy (PTT). The growth of Pt nanodots on the surface of spherical Au nanoparticles enhanced the absorbance in the NIR region and broadened the absorption bandwidth of HA-Au@Pt nanoparticles by the surface plasmon resonance (SPR) coupling effect. In addition, HA facilitated the transdermal delivery of HA-Au@Pt nanoparticles through the skin barrier and enabled clear tumor-targeted PA imaging. Compared to conventional PTT via injection, HA-Au@Pt nanoparticles were noninvasively delivered into deep tumor tissues and completely ablated the targeted tumor tissues by NIR light irradiation. Taken together, we could confirm the feasibility of HA-Au@Pt nanoparticles as a NIR light-mediated biophotonic agent for noninvasive skin cancer theranostics.

Dopamine multivalent-modified polyaspartic acid for MRI-guided near-infrared photothermal therapy.

Nanophotothermal agents that provide efficient and precise treatment at tumor sites are attracting increasing attention in biomedicine. In particular, the method combination of nanophotothermal agents and magnetic resonance imaging (MRI) shows great promise for biomedical therapeutic applications. Herein, a simple nanophotothermal agent with dopamine multivalent-modified polyaspartic acid chelated superparamagnetic iron oxide (SPIO) and ferric ion (SPIO@PAsp-DAFe/PEG) was developed for MRI-guided near-infrared photothermal therapy (PTT). SPIO@PAsp-DAFe/PEG was random SPIO nanocluster with good water solubility, had a diameter of 57.8 ± 7.8 nm in dynamic light scattering, negatively charged surface (zeta potential = -11 mV), exhibited good stability and outstanding photothermal conversion efficiency (35.4%) and produced superior magnetic resonance enhanced imaging. In the experiment with tumor-bearing mice, the MRI not only monitored the accumulation of SPIO@PAsp-DAFe/PEG nanocomposites enhanced by near-infrared irradiation after intravenous administration but also determined the appropriate time window for PTT. With the use of MRI-guided near-infrared therapy, the SPIO@PAsp-DAFe/PEG nanocomposites provided excellent therapeutic effects, confirming their great potential as effective MRI/PTT therapeutic agents.

Aqueous green synthesis of organic/inorganic nanohybrids with an unprecedented synergistic mechanism for enhanced near-infrared photothermal performance.

Silver sulfide (Ag2S) nanoparticles (NPs) represent one of the most popular inorganic reagents for near-infrared (NIR) photothermal therapy (PTT). However, the extensive biomedical applications of Ag2S NPs are greatly compromised by the hydrophobicity of the NPs prepared in organic solvents, their low photothermal conversion efficiency, certain surface modification-induced damage to their intrinsic properties and short circulation time. To develop a facile yet efficient green approach to overcome these shortcomings for improved properties and performance of Ag2S NPs, we report herein the construction of Ag2S@polydopamine (PDA) nanohybrids via a "one-pot" organic-inorganic hybridization strategy, which produces uniform Ag2S@PDA nanohybrids with well-modulated sizes in the range of 100-300 nm via the self-polymerization of dopamine (DA) and subsequent synergistic assembly of PDA with Ag2S NPs in a three-phase mixed medium containing water, ethanol and trimethylbenzene (TMB). Integration of dual photothermal moieties, i.e., Ag2S and PDA at a molecular level, endows Ag2S@PDA nanohybrids with synergistically enhanced NIR photothermal properties that are much better than those of either PDA or Ag2S NPs due to calculated combination indexes (CIs) of 0.3-0.7 between Ag2S NPs and PDA based on a modified Chou-Talalay method. Therefore, this study not only developed a facile "one-pot" green approach toward producing uniform Ag2S@PDA nanohybrids with well-modulated dimensions, but also revealed an unprecedented synergistic mechanism for organic/inorganic nanohybrids that is based on dual photothermal moieties providing enhanced near-infrared photothermal performance.

Flower-like Cu9S8 nanocatalysts with highly active sites for synergistic NIR-II photothermal therapy and chemodynamic therapy.

Chemodynamic therapy (CDT) is a promising reactive oxygen species-based therapeutic strategy for tumor therapy. However, the poor reaction kinetics of CDT agents severely restricts its further application. Herein, protamine stabilized flower-like Cu9S8 (PS@Cu9S8) nanocatalysts are fabricated via a one-pot biomineralization strategy for synergistic second near-infrared (NIR-II) photothermal therapy (PTT) and CDT of tumor. The PS@Cu9S8 nanocatalysts possess a high surface area (40.10 m2 g-1), which is higher than those of the previously reported solid and hollow copper sulfide nanoparticles. The high surface area of PS@Cu9S8 nanocatalysts increases the number of active sites during the Fenton-like reaction, thereby accelerating the efficiency of CDT. Meanwhile, the PS@Cu9S8 nanocatalysts show a high extinction coefficient (21.41 L g-1 cm-1) and photothermal conversion efficiency (42.34%), which results in an outstanding PTT efficiency and facilitate ˙OH generation for CDT. Furthermore, RNA-sequencing unveils the whole-genome expression change of 4T1 cells after PS@Cu9S8 nanocatalyst treatment, revealing the apparent changes in ROS, cell cycle, and apoptosis-related pathways. In vivo experiments proved the good therapeutic efficiency and negligible systematic toxicity of PS@Cu9S8 nanocatalysts. This work not only develops a superior multifunctional nanocatalyst for synergistic PTT and CDT of tumor, but also provides a facile approach to construct high-performance agents for cancer therapy.

A carbon dot-doped Cu-MOF-based smart nanoplatform for enhanced immune checkpoint blockade therapy and synergistic multimodal cancer therapy.

Immune checkpoint blockade (ICB) is a kind of promising anti-tumor immunotherapy that can block the negative immune regulatory pathways using a particular antibody. Weak immunogenicity in most patients is a key obstacle to ICB therapy. Photodynamic therapy (PDT) is a non-invasive treatment that can enhance the immunogenicity of the host and realize systemic anti-tumor immunotherapy; yet tumor microenvironment hypoxia and glutathione overexpression severely restrict the PDT effect. To overcome the above issues, we design a combination therapy based on PDT and ICB. We prepared red carbon dot (RCD)-doped Cu-metal-organic framework nanoparticles (Cu-MOF@RCD) as smart nano-reactors because their tumor microenvironment and near-infrared light responsive property can decompose tumor endogenous H2O2 through Fenton-like reactions. Cu-MOF@RCD also shows clear near-infrared photothermal therapy (PTT) effect and has an ability to deplete glutathione (DG), which together enhances decomposition of cellular H2O2 and amplifies reactive oxygen species (ROS) levels in cells, thus leading to enhanced PDT and chemodynamic therapy (CDT) effect. Moreover, programmed cell death-ligand 1 antibody (anti-PD-L1) is used together to enable combination therapy, as Cu-MOF@RCD can significantly enhance host immunogenicity. In summary, the combination of Cu-MOF@RCD with anti-PD-L1 antibody exerts a synergistic PDT/PTT/CDT/DG/ICB therapy and can be used to eradicate the primary tumors and inhibit the growth of untreated distant tumors and tumor metastasis.

Near-infrared photothermal therapy of chiral Au helicoids with broadband optical absorption

Chiral Au helicoids have broadband optical absorption and a high anisotropy factor from 550 nm to 1100 nm and have a chirality dependent PTT inactivation effect on HeLa cells under NIR CPL.

Amylase degradation enhanced NIR photothermal therapy and fluorescence imaging of bacterial biofilm infections.

Effective treatment of bacterial biofilm-related infections is a great challenge for the medical community. During the formation of biofilms, bacteria excrete extracellular polymeric substances (EPS), including polysaccharides, proteins, nucleic acids, etc., to encapsulate themselves and form a "fort-like" structure, which greatly reduces the efficiency of therapeutic agents. Herein, we prepared a nanoagent (MnO2-amylase-PEG-ICG nanosheets, MAPI NSs) with biofilm degradation capability for efficient photothermal therapy and fluorescence imaging of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections. MAPI NSs were constructed by sequentially modifying α-amylase, polyethylene glycol (PEG), and indocyanine green (ICG) on manganese dioxide nanosheets (MnO2 NSs). Experimental results exhibited that MAPI NSs could accumulate in infected tissues after intravenous injection, degrade in the acidic biofilm microenvironment, and release the loaded ICG for near-infrared (NIR) fluorescence imaging of the infected tissues. Importantly, MAPI NSs could efficiently eliminate MRSA biofilm infections in mice by α-amylase enhanced photothermal therapy. In addition, MAPI NSs exhibited neglectable toxicity towards mice. Given the superior properties of MAPI NSs, the enzyme-degradation enhanced therapeutic strategy presented in this work offers a promising solution for effectively combating biofilm infectious diseases.

Heterojunction structured BiOCl-Bi2S3 nanosheets as mitochondria-targeted near-infrared photothermal and photodynamic therapy agent

Mitochondria-targeted phototherapy, especially combined photothermal therapy (PTT) and photodynamic therapy (PDT), has been regarded as an attractive strategy for the treatment of tumor. In this study, a facile approach to prepare two-dimensional (2D) BiOCl-Bi2S3 nanostructures was developed, where Bi2S3 quantum dots were doped in/on the ultrathin BiOCl nanosheets, forming a p-n heterojunction. The BiOCl-Bi2S3 shows favorable photothermal conversion efficiency (32%) and synergistically reactive oxygen species (ROS) generating capability under near-infrared (NIR) irradiation. Moreover, the conjugation of synthetic targeting ligand to the surface of BiOCl-Bi2S3 endows the heterojunction effective tumor targeting ability and selective mitochondrial accumulation. The combined cancer targeting ability and synergistic PTT/PDT permit enhanced cooperative phototherapeutic efficiency of the 2D heterojunction. This study provides an attractive way for designing new class of heterostructure materials for potential applications in subcellular-targeted phototherapy.

Semiconducting polymer nanomanipulators for thermal sensitization and metastasis-inhibited synergistic cancer therapy

Manipulation of intracellular protein expression is a promising cancer therapeutic approach; however, traditional strategies relying on nonspecific molecular drugs often suffer from limited therapeutic benefits and off-target adverse events. Here, we report a semiconducting polymer nanomanipulator (SPNm) that can photothermally manipulate intracellular protein expression to synergize with its own function of second near-infrared (NIR-II) photothermal therapy (PTT) for thermal sensitization and metastasis-inhibited cancer therapy. SPNm comprises an NIR-II absorbing semiconducting polymer core as a photothermal transduction agent and a lysine-specific histone demethylase 3 A (KDM3A) inhibitor as a downstream effector protein expression manipulator, which are encapsulated into a thermo-responsive lipid shell. Upon 1064 nm laser irradiation, SPNm mediates the photothermal effect to melt the lipid shell for on-demand release of the KDM3A inhibitor to inhibit the demethylation function of KDM3A to upregulate the level of di-methylation of histone H3 lysine 9 (H3K9me2), and in turn simultaneously downregulate the expression of heat-shock protein 90 (HSP90) and cancer cell metastasis-related proteins, consequently inhibiting the thermotolerance response and metastasis of cancer cells. Thus, a single treatment of SPNm-mediated two-step NIR-II phototherapy achieves efficient tumor growth suppression at an unprecedented photothermal ablation depth (1 cm) and lung metastasis inhibition. Therefore, this study provides a promising thermal-controlled strategy to synergize phototherapeutics with protein expression manipulation for enhanced cancer treatment.

Phosphotungstate Acid Doped Polyanilines Nanorods for in situ NIR-II Photothermal Therapy of Orthotopic Hepatocellular Carcinoma in Rabbit.

Second near-infrared photothermal therapy (NIR-II PTT) has become a promising strategy for treating cancer in terms of safety and potency. However, the application of NIR-II PTT was limited in the treatment of deep-buried solid tumors due to the low dose of NIR-II absorption nanomaterials and the inadequate laser energy in the deep tumor. Herein, the authors report the engineering of NIR-II absorbing polyaniline nanorods, termed HPW@PANI Nanorods, for in situ NIR-II PTT based on optical fibers transmission of laser power and transarterial infusion for the treatment of orthotopic hepatocellular carcinoma in the rabbit. HPW@PANI Nanorods were prepared via chemical oxidant polymerization of aniline under phosphotungstic acid, which exhibited effective NIR-II absorption for hyperthermia ablation cells. HPW@PANI Nanorods were fast and efficiently deposited into primary orthotopic transplantation VX2 tumor in rabbits via transarterial infusion. Furthermore, an optical fiber was interventionally inserted into the primary VX2 tumor to transmit 1064nm laser energy for in situ NIR-II PTT, which could ablate primary tumor, inhibit distant tumor, and suppress peritoneal metastasis. This study provides new insights into the application of in situ NIR-II PTT based on optical fibers transmission of laser power and transarterial injection of NIR-II absorption nanomaterials to treat deep-buried tumors.

Molecularly Targeted Photothermal Ablation of Epidermal Growth Factor Receptor-Expressing Cancer Cells with a Polypyrrole-Iron Oxide-Afatinib Nanocomposite.

Simple SummaryIn this manuscript, we describe the design and synthesis of a nanocomposite containing afatinib, polypyrrole, and iron oxide (PIA-NC) to molecularly target epidermal growth factor receptor (EGFR)-overexpressing cancer cells for photothermal conversion. In addition to physical and chemical characterization, we also showed that PIA-NC induces selective reactive oxygen species surge and apoptosis in response to sublethal near-infrared light only in EGFR-overexpressing cancer cells, not in EGFR-negative fibroblasts. The work demonstrates the feasibility of photothermal therapy with cellular precision.Near-infrared–photothermal therapy (NIR-PTT) is a potential modality for cancer treatment. Directing photothermal effects specifically to cancer cells may enhance the therapeutic index for the best treatment outcome. While epithelial growth factor receptor (EGFR) is commonly overexpressed/genetically altered in human malignancy, it remains unknown whether targeting EGFR with tyrosine kinase inhibitor (TKI)-conjugated nanoparticles may direct NIR-PTT to cancers with cellular precision. In the present study, we tested this possibility through the fabrication of a polypyrrole–iron oxide–afatinib nanocomposite (PIA-NC). In the PIA-NC, a biocompatible and photothermally conductive polymer (polypyrrole) was conjugated to a TKI (afatinib) that binds to overexpressed wild-type EGFR without overt cytotoxicity. A Fenton catalyst (iron oxide) was further encapsulated in the NC to drive the intracellular ROS surge upon heat activation. Diverse physical and chemical characterization experiments were conducted. Particle internalization, cytotoxicity, ROS production, and apoptosis in EGFR-positive and -negative cell lines were investigated in the presence and absence of NIR. We found that the PIA-NCs were stable with a size of 243 nm and a zeta potential of +35 mV. These PIA-NCs were readily internalized close to the cell membrane by all types of cells used in the study. The Fourier transform infrared spectra showed 3295 cm−1 peaks; substantial O–H stretching was seen, with significant C=C stretching at 1637 cm−1; and a modest appearance of C–O–H bending at 1444 cm−1 confirmed the chemical conjugation of afatinib but not iron oxide to the NC. At a NIR-PTT energy level that has a minimal cytotoxic effect, PIA-NC significantly sensitizes EGFR-overexpressing A549 lung cancer cells to NIR-PTT-induced cytotoxicity at a rate of 70%, but in EGFR-negative 3T3 fibroblasts the rate was 30%. Within 1 min of NIR-PTT, a surge of intracellular ROS was found in PIA-NC-treated A549 cells. This was followed by early induction of cellular apoptosis for 54 ± 0.081% of A549 cells. The number of viable cells was less than a quarter of a percent. Viability levels of A549 cells that had been treated with NIR or PIA were only 50 ± 0.216% and 80 ± 0.216%, respectively. Only 10 ± 0.816% of NIH3T3 cells had undergone necrosis, meaning that 90 ± 0.124% were alive. Viability levels were 65 ± 0.081% and 81 ± 0.2%, respectively, when only NIR and PIA were used. PIA binding was effective against A549 cells but not against NIH3T3 cells. The outcome revealed that higher levels of NC + NIR exposure caused cancer cells to produce more ROS. In summary, our findings proved that a molecularly targeted NC provides an orchestrated platform for cancer cell-specific delivery of NIR-PTT. The geometric proximity design indicates a novel approach to minimizing the off-target biological effects of NIR-PTT. The potential of PIA-NC to be further developed into real-world application warrants further investigation.