Article ; Online: Novel design principles enable specific targeting of imaging and therapeutic agents to necrotic domains in breast tumors.
2010 Volume 12, Issue 3, Page(s) R29
Abstract: Introduction: Necrosis at the tumor center is a common feature of aggressive breast cancers and has been associated with poor prognosis. It is commonly identified by means of invasive histopathology, which often correlates with morbidity and potential ... ...
| Abstract | Introduction: Necrosis at the tumor center is a common feature of aggressive breast cancers and has been associated with poor prognosis. It is commonly identified by means of invasive histopathology, which often correlates with morbidity and potential tumor cell dissemination, and limits the reconstruction of the whole necrotic domain. In this study we hypothesized that non covalent association to serum albumin (SA) and covalent binding to ligands for tumor-abundant cell receptors should synergistically drive selective accumulation and prolonged retention of imaging and therapeutic agents in breast tumor necrotic domains enabling in vivo identification, imaging and possibly treatment of such tumors. Methods: Cyclo-Arg-Gly-Asp-D-Phe-Lys (c(RGDfK)) were conjugated to bacteriochlorophyll-derivatives (Bchl-Ds), previously developed as photodynamic agents, fluorescent probes and metal chelators in our lab. The c(RGDfK) component drives ligation to alphaVbeta3 integrin receptors over-expressed by tumor cells and neo-vessels, and the Bchl-D component associates to SA in a non-covalent manner. STL-6014, a c(RGDfK)-Bchl-D representative, was i.v. injected to CD-1, nude female mice bearing necrotic and non-necrotic human MDA-MB-231-RFP breast cancer tumors. The fluorescence signals of the Bchl-Ds and RFP were monitored over days after treatment, by quantitative whole body imaging and excised tumor/tissue samples derived thereof. Complementary experiments included competitive inhibition of STL-6014 uptake by free c(RGDfK), comparative pharmacokinetics of nonconjugated c(RGDfK) Bchl-D (STL-7012) and of two human serum albumin (HSA) conjugates: HSA-STL-7012 and HSA-STL-6014. Results: STL-6014 and STL-7012 formed complexes with HSA (HSA/STL-6014, HSA/STL-7012). STL-6014, HSA-STL-7012 and HSA-STL-6014, selectively accumulated at similar rates, in tumor viable regions over the first 8 h post administration. They then migrated into the necrotic tumor domain and presented tumor half lifetimes (T1/2) in the range of days where T1/2 for HSA-STL-6014 > STL-6014 > HSA-STL-7012. No accumulation of STL-7012 was observed. Pre-injection of c(RGDfK) excess, prevented the uptake of STL-6014 in the small, but not in the large tumors. Conclusions: Non-covalent association to SA and covalent binding to c(RGDfK), synergistically enable the accumulation and prolonged retention of Bchl-Ds in the necrotic regions of tumors. These findings provide novel guidelines and strategy for imaging and treatment of necrotic tumors. |
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| MeSH term(s) | Animals ; Bacteriochlorophylls/chemistry ; Breast Neoplasms/diagnosis ; Breast Neoplasms/metabolism ; Breast Neoplasms/therapy ; Diagnostic Imaging ; Drug Design ; Female ; Humans ; Mice ; Mice, Nude ; Necrosis ; Oligopeptides/administration & dosage ; Oligopeptides/metabolism ; Oligopeptides/pharmacokinetics ; Serum Albumin/administration & dosage ; Serum Albumin/therapeutic use ; Tissue Distribution | |||||
| Chemical Substances | Bacteriochlorophylls ; Oligopeptides ; Serum Albumin ; arginyl-glycyl-aspartic acid (78VO7F77PN) | |||||
| Language | English | |||||
| Publishing date | 2010-05-24 | |||||
| Publishing country | England | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2015059-3 | |||||
| ISSN | 1465-542X ; 1465-5411 | |||||
| ISSN (online) | 1465-542X | |||||
| ISSN | 1465-5411 | |||||
| DOI | 10.1186/bcr2579 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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