Nanomedicine of tyrosine kinase inhibitors

Abstract

Recent progress in nanomedicine and targeted therapy brings new breeze into the field of therapeutic applications of tyrosine kinase inhibitors (TKIs). These drugs are known for many side effects due to non-targeted mechanism of action that negatively impact quality of patients' lives or that are responsible for failure of the drugs in clinical trials. Some nanocarrier properties provide improvement of drug efficacy, reduce the incidence of adverse events, enhance drug bioavailability, helps to overcome the blood-brain barrier, increase drug stability or allow for specific delivery of TKIs to the diseased cells. Moreover, nanotechnology can bring new perspectives into combination therapy, which can be highly efficient in connection with TKIs. Lastly, nanotechnology in combination with TKIs can be utilized in the field of theranostics, i.e. for simultaneous therapeutic and diagnostic purposes. The review provides a comprehensive overview of advantages and future prospects of conjunction of nanotransporters with TKIs as a highly promising approach to anticancer therapy.

Keywords: Bioavailability; Drug delivery; Nanotechnology; Targeted therapy.

Figure 1

Schematic representation of RTK downstream signaling - modified from KEGG: Kyoto Encyclopedia of Genes and Genomes Database.

Figure 2

Major sites of absorption, pharmacokinetic drug-drug interactions and elimination in TKI therapy. Abbreviations: TKI, tyrosine kinase inhibitor; MRPs, multidrug resistance protein drug transporters; P-gp, P-glycoprotein; CYPs, cytochrome P450 enzymes. *With increasing stomach pH the bioavailability of TKIs decreases. †Protein-bound molecules are not available to exert pharmacological effects. ‡Shows the association between CYPs and drug transporters in TKI absorption or metabolism. Adapted from Van Leeuwen et al. with publisher´s permission (license no. 4802950894525).

Figure 3

Pathways across the BBB. BBB consists of endothelial cells linked by tight junctions, encircled by pericytes and astrocytes, together with basal lamina and neurons. In between adjacent cells (paracellular pathway - A), some ions and solutes cross freely by passive diffusion. Other molecules utilize various transcellular pathways (B-F), like specific transporter proteins or receptor-mediated transcytosis and diffusion. Efflux transporters, such as P-glycoprotein (P-gp), prevent some substances from crossing the BBB. Adapted from Wang and Wu with publisher´s permission (license no. 4892530338842).

Figure 4

Schematic representation of the complexity of theranostic agents'. Basic approach employs a therapeutic molecule conjugated with a label. Nanoformulation allows attaching variety of different ligands and functional surface modifications to achieve prolonged blood circulation (e.g. PEGylation), controlled release of therapeutic agent (e.g. chitosan) or targeting for particular tissue or cell type (e.g. antibodies, peptides).

Figure 5

External and internal stimuli for controlled drug release. External stimuli allow for time and site-specific drug release triggered by the application of physical forces, as is magnetic field, temperature, ultrasound, electromagnetic field, light etc. On the other hand, internal stimuli stem from the nature of the tumor and its microenvironment, where specific pH, redox potential or enzyme activity act as a trigger in the tumor tissue or intracellularly. Adapted from Cheng et al. with publisher´s permission (license no. 4892530661903).

Figure 6

Representation of diagnostic and therapeutic properties of erlotinib-conjugated iron oxide NPs (FeDC-E NPs). Additionally to FeDC-E NPs capability of tumor growth inhibition, demonstrated by decrease of ectopic lung tumor mass and suppression of NF-κB expression captured (right), assessment of delivery efficacy and drug concentration estimation can be made, using MRI (left). Abbreviations: CTRL, control; FeDC-E NPs, erlotinib-conjugated iron oxide NPs; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; T2* decay of transverse magnetization caused by a combination of spin-spin relaxation and magnetic field inhomogeneity. Adapted from Hsu et al. with publisher´s permission (license no. 4802960989730).

Figure 7

The idea of future personalized medicine. AI-based technologies could be utilized in de novo target and drug discovery, prediction of drug efficacy, dosage or combination and response to therapy. Suitable drug candidates and strategies would then be tested and resulting final therapeutic approaches would be monitored by nanotheranostics. Obtained data could be fed back to AI to generate prediction of treatment success and adjustments of treatment plan. Adapted from Adir et al. with publisher's permission (license no. 4892531028481).