Table 2.

Summary of ECM targeting strategies

Mechanism	Agent	Treatment objective	Pathological conditions
Collagen
Inhibition of collagen synthesis via TGF-β signaling	Intraperitoneal injection 109 or oral administration 110 of Halofuginone	Reduce fibrosis	Murine models of pancreas 109 and liver fibrosis 110
	Intraperitoneal injection of Halofuginone	Inhibit the establishment and progression of melanoma bone metastases	Murine melanoma 111
	Oral administration of Losartan	Enhance the efficacy of FOLFIRINOX chemotherapy	Human pancreatic cancer (NCT01821729) 114
Degradation of stromal collagen	Intratumoral injection of collagenase	Enhance the distribution of a herpes simplex virus vector	Human melanoma xenograft 124
	Intravenous injection of collagenase	Improve the accumulation of a liposome/plasmid DNA complex	Murine lung tumor model 125
	Collagenase-functionalized polystyrene nanoparticles	Enhance the penetration of the nanoparticles in multicellular spheroids	Human cervical carcinoma multicellular tumor spheroids 126
Stimulation of collagenase synthesis and downregulation of collagen production	Relaxin	Enhance the penetration of fluorescent-labeled dextran	Human osteosarcoma spheroids 131
Binding to denatured collagen	Collagen mimetic peptides	Monitor ECM-remodeling	Human prostate cancer xenograft 138
Binding to intact collagen	High density lipoprotein nanoparticles decorated with collagen binding molecules	Imaging of exposed collagen network	Murine model of atherosclerosis regression 182
Inhibition of collagen cross-linking	Simtuzumab (anti-LOXL2)	Enhance the efficacy of combination therapy with gemcitabine	Pancreatic cancer (NCT01472198) 145
Inhibition of collagen cross-linking	Poly(lactide-co-glycolide) nanoparticles decorated with LOX inhibitory antibody	Reduce tumor growth	Breast cancer xenograft mouse model 144
Imaging MMP-overexpressing cells	Nanoprobe system with a MMP-labile linker	Image MMP-2-overexpressing tumors	Human fibrosarcoma and glioma xenografts 183
Binding to integrins	Nanoparticles decorated with integrin binding molecules	Enhance tumor treatment and imaging	Multiple models 78
Hyaluronic acid
Degradation of hyaluronic acid	Intravenous infusion of PEGylated human hyaluronidase (PEGPH20)	Enhance the efficacy of combination therapy with gemcitabine and nab-paclitaxel	Human pancreatic cancer (NCT02715804) 158
Hyaluronidase substrate	Hyaluronic acid tagged-gold nanoparticles	Detect hyaluronidase-overexpressing tumors	Ovarian tumor xenograft 186
Hyaluronidase substrate	Complexation of hyaluronic acid and cationic agent	Enhanced tumor penetration of polycationic agents	Multiple models 161
Inhibition of hyaluronic acid synthesis	4-methylumbelliferone	Reduce tumor progression	Multiple cell lines (in vitro) 163, 164
Inhibition of hyaluronic acid synthesis	Liposome-encapsulated 4-methylumbelliferone	Enhance the efficacy of combination therapy with liposomal doxorubicin	4T1 murine breast tumor model 165

ECM, extracellular matrix; FOLFIRINOX, the FOLFIRINOX chemotherapy regimen is a combination of the drugs 5-fluorouracil, leucovorin and oxaliplatin; LOXL2, Lysyl oxidase‐like 2; MMPs, matrix metalloproteinases; TGF-β, transforming growth factor beta.