Physicochemical Properties of Epidermal Growth Factor Receptor Inhibitors and Development of a Nanoliposomal Formulation of Gefitinib

Abstract

Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinases show efficacy in cancers that are highly addicted to non-mutated EGF signaling, but off-target effects limit therapy. Carrier-based formulations could reduce drug deposition in normal tissues, enhance tumor deposition, and reduce free drug concentrations, thereby reducing side effects. Therefore, the feasibility of developing nano-liposomal formulations of EGF receptor inhibitors was investigated. Gefitinib and erlotinib fluorescence was characterized as a tool for formulation development. Peak excitation was 345 nm and peak emission was 385–465 nm, depending upon environment polarity. Emission was negligible in water but intense in non-polar solvents, membranes, or bound to serum proteins. Cellular uptake and distribution also could be imaged by fluorescence in drug-resistant tumor spheroids. Gefitinib fluorescence characteristics enabled facile optimization of formulations. Whereas 4–6 mol% gefitinib could be incorporated in the liposome bilayer, 40–60 mol% could be encapsulated in stable, remote-loaded liposomes consisting of distearoylphosphatidylcholine:polyethylene glycol-distereoylphosphatidylethanolamine:cholesterol (9:1:5 mol:mol:mol). Drug leakage in serum, monitored by fluorescence, was minimal over 24 h at 37°C. The results provide both promising lead formulations as well as novel tools for evaluating new formulations of structurally-similar receptor tyrosine kinase inhibitors and their cellular uptake and tissue biodistribution.

An Apoferritin‐based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib

“…Cytoplasmic Gefi tinib fl uorescence was punctuate consistent with localization in acidic lysosomes and endosomes within these cells. [ 31 ] SKBR3 cells treated with H-AFt alone appeared to be identical to control cells and did not show fl uorescence. Also MDA-MB-231 cells treated with H-AFt-encapsulated-Gefi tinib did not show bright fl uorescence compared to MDA-MB-231 cells treated with Gefi tinib indicating uptake suppression.…”

“…However, the reduced potency of H-AFt-encapsulated-Gefi tinib compared to Gefi tinib alone implies that encapsulated Gefi tinib may require time to be released from the H-AFt cavity as it is processed by endosome and lysosome systems with a local pH gradually reducing. [ 31 ] Conversely the MDA-MB-231 cell line demonstrated signifi cantly reduced sensitivity to both Gefi tinib (GI 50 = 21.80 ± 0.52 × 10 −6 M ) and H-AFt-encapsulated-Gefi tinib (GI 50 > 25 × 10 −6 M ).…”

“…The fl uorescence of Gefi tinib is environmentally sensitive: peak excitation and emission depends upon environment polarity and is intense in nonpolar solvents. [ 31 ] This property has allowed cellular uptake and distribution studies to be performed. Intracellular Gefi tinib was evident from the bright fl uorescence observed within the cytoplasm of SKBR3 cells treated with H-AFt-encapsulated-Gefi tinib.…”

In vitro and in vivo antitumor effect of gefitinib nanoparticles on human lung cancer

“…Lee et al synthetized GEF-cyclodextrin inclusion complexes and the solubility rate of the drug was significantly increased (Lee et al, 2009). Trummer et al developed a nanoliposomal GEF formulation in 2012 (Trummer et al, 2012). Colloidal gold nanoparticle also can be successfully employed for conjugating GEF, as shown by Lam et al (Lam et al, 2014).…”

Nanoparticulation improves bioavailability of Erlotinib

“…Oral BA of drugs is dependent on their particle size because the size reduction can enhance surface area of drug particles, thus increasing their dissolution. To improve the BA of Ert, various approaches have been tested such as cyclodextrin complexes [16], reverse micelle-loaded lipid nanoparticles [17], poly (D,L-lactic-co-glycolic acid) nanoparticles [18], hybrid nanoparticles [19], liposomes [20,21], and other types of nanoparticles [22,23].…”