Magnetically Actuated Protease Sensors for in Vivo Tumor Profiling.
Targeted cancer therapies require a precise determination of the underlying biological processes driving tumorigenesis within the complex tumor microenvironment. Therefore, new diagnostic tools that capture the molecular activity at the disease site in vivo are needed to better understand tumor behavior and ultimately maximize therapeutic responses. Matrix metalloproteinases (MMPs) drive multiple aspects of tumorigenesis, and their activity can be monitored using engineered peptide substrates as protease-specific probes. To identify tumor specific activity profiles, local sampling of the tumor microenvironment is necessary, such as through remote control of probes, which are only activated at the tumor site. Alternating magnetic fields (AMFs) provide an attractive option to remotely apply local triggering signals because they penetrate deep into the body and are not likely to interfere with biological processes due to the weak magnetic properties of tissue. Here, we report the design and evaluation of a protease-activity nanosensor that can be remotely activated at the site of disease via an AMF at 515 kHz and 15 kA/m. Our nanosensor was composed of thermosensitive liposomes containing functionalized protease substrates that were unveiled at the target site by remotely triggered heat dissipation of coencapsulated magnetic nanoparticles (MNPs). This nanosensor was combined with a unique detection assay to quantify the amount of cleaved substrates in the urine. We applied this spatiotemporally controlled system to determine tumor protease activity in vivo and identified differences in substrate cleavage profiles between two mouse models of human colorectal cancer.
Simone
S
Schuerle
Jaideep S
JS
Dudani
Michael G
MG
Christiansen
Polina
P
Anikeeva
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard , Cambridge, Massachusetts 02139, United States.|Howard Hughes Medical Institute , Cambridge, Massachusetts 02139, United States.
Sangeeta N
SN
Bhatia
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000453:epidemiology*; D005290:Ferric Compounds; D006801:Humans; D008081:Liposomes; D060526:Magnetic Fields; D058185:Magnetite Nanoparticles; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D010455:Peptides
D005290:Ferric Compounds; D008081:Liposomes; D058185:Magnetite Nanoparticles; D010455:Peptides; C000499:ferric oxide; D020782:Matrix Metalloproteinases
Thermoliposomes; activity-based biomarkers; hysteresis-loss heating; magnetic nanoparticles; nanosensors; proteases