Novel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors

Abstract

Epidermal growth factor receptors (EGFRs) have potential to be considered as therapeutic target for cancer treatment especially in cancer patients with overexpression of EGFR. Cetuximab as a first monoclonal antibody and Imatinib as the first small molecule tyrosine kinase inhibitor (SMTKI) were approved by FDA in 1998 and 2001. About 28 SMTKIs have been approved until 2015 and a large number of compound with kinase inhibitory activity are at the different phases of clinical trials. Although Kinase inhibitors target specific intracellular pathways, their tissue or cellular distribution are not specific. So treatment with these drugs causes serious dose dependent side effects. Targeted delivery of kinase inhibitors via dendrimers, polymeric nanoparticles, magnetic nanoparticles and lipid based delivery systems such as liposomes, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can lead to reduction of side effects and improving therapeutic efficacy of the drugs in the target organs. Furthermore formulation of these drugs is challenged by their physicochemical properties such as solubility and dissolution rate. The main approaches in order to increase dissolution rate, are particle size reduction, self-emulsification, cyclodextrin complexation, crystal modification and amorphous solid dispersion. Synergistic therapeutic effect, decreased side effects and drug resistant, reduced cost and increased patient compliance are the advantages associated with using combination therapy especially in the treatment of cancer. Combination of TKIs with chemotherapeutic agents or biopharmaceuticals such as monoclonal antibodies and oligonucleotides and also combination of two TKIs within one formulation is possible by new targeting delivery systems. This article reviews the recent advances in the design and development of delivery systems for TKIs.

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

“…It should be prevented by a better determination of RTKI affinity for other targets, in order to select the most specific RTKIs [58]. Another approach consisting in reducing the distribution of RTKIs in healthy tissues using nanoparticles or pegylated liposomes is under intense research, while their clinical benefits remain to be proven [59].…”

Nanomedicine of tyrosine kinase inhibitors

“…In the fashion of poorly soluble small molecule anticancer drugs 68 , 69 , TKIs are recently in the focus of nanomedicine research. Recent review written by Moradpour and Barghi discusses different types of targeted delivery of TKIs 70 . In contrast to this paper, we focus on the particulars of nanoconstruct applications in combination with TKIs.…”

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective

“…In Table 1 , selected TKIs (the most important for CML treatment and more recent and innovative than other ones) and their applications are reported. Issues related to solubility and resistance onset could be solved using safe and efficient delivery vehicles, that could improve the therapeutic efficacy, minimize toxicity, ameliorate tumor targetability and decrease drug resistance [ 2 , 3 ].…”