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

Abstract

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.

Zebrafish Insights into Nanomaterial Toxicity: A Focused Exploration on Metallic, Metal Oxide, Semiconductor, and Mixed-Metal Nanoparticles

“…A survey of European consumers found that NPs were present in over 2300 commercial products. Titanium dioxide (TiO 2 ), aluminum oxide (Al 2 O 3 ), silicon oxide (SiO 2 ), carbon nanotubes, ZnO, ferrous oxide, ceric oxide, Au, and CuS are common NPs [82][83][84][85][86][87]. The majority of nanoparticles (NPs) exhibit biocompatibility and chemical inertness, with examples such as gold and titanium dioxide [88].…”

Targeted EGFR Nanotherapy in Non-Small Cell Lung Cancer

“…When conjugating a biocompatible and photothermally conductive polymer (polypyrrole) to a TKI (afatinib) to direct near-infrared-photothermal therapy (NIR-PTT) in NSCLC, a research team found that polypyrrole-iron oxide-afatinib nanocomposite (PIA-NC) caused cancer cells to produce more reactive oxygen species (ROS), increased cytotoxicity, and minimized off-target biological effects of NIR-PTT [ 132 ].…”

Interventional Hydrogel Microsphere Controlled‐Releasing Curcumin for Photothermal Therapy against Endometriosis

“…[ 7 ] By increasing the temperature of the surrounding tissue of photothermal agents through PTT, cell apoptosis (42–46 °C) or necrosis (>46 °C, thermal ablation) can be achieved, facilitating localized elimination of pathological tissue. [ 8,9 ] The near‐infrared (NIR) region is known as the biological window because NIR light has a relatively low absorption coefficient of biological systems and deep penetration capabilities, which can enable many nanoparticles (NPs) to produce photothermal activity, such as Au NPs and iron oxide NPs. [ 10 ] However, due to the small size of NPs and their rapid migration to the liver, spleen, and lung (>80%) as a result of blood circulation and metabolic scavenging, nanoparticle localization period and dosage in target tissues are not ideal.…”