Specific delivery of kinase inhibitors in nonmalignant and malignant diseases

Figures & data

Table 1. An overview of studies examining the cell-specific delivery of several kinase inhibitors in different experimental models of malignant and nonmalignant diseases.

Disease	Pathway	Ref.	Delivery system	Effects in vitro	Effects in vivo
Liver fibrosis	PDGFR	[35]	M6PHSA	Anti-fibrotic effects on HSC	Liver accumulation in d10 BDL rats, sustained drug levels. Inhibits collagen and α-SMA in d10 BDL rats
	Rho-kinase	[46,47]	M6PHSA	Specific receptor binding. Anti-fibrotic effects in HSC	Binds to target cells. High drug concentration in liver during 48 h. Stronger anti-fibrotic effects than free drug
Renal fibrosis	p38 MAPK	[55]	Lysozyme	Inhibition of collagen gene expression in TGF-activated HK-2 cells	Accumulation in tubular cells during 3 days. Reduction of p38 phosphorylation and α-SMA expression after ischemia–reperfusion in rat kidney
	ALK5	[58,59]	Lysozyme	Inhibition of collagen gene expression in HK-2 cells	Accumulation in tubular cells during 3 days. Inhibition of activation of tubular cells and fibroblasts and reduced renal inflammation in unilateral urethra obstruction in rats. Stronger effects than equivalent free drug
	Rho-kinase	[60]	Lysozyme	–	Accumulation in kidney. Inhibition of tubular damage, Rho-kinase activation, inflammation and fibrogenesis after ischemia–reperfusion in rat kidney. Unconjugated drug did not have beneficial effects
Cardiovascular diseases	MAPK	[63]	RGD-albumin conjugate	Binds to HUVEC. Inhibits expression and secretion of pro-inflammatory cytokines in TNF-activated HUVEC	–
	c-Abl and PDGFR	[66]	Nanoparticles	Inhibition of cell proliferation and PDGFR phosphorylation	Reduction of neointima formation after graft surgery
Malignant diseases	PI3K	[69]	RGDS-conjugate	pAKT and pERK reduced in U937 and endothelial cells	Accumulation in tumor. Stronger reduction of tumor size in U87MG and PC3 tumor-bearing mice than untargeted inhibitor
		[70]	PEG-PE micelles, coupled to 2C5 mAb	Cytotoxic against U87MG, B16 and 4T1 cells	–
		[71]	Nanoparticles	Inhibition of Akt phosphorylation in B16 melanoma cells	Inhibition of endothelium proliferation and tubulogenesis in zebrafish xenotransplant model
	MAPK	[72]	Nanoparticles	Cytotoxic against B16 melanoma and lung carcinoma cells Inhibition of pERK in B16 cells	Stronger antitumor effect on B16-melanoma-bearing mice than free drug, particularly when both are combined with cisplatin
	EGFR	[75]	PLGA microspheres	Inhibition of EGFR activity in fibroblasts and carcinoma cells	–
		[76]	Liposomes	–	Three- to sixfold higher uptake of liposomal form than free drug in xenograft tumors
	VEGFR	[78]	RGD-albumin conjugate	Binds to angiogenic endothelium. Inhibits VEGF-induced gene expression in HUVEC	–
		[79]	APRPG-targeted liposomes	Inhibition of VEGF-induced endothelial cell proliferation	Inhibition of C26 tumor size in mice and prolonged survival. Effects stronger than untargeted liposomes with inhibitor

Schematic overview of the studies into specific delivery of kinase inhibitors, which are discussed in this review.

α-SMA: α-Smooth muscle actin; ALK5: Activin-like kinase 5 (TGF-receptor type I); BDL: Bile-duct ligation; EGFR: Epidermal growth factor receptor; ERK: Extracellular signal-regulated kinase; HSC: Hepatic stellate cell; M6PHSA: Mannose-6-phosphate human serum albumin; PDGFR: Platelet-derived growth factor receptor; PEG-PE: Poly-ethylene glycol-phosphatidylethanolamine; PLGA: Poly(lactic-co-glycolic acid); p38 MAPK: p38-mitogen-activated protein kinase; PI3K: Phosphatidylinositol 3-kinase; TGF: Transforming growth factor; TNF: Tumor necrosis factor; VEGF: Vascular endothelial growth factor.

Box 1. Key points for further research.

• Comparative analysis of targeted and free drugs

• Search for cell-specific or disease-specific kinases

• Search for disease-specific receptors or other targets

• Comparative analysis of different carriers and/or targeting methods

• Combination therapies with different kinase inhibitors in one vehicle

Yoshiji H, Noguchi R, Kuriyama S, Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol 2004;288:G907-13

 PubMed Web of Science ®Google Scholar

de Borst MH, Wassef L, Kelly DJ, Mitogen activated protein kinase signaling in the kidney: target for intervention? Signal Transduct 2005;5:1-22

 Google Scholar

Fretz M, Dolman MEM, Lacombe M, Intervention in growth factor activated signaling pathways by renally targeted kinase inhibitors. J Control Release 2008;132(3):200-7

 PubMed Web of Science ®Google Scholar

Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 2009;78(6):539-52

 PubMed Web of Science ®Google Scholar

Fitzgibbon GM, Kafka HP, Leach AJ, Coronary bypass graft fate and patient outcome: Angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28(3):616-26

 PubMed Web of Science ®Google Scholar

Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 2010;7(11):653-64

 PubMed Web of Science ®Google Scholar

Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2(7):489-501

 PubMed Web of Science ®Google Scholar

Garlich J, De P, Dey N, A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 2008;68(1):206-15

 PubMed Web of Science ®Google Scholar

Skidan I, Miao B, Thekkedath R, In vitro cytotoxicity of novel pro-apoptotic agent DM-PIT-1 in PEG-PE-based micelles alone and in combination with TRAIL. Drug Deliv 2009;16(1):45-51

 PubMed Web of Science ®Google Scholar

Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3(1):11-22

 PubMed Web of Science ®Google Scholar

Davies H, Bignell GR, Cox C, Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54

 PubMed Web of Science ®Google Scholar

Larsen AK, Ouaret D, El Ouadrani K, Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 2011;131(1):80-90

 PubMed Web of Science ®Google Scholar

Gild ML, Bullock M, Robinson BG, Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol 2011;7(10):617-24

 PubMed Web of Science ®Google Scholar