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

Overview

Journal J Pharm Sci

Publisher Elsevier

Specialties Pharmacology
Pharmacy

Date 2012 May 15

PMID 22581704

Citations 13

Authors

Brian J Trummer

Vandana Iyer

Sathy V Balu-Iyer

Robert OConnor

Robert M Straubinger

Affiliations

Soon will be listed here.

Abstract

Inhibitors of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases show efficacy in cancers that are highly addicted to nonmutated 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 the side effects. Therefore, the feasibility of developing nanoliposomal formulations of EGFR 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 the environment polarity. Emission was negligible in water but intense in nonpolar solvents, membranes, or bound to serum proteins. Cellular uptake and distribution could also be imaged by fluorescence in drug-resistant tumor spheroids. Gefitinib fluorescence characteristics enabled facile optimization of formulations. Although 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.

Citing Articles

Dissolution enhancement of Gefitinib by solid dispersion and complexation with β-cyclodextrins: In vitro testing, cytotoxic activity, and tablet formulation.

Alghaith A, Mahrous G, Alenazi A, ALMufarrij S, Alhazzaa M, Radwan A Saudi Pharm J. 2024; 32(6):102070.

PMID: 38645413 PMC: 11031755. DOI: 10.1016/j.jsps.2024.102070.

Busting the Breast Cancer with AstraZeneca's Gefitinib.

Chemmalar S, Intan Shameha A, Abdullah C, Ab Razak N, Mohamad Yusof L, Ajat M Adv Pharmacol Pharm Sci. 2023; 2023:8127695.

PMID: 38090376 PMC: 10713255. DOI: 10.1155/2023/8127695.

Modified gefitinib conjugated FeO NPs for improved delivery of chemo drugs following an image-guided mechanistic study of inner vs. outer tumor uptake for the treatment of non-small cell lung cancer.

Thangudu S, Tsai C, Lin W, Su C Front Bioeng Biotechnol. 2023; 11:1272492.

PMID: 37877039 PMC: 10591449. DOI: 10.3389/fbioe.2023.1272492.

PEGylated Erlotinib HCl Injectable Nanoformulation for Improved Bioavailability.

Bhargave H, Nijhawan H, Yadav K AAPS PharmSciTech. 2023; 24(4):101.

PMID: 37038015 DOI: 10.1208/s12249-023-02560-5.

Intrinsically Fluorescent Anti-Cancer Drugs.

Kabir M, Wang F, Clayton A Biology (Basel). 2022; 11(8).

PMID: 36009762 PMC: 9405238. DOI: 10.3390/biology11081135.

References

Maeda H, Wu J, Sawa T, Matsumura Y, Hori K . Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000; 65(1-2):271-84. DOI: 10.1016/s0168-3659(99)00248-5. View

Abraham S, Edwards K, Karlsson G, MacIntosh S, Mayer L, McKenzie C . Formation of transition metal-doxorubicin complexes inside liposomes. Biochim Biophys Acta. 2002; 1565(1):41-54. DOI: 10.1016/s0005-2736(02)00507-2. View

Tu S, McGinnis T, Krugner-Higby L, Heath T . A mathematical relationship for hydromorphone loading into liposomes with trans-membrane ammonium sulfate gradients. J Pharm Sci. 2009; 99(6):2672-80. PMC: 4240746. DOI: 10.1002/jps.22017. View

Bergman E, Forsell P, Persson E, Knutson L, Dickinson P, Smith R . Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors. Int J Pharm. 2007; 341(1-2):134-42. DOI: 10.1016/j.ijpharm.2007.04.002. View

Haran G, Cohen R, Bar L, Barenholz Y . Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta. 1993; 1151(2):201-15. DOI: 10.1016/0005-2736(93)90105-9. View

Higgins C . Multiple molecular mechanisms for multidrug resistance transporters. Nature. 2007; 446(7137):749-57. DOI: 10.1038/nature05630. View

Parasassi T, di Stefano M, Loiero M, Ravagnan G, Gratton E . Influence of cholesterol on phospholipid bilayers phase domains as detected by Laurdan fluorescence. Biophys J. 1994; 66(1):120-32. PMC: 1275671. DOI: 10.1016/S0006-3495(94)80763-5. View

Madden T, Harrigan P, Tai L, Bally M, Mayer L, Redelmeier T . The accumulation of drugs within large unilamellar vesicles exhibiting a proton gradient: a survey. Chem Phys Lipids. 1990; 53(1):37-46. DOI: 10.1016/0009-3084(90)90131-a. View

Guo A, Villen J, Kornhauser J, Lee K, Stokes M, Rikova K . Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A. 2008; 105(2):692-7. PMC: 2206598. DOI: 10.1073/pnas.0707270105. View

10.

Ghods A, Irvin D, Liu G, Yuan X, Abdulkadir I, Tunici P . Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells. 2007; 25(7):1645-53. DOI: 10.1634/stemcells.2006-0624. View

11.

Kim E, Hirsh V, Mok T, Socinski M, Gervais R, Wu Y . Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008; 372(9652):1809-18. DOI: 10.1016/S0140-6736(08)61758-4. View

12.

McKillop D, Hutchison M, Partridge E, Bushby N, Cooper C, Clarkson-Jones J . Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man. Xenobiotica. 2005; 34(10):917-34. DOI: 10.1080/00498250400009171. View

13.

Charrois G, Allen T . Rate of biodistribution of STEALTH liposomes to tumor and skin: influence of liposome diameter and implications for toxicity and therapeutic activity. Biochim Biophys Acta. 2003; 1609(1):102-8. DOI: 10.1016/s0005-2736(02)00661-2. View

14.

Wakeling A, Guy S, Woodburn J, Ashton S, Curry B, Barker A . ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002; 62(20):5749-54. View

15.

Minchinton A, Tannock I . Drug penetration in solid tumours. Nat Rev Cancer. 2006; 6(8):583-92. DOI: 10.1038/nrc1893. View

16.

Parikh H, McElwain K, Balasubramanian V, Leung W, Wong D, Morris M . A rapid spectrofluorimetric technique for determining drug-serum protein binding suitable for high-throughput screening. Pharm Res. 2000; 17(5):632-7. DOI: 10.1023/a:1007537520620. View

17.

McKillop D, Partridge E, Kemp J, Spence M, Kendrew J, Barnett S . Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2005; 4(4):641-9. DOI: 10.1158/1535-7163.MCT-04-0329. View

18.

Lasic D, Martin F, Gabizon A, Huang S, Papahadjopoulos D . Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta. 1991; 1070(1):187-92. DOI: 10.1016/0005-2736(91)90162-2. View

19.

Yoshimura M, Nakamura S, Imamura F, Ueno K, Yamamoto S, Igarashi T . Severe myelotoxicity in a combination of gefitinib and vinorelbine. Lung Cancer. 2004; 45(1):121-3. DOI: 10.1016/j.lungcan.2004.01.006. View

20.

Dreher M, Liu W, Michelich C, Dewhirst M, Yuan F, Chilkoti A . Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst. 2006; 98(5):335-44. DOI: 10.1093/jnci/djj070. View