The Ruoslahti Lab in La Jolla, in collaboration with our lab, has found a biomarker of early Alzheimer's disease (AD). This biomarker, identified as the protein Connective tissue growth factor (CTGF) is deposited on the brain blood vessels of early AD mice. We have also identified a peptide (named DAG) that recognizes CTGF and homes to early AD mice, well before the appearance of amyloid beta plaques. This peptide can take with it iron oxide nanoparticles that can serve as contrast in Magnetic Resonance Imaging of AD lesions.
Link to the paper: https://www.nature.com/articles/s41467-017-01096-0
Link to the news coverage: Cancer biologists from the University of Tartu help make an important discovery on Alzheimer’s disease
Image: Brain of a mouse with early Alzheimer's disease injected with green fluorescent DAG peptide.. The target protein, CTGF (magenta), appears on the blood vessels (red) of AD brains much before the appearance of amyloid beta plaques. The DAG peptide (green) specifically recognizes CTGF on these blood vessels upon intravenous administration. Credit: Pablo Scodeller and Aman Mann.
We have identified a peptide (nicknamed "UNO") that internalizes in M2 tumor associated macrophages (TAMs) by binding to CD206. Systemically administered UNO homed to M2 TAMs in 5 differerent solid tumor models and was able to carry with it a fluorescent payload and nanoscale polymeric vesicles, polymersomes. Importantly, the cyclic UNO peptide preferentially recognizes CD206 in the tumor and not in the healthy tissues, as it is activated by the reducing environment found in the tumor microenvironment.
Link to the paper: https://www.nature.com/articles/s41598-017-14709-x
Image: Cell-free interation of UNO with recombinant CD206. Increase of anisotropy indicates binding of the peptide to CD206. Credit: Pablo Scodeller and Sergei Kopanchuk.
We report in the Journal of Controlled Release application of a novel tumor penetrating peptide, linTT1 (AKRGARSTA) for targeting nanoparticles for the detection and treatment of peritoneal carcinomatosis. Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide were taken up and routed to mitochondria in cultured peritoneal carcinomatosis cells. NWs functionalized with linTT1 peptide in tandem with a pro-apoptotic [D(KLAKLAK)2] peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT-26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26 tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. Finally, experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic tumors with IP linTT1-D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our findings suggest that linTT1-targeted nanoparticles may potentially be translated to therapeutic interventions against peritoneal carcinomatosis.
Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles. Hunt H, Simón-Gracia L, Tobi A, Kotamraju VR, Sharma S, Nigul M, Sugahara KN, Ruoslahti E, Teesalu T.J Control Release. 2017 Aug 28;260:142-153. doi: 10.1016/j.jconrel.2017.06.005. Epub 2017 Jun 8. PMID:28603028
Image (Hedi Hunt M.Sc.): Internalized linTT1-NWs colocalize with a mitochondrial marker, cytochrome C in cultured MKN-45P cells. linTT1-NW: green; cytochrome C (Cyt-C): red; DAPI: blue; colocalization of FAM and cytochrome C signal: white. Scale bar: 5 mm.
We report in the Nanoscale the in vivo application of the technology of isotopically-barcoded ratiometric silver nanoparticles for quantitative biodistribution studies. In a proof of concept study we used peptides with previously described tissue tropism; one peptide that favors vascular beds of the normal lungs (RPARPAR; receptor neuropilin-1, or NRP-1) and another that is selective for central nervous system vessels (CAGALCY). Equimolar mixtures of the peptide-targeted Ag107-NPs and Ag109 control particles were mixed and injected intravenously. Distribution profiles of Ag107 and Ag109 in tissue extracts were determined simultaneously through inductively coupled plasma mass spectrometry (ICP-MS, both on tissue extracts and on cryosections to obtain spatial information). Internally controlled ratiometric AgNP system appears to be suitable for quantitative studies of the effect of targeting ligands on NP biodistribution, at average tissue concentration and distribution at the microscopic level. The platform might be particularly relevant for target sites with high local variability in uptake, such as tumors.
Schematic representation of the concept of isotopically-barcoded silver nanoparticles for in vivo biodistribution studies (Tambet Teesalu).
Ratiometric in vivo auditioning of targeted silver nanoparticles.Toome K, Willmore AA, Paiste P, Tobi A, Sugahara KN, Kirsimäe K, Ruoslahti E, Braun GB, Teesalu T.Nanoscale. 2017 Jul 20;9(28):10094-10100. doi: 10.1039/c7nr04056c. PMID: 28695222
This workshop provides an opportunity to get an overview of translational nanobiomedicine research from the leading European experts. The overarching themes are interactions of nanoparticles with biological systems, applications of precision-guided nanosystems for imaging and more efficient therapies, and the relationship of nanotechnology with personalized medicine.
Targeted nanosystems for imaging and therapy
Spring workshop, Tartu (Estonia)
May 10-12, 2017
Venue: V-Spa Hotel and Conference Center, Riia 2, Tartu
Target audience : Graduate students , research staff
Free Registration at: http://registration.amarela.ee/spring-workshop/
Program and more information : Click Here
We report in Biomaterials development of a tumor-specific delivery system for the treatment of peritoneal carcinomatosis. We demonstrate that after intraperitoneal administration, pH-sensitive polymeric vesicles loaded with an anticancer drug paclitaxel and functionalized with the tumor penetrating peptide iRGD specifically accumulate in peritoneal tumors in mice and have higher antitumor activity than free paclitaxel or Abraxane (a nano-formulation currently used in the therapy of several types of carcinoma). Our findings suggest that iRGD polymersomes may potentially be translated to therapeutic interventions against peritoneal carcinomatosis.
This collaborative study was driven and coordinated by our senior researcher Lorena Simón-Gracia and carried out together with Prof. Giuseppe Battaglia’s lab in UC London (UK) and with Drs. Kazuki N Sugahara and Ramana Kotamraju and Prof. Erkki Ruoslahti at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Calif. (USA).
iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes Biomaterials. 2016 Jul 20;104:247-257.
Image: Homing of green fluorescent iRGD polymersomes in CT26 peritoneal tumor (Tu). Note that control organs (liver, Li; lung, Lu; spleen, Sp; kidney, Ki) and subcutaneous tumors (Tu s.c.) show minimal labeling.
This peptide can guide drugs and imaging agents to acute brain injuries and result in enhanced benefit. The peptide was identified by Aman Mann and Pablo Scodeller in the lab of Dr. Erkki Ruoslahti in collaboration with the cancer biology lab.
Link to the paper: Nature Communications
Image: The tiny peptide CAQK improves the delivery of imaging agents to acute brain injuries. (Luminiscence from porous silicon nanoparticles targeted with CAQK and control peptide CGGK in brain injuries)
Our article titled "Targeted Silver Nanoparticles for Ratiometric Cell Phenotyping" is well received. It has been chosen to the cover of the May issue of Nanoscale and the Atlas of Science has published a layman's summary about the work.
Artwork: Peter and Ryan Allen, UC Santa Barbara, USA.