Background
uPAR in cancer progression
Targeting uPAR for antitumour therapy
Peptides/small-molecule inhibitors/ligand-targeted toxins | Sequence/structure/composition | Action site/target | References |
---|---|---|---|
AE105 | D-Cha-F-s-r-Y-L-W-S | uPA/uPAR | [102] |
AE120 | [D-Cha-F-s-r-Y-L-W-S]2-βA-K | uPA/uPAR | [102] |
Å6 | Ac-KPSSPPEE-Am | uPA/uPAR | [103] |
ATF | An amino-terminal fragment of urokinase with EGF-like domain and kringle domain | uPA/uPAR | [104] |
U11 | VSNKYFSNIHW | uPA/uPAR | [105] |
A stable disulfide-bridged cyclic form of the linear peptide uPA19–31 | cyclo19,31uPA19–31 | uPA/uPAR | [106] |
A peptide variant of cyclo19,31uPA19–31 | cyclo19,31[D-Cys19]-uPA19–31 | uPA/uPAR | [107] |
WX-360 | cyclo21,29[D-Cys21]-uPA21–30[S21C;H29C] | uPA/uPAR | [108] |
WX-360-Nle | cyclo21,29[D-Cys21]-uPA21–30[S21C;K23Nle;H29C] | uPA/uPAR | [108] |
M25 | PRYQHIGLVAMFRQNTG | uPAR/β1-integrins | [109] |
α325 | PRHRHMGAVFLLSQEAG | uPAR/Vn | [110] |
p25 | AESTYHHLSLGYMYTLN-NH2 | uPAR-integrin uPAR/Vn | [111] |
m.P243-251 | TASWCQGSH | uPAR/integrin α5β1 | [112] |
D2A-Ala | IQEGAAGRPKDDR | uPAR/integrin avβ3/a5β1 | [113] |
PEGylated D2A-Ala | PEG-D2A-Ala | uPAR/integrin avβ3/a5β1 | [114] |
pERERY-NH2 | Pyro glutamic acid (pGlu)-Arg-Glu-Arg-Tyr-NH2 | fMLF/FPR | [115] |
RERF | Ac-Arg-Glu-Arg-Phe-NH2 | SRSRY/FPR fMLF/FPR | [116] |
UPARANT | Ac-L-Arg-Aib-L-Arg-D-Ca(Me)Phe-NH2 | fMLF/FPR | [117] |
cyclic SRSRY peptide ([SRSRY]) | [Ser-Arg-Ser-Arg-Tyr]§ | SRSRY/FPR1 fMLF/FPR1 | [118] |
RI-3 | Ac-(D)-Tyr-(D)-Arg-Aib-(D)-Arg-NH2 | fMLF/FPR1 | [119] |
huPA1-48 and muPA1-48 | The growth factor domains of human and murine urokinase | Tumour stromal cell uPAR dependent plasminogen activation | [120] |
huPA1-48Ig and muPA1-48Ig | Modify huPA1-48 and muPA1-48 with the constant region of human IgG1 | Tumour stromal cell uPAR dependent plasminogen activation | [120] |
PEGh1-48 and PEGhm1-48 | Human and mouse pegylated uPA1-48 | Tumour stromal cell uPAR dependent plasminogen activation | [121] |
IPR-456 | uPA/uPAR | [122] | |
IPR-803 | uPA/uPAR | [123] | |
IPR-3011 | uPA/uPAR | [124] | |
IPR-3577 | uPA/uPAR | [125] | |
7 | uPAR/uPAATF uPAR/Vn | [126] | |
LLL-1fsi | uPA/uPAR | [127] | |
MS#479 [2-(Pyridin-2-ylamino)-quinolin-8-ol] | uPAR/integrin | [128] | |
MS#305 [2,2′-(methylimino)di (8-quinolinol)] |
〹 | uPAR/integrin | [128] |
Compounds 6 | uPAR/Vn uPAR/FPR | [129] | |
Compounds 37 | uPAR/Vn uPAR/FPR | [129] | |
Docosahexaenoic acid (DHA) | suppress uPAR expression | [130] | |
DTAT | DT and ATF | uPAR | |
DTATEGF | ATF, EGF and DT | uPAR, EGFR | [133] |
DTAT13 | ATF, IL-13 and DT | uPAR, IL-13 receptors | |
eBAT (EGFATFKDEL 7mut) | ATF, EGF, truncated PE38 with a terminal lysyl-aspartyl-glutamyl-leucine (KDEL) sequence and eight amino acids representing the seven major epitopes on PE38 were mutated | uPAR, EGFR | |
ATF-SAP | ATF and SAP | uPAR | |
PAI-2-N-AIE | PAI-2 and N-AIE | uPAR | [144] |
DTU2GMCSF | DT, GM-CSF and uPA | uPAR, GM-CSF receptor | [145] |
ATF-PE38 | ATF and PE38 | uPAR | [146] |
ATF-PE38KDEL | ATF and PE38 with a terminal KDEL sequence | uPAR | [146] |
uPAR-targeted nanoplatforms carrying therapeutic agents
Nano platform | Target | Drug | Imaging | Effect | References, year |
---|---|---|---|---|---|
uPA-SP@CaP NPs | uPA peptide, amino acid sequence: VSNKYFSNIHWGC (uPAR) | BRCA1 siRNA, Pro-Pt | Fluorescence imaging (Dir) | Improve anticancer efficacy of the TNBC (pH-responsive sequential release ability, lysosomal escape property, dual tumour targeting, and irreversible DNA damage behavior) | [161], 2019 |
ATF-IO-Dox | ATF (uPAR) | Dox | MRI | A marked inhibition of tumour cell growth in 4T1 and MDA-MB-231 cells | [162], 2008 |
iWnt-ATF24-IONP-Dox | iWnt, amino acid sequence: NSNAIKNKKHHH (Wnt/LRP5/6), ATF24, amino acid sequence: CHHHCLNGGTCVSNKYFSNIHWCNCPKK (uPAR) | Dox | NIR-830 dye for optical imaging | Strong tumour growth inhibition in a human chemo-resistant cancer patient-derived xenograft model (inhibited Wnt/β-catenin signaling and cancer stem-like phenotype of tumour cells; marked reduction of Wnt ligand, CD44 and uPAR) | [163], 2018 |
ATF-IONP-Gem | ATF (uPAR) | Gem | MRI | Inhibit the growth of orthotopic human pancreatic cancer xenografts in nude mice (overcoming the tumour stromal barrier) | [164], 2013 |
ATF-PEG-IONP-Cis or ATF-PEG-IONP-Dox | ATF (uPAR) | Cis or Dox | NIR optical imaging and MRI | Inhibit the growth of pancreatic tumours (i.p.); decrease proliferating tumour cells and tumour vessels; reduce the amount of ascites production | [165], 2017 |
LHRH-AE105-IONPs-PTX | LHRH (LHRH-R), AE105 (uPAR) | PTX | MRI | 10 times reduction in the concentration of PTX required to achieve similar cytotoxic effect produced by the free drug (LHRH-R- and uPAR-overexpressing PC-3 cells) | [166], 2017 |
DTX/AE Lipo | AE147 (uPAR) | DTX | Fluorescence imaging | DTX/AE-Lipo (IC50 4.61 µg/mL) achieves better anticancer activity than free DTX (IC50 7.18 µg/mL) or DTX/Lipo (IC50 8.59 µg/mL) | [167], 2021 |
PAI-2 N-AI liposomes | PAI-2 (uPAR) | N-alkylisatin | NA | An increased accumulation at the primary tumour site in an orthotopic MDA-MB-231 BALB/c-Fox1nu/Ausb xenograft mouse model | [168], 2020 |
U11 peptide targeted NPs | U11 peptide (uPAR) | Plasmid DNA | Fluorescence imaging (Rhodamine) | Transfection of uPAR positive DU145 cells is essentially tenfold higher compared to transfection achieved by NPs having a scrambled peptide sequence on their surface | [105], 2009 |
U11-Dox/Cur NPs | U11 peptide (uPAR) | Dox/Cur | Fluorescence imaging (Coumarin 6) | Inhibit the tumour growth to a level of 85% | [169], 2019 |
ATF24-PEG-Lipo-β-E | ATF24 (uPAR) | β-E | Fluorescence imaging (Did) | Combined with Cis, exert a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase (dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways) | [170], 2020 |
uPA-Anti-miR-21-Anti-miR-10b-NPs | uPA peptide (VSNKYFSNIHWGC) | Antisense-miR-21, antisense-miR-10b | Optical bioluminescence imaging (MDA-MB-231-Fluc-eGFP cells) | 40% reduction in tumour growth compared to scrambled peptide conjugated NPs treated mice (0.15 mg/kg) | [171], 2015 |
uPAR-targeted PDT/PTT platforms
uPAR-targeted PDT/PTT platform | Target | Photosensitizer and drug | Imaging | Effect | References, year |
---|---|---|---|---|---|
AuS-U11 for confocal laser endomicroscopy-guided PTT/ PDT | U11 peptide (uPAR) | PTT-carrier gold nanocluster, CRQAGFSL-5-ALA, CRQAGFSL-Cy5.5 | Fluorescence images (enzyme-triggered release of NIR fluorescent dye Cy5.5) | Better synergistic therapeutic effects as well as the reduced side effects in normal pancreas tissue (human pancreatic tumour cell line PANC1-CSTE and its orthotopic tumour model) | [172], 2017 |
hATF-HSA:CPZ | hATF (uPAR) | CPZ | FMT imaging (CPZ, 0.08 μmol/kg or 0.05 mg/kg) | A significant reduced tumour growth rate (H22 tumour-bearing Kunming mice model) | [175], 2014 |
mATF-HSA:CPZ | mATF (uPAR) | CPZ | FMT imaging (CPZ, 0.05 mg/kg) | A higher tumour killing efficacy than hATF-HSA:CPZ (H22 tumour-bearing mouse model) | [176], 2015 |
ATF-HSA: CPZ@RRNP | ATF (uPAR) | CPZ-loaded receptor-responsive nanoparticles | FMT imaging (CPZ, 0.05 mg/kg) | Higher uptake and cytotoxicity (H1299 lung cancer cells), higher tumour accumulation and better antitumour effect (H22 tumour-bearing mice), lower CPZ concentration (liver, kidney, spleen, lung, and heart) | [177], 2019 |
ATF-ZnPc | ATF (uPAR) | ZnPc | FMT imaging (ATF-ZnPc, 0.4 μmol/kg) | Potent PDT activities and enhanced antitumour activity (U937 and H1299 cells and H22 tumour-bearing mice) | [178], 2014 |
GNS@Ir@P-AE105 | AE105 (uPAR) | GNS, Ir complex | PT/PA/X-ray CT trimodal imaging | Combinational photothermal-chemotherapeutic efficiency against TNBC via a ROS-induced p53 apoptotic pathway | [179], 2020 |
Cisplatin-AuNRs@SiO2-Avastin@PEI/AE105 | AE105 (uPAR) | Gold nanorod mesoporous silica heterostructure, cisplatin, Avastin | Photothermal imaging (3 mg/kg) | Photodynamic activity via induction of ROS overproduction-mediated cell apoptosis, suppresses HeLa tumour growth and angiogenesis | [180], 2019 |
Cu2−xS-RB@DMSN-AE105 | AE105 (uPAR) | Cu2−xS NPs, Rose Bengal | Infrared thermal imaging | Synergetic PTT/SDT nanotherapeutics against the OSCC both in vitro and in vivo, a prominent tumour inhibition rate of 103.4% | [181], 2020 |
uIGNs | Anti-uPAR antibody | ICG modifed gold nanoshells | CT and optical imaging (bioluminescence imaging and fluorescence imaging) | 25% higher median survival rate of IPTT and complete tumour ablation by one-time intervention, inhibit pancreatic tumour metastasis | [182], 2017 |