Abstract
Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.
Highlights
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The evolutionary probability of resistance can be overcome with the association of two or more compounds, but this approach does not seem to be conclusive; the advent of nanotechnologies seems to be of great importance
These NPs showed good in vitro serum stability and hemocompatibility with a sustained release of Dasatinib in acidic pH and showed a 1.35-fold increased cytotoxicity against the triplenegative human breast cancer cell line (MDA-MB-231). These results suggest that Dasatinib-loaded Magnetic nanoparticles (MNPs) possess a great potential for breast cancer targeted therapy
Summary
Intracellular protein tyrosine kinases, including Abelson (Abl), Src, JNK and many others, play a pivotal role in signal transduction pathways and cancer development, being highly activated in malignant tumor cells, but having very low activity and expression in normal cells [1]. The greatest progress has been made with the use of TKIs in the treatment of chronic myeloid leukemia (CML) The majority of these molecules are ATP-competitive inhibitors and are not selective, acting on receptor tyrosine kinases (in particular, platelet-derived growth factor receptor, PDGFR, and vascular endothelial growth receptor, VEGFR) or other intracellular kinases with different selectivity and potency. As IM inhibits PDGFR and c-Kit, two other transmembrane TKs, it has been approved as frontline therapy for: (i) gastrointestinal stromal tumors (GIST), characterized by mutated and over-expressed c-Kit or PDGFR-b [5]; (ii) other myeloid malignancies and hypereosinophilic syndromes and (iii) systemic mastocytosis [6,7] Today this molecule is the object of 754 clinical trials, 81 of which are in recruitment. It is possible that the administration of one single nanoparticle containing several drugs may be more effective than the administration of several nanoparticles each containing one compound [25]
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