Innovative Approaches in Cancer Treatment: Emphasizing the Role of Nanomaterials in Tyrosine Kinase Inhibition

Abstract

Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge technologies, structure-based drug design, and personalized medicine, is critical for developing effective therapies, specifically anticancer treatments. Background/Objectives: One of the key drivers of cancer at the cellular level is the abnormal activity of protein enzymes, specifically serine, threonine, or tyrosine residues, through a process known as phosphorylation. While tyrosine kinase-mediated phosphorylation constitutes a minor fraction of total cellular phosphorylation, its dysregulation is critically linked to carcinogenesis and tumor progression. Methods: Small-molecule inhibitors, such as imatinib or erlotinib, are designed to halt this process, restoring cellular equilibrium and offering targeted therapeutic approaches. However, challenges persist, including frequent drug resistance and severe side effects associated with these therapies. Nanomedicine offers a transformative potential to overcome these limitations. Results: By leveraging the unique properties of nanomaterials, it is possible to achieve precise drug delivery, enhance accumulation at target sites, and improve therapeutic efficacy. Examples include nanoparticle-based delivery systems for TKIs and the combination of nanomaterials with photothermal or photodynamic therapies to enhance treatment effectiveness. Combining nanomedicine with traditional treatments holds promise and perspective for synergistic and more effective cancer management. Conclusions: This review delves into recent advances in understanding tyrosine kinase activity, the mechanisms of their inhibition, and the innovative integration of nanomedicine to revolutionize cancer treatment strategies.

Keywords: anticancer treatment; drug delivery; gold nanoparticles; metal nanoparticles; nanomaterials; nanomedicine; tyrosine kinase inhibitors.

Figure 1

Structure of receptor tyrosine kinase. Receptor tyrosine kinase is composed of an outer and an inner part that are joined by the cell membrane. The extracellular part contains the ligand binding site, and the internal, cytoplasmic part is formed by the juxtamembrane region and TK domain with an N-lobe, an activation loop, a C-lobe, and a tail end with a phosphate binding site. The ATP binding site forms the interface between the N- and C-lobe. Created in BioRender.

Figure 2

Activation of receptor tyrosine kinase. 1 The inactive RTK monomer. 2 Receptor kinase activation begins with ligand binding to the extracellular portion of the receptor. This leads to activation and subsequent dimerization of the receptor. 3 The response is activation of protein kinase activity in the cytoplasmic portion of the receptor. 4 Activation of TKD in the intrinsic region promotes autophosphorylation of tyrosine residues at the C-terminal tail, the JMR, and at the activation loop and leads to further activation. Abnormal tyrosine kinase activity usually causes cell proliferation disorders. Created in BioRender.

Figure 3

Timeline of EMA (top) and FDA (bottom) approved TKIs. The first approved tyrosine kinase inhibitor was a drug named Glivec (Europe)/Gleevec (US) in 2001, which targets the non-receptor tyrosine kinase BCR-ABL. Active substance imatinib is intended for the treatment of myeloproliferative disorders. The first TKI targeting receptor tyrosine kinase was Iressa with the therapeutic substance gefitinib (EGFR primary target), which was approved by the FDA in 2003. The EMA approved the drug under the same name in 2009. Iressa is used for the treatment of non-small-cell lung carcinoma. In 2023, the FDA approved a total of 6 new drugs directed to treat acute myeloid leukemia (Vanflyta), non-small-cell lung carcinoma (Augtyro; disapproved by EMA), mantle cell lymphoma (Jaypirca) or alopecia areata (Litfulo). Currently, the latest approved drugs in the EU are Fruzaqla (Fruguintinib) for the treatment of metastatic colorectal cancer, Balversa (Erdafitinib) for the treatment of urothelial bladder and urinary cancer, which was already approved by the FDA in 2019, and one non-receptor inhibitor Omjjara (US Ojjaara) for the treatment of myeloproliferative diseases.

Figure 4

Procedure of PEG-PEI-AuAg@PYR@HCT (PPAPH) synthesis and PPAPH therapy for HER2 positive breast cancer. Hollow gold–silver nanocarriers with a porous structure for efficient Pyrotinib (PYR) loading were prepared using an electrodisplacement method. Premature drug release was prevented by surface modification with lipoic acid and polyethyleneimine (LA-PEI) and thiolated polyethylene glycol (SH-PEG). Subsequent modification with Herceptin (HCT) allowed precise targeting of HER2-overexpressing tumor cells. Localized, laser-induced hyperthermia and chemotherapy enhanced cytotoxicity and was highly effective in suppressing HER2-overexpressing BT474 cells. Tumor cell death was significantly promoted by the increase in ROS induced by AuAg hollow nanoshells. The synergistic effect of the nanosystem led to significant tumor shrinking in a mouse model of HER2-positive breast cancer. Reprinted with permission from Ref. [145]. Copyright 2024, John Wiley and Sons.

Figure 5

In vivo therapeutic effect of cRGD-GIPG NPs on a PC-9GR tumor-bearing mouse model. Real-time fluorescence images (a) demonstrate that GIPg and cRGD-GIPG rapidly accumulated in the tumor area after intravenous administration due to increased permeability. The fluorescence intensity (b) and accumulation rate in tumor sites were higher in the cRGD-GIPG group. Real-time infrared thermography (c) and temperature change curve (d) showed that cRGD-GIPG nanoparticles could significantly increase the tumor temperature to 42.8 °C after 5 min of irradiation, indicating nanoparticle accumulation in the tumor tissue and undergoing photothermal transformation. The H&E (e) staining assay was used to verify the therapeutic efficacy of different treatment groups demonstrated the most severe degree of apoptosis and cell necrosis in cRGD-GIPG+laser+US tissues. The reason behind this was that temperature change in the tumor area caused by laser irradiation was not uniform enough, while US irradiation reached deeper tissue layers and thus achieved a synergistic effect of the treatment (scale bar = 200 μm). Reprinted with permission from Ref. [148]. Copyright 2023, Royal Society of Chemistry.

Figure 6

Confocal images of gold nanoparticles cell internalization. CD44 receptor-mediated nanocarrier internalization in pathological cells was demonstrated by treating lung fibroblasts with GNP-HC and GNP-IgG labeled with Alexa 488 fluorescent dye. Confocal microscopy demonstrated rapid selective internalization of GNP-HC in LF as evidenced by the green, fluorescent signal (A). GNPs-IgG were not internalized by the cells within 2 h of incubation (B) and the reason for this is that internalization requires the presence of a specific anti-CD44 antibody on the surface of the GNPs. Competition with specific antibody for CD44 formed an aggregate within the cells (C), and pretreatment with anti-CD44 did not alter the GNP-IgG-cell interaction (D). Reprinted with permission from Ref. [155]. Copyright 2019, Elsevier.

Figure 7

In vivo tumor delivery and biodistribution. Gold nanoparticles synthesized in micellar networks of amphiphilic block copolymer (AuNM) and conjugated with IR680 dye were fluorescently imaged (A) using IVIS spectra, while female mice with MDA-MB-231 human breast xenografts were injected with PBS or IR680-AuNM. After 18 h, a distinct fluorescent signal was observed in the tumor area. To further define AuNM biodistribution (B), ex vivo organ imaging was performed and the presence of AuNM was confirmed mainly in the liver (Li), lung (Lu), kidney (Ki) and intestine (In). Increased fluorescence signal was also observed in the tumor area, indicating the retention of Ir680-AuNM in the tissue. Reprinted with permission from Ref. [158]. Copyright 2017, American Chemical Society.