RESUMO
Folate receptor (FR) overexpression in a wide range of solid tumors provides an opportunity to develop novel, targeted cancer therapeutics. In this study, we investigated whether prebinding the chemotherapeutic methotrexate (MTX) to folate-binding protein (FBP), the soluble form of FR, would enable the protein to serve as a targeted therapeutic vector, enhancing uptake into tumor cells and improving therapeutic efficacy. In an in vivo study, using an FR-overexpressing KB xenograft model in SCID mice, modest improvement in inhibiting tumor growth was observed for the MTX/FBP mixtures as compared to saline control and free MTX. Surprisingly, FBP alone inhibited tumor growth compared to saline control, free MTX, and FBP/MTX. In order to better understand this effect, we investigated the cytotoxicity of micromolar concentrations of FBP in vitro using the KB, HeLa, and A549 cancer cell lines. Our results revealed concentration-dependent apoptosis (24 h; 10-50 µM) in all three cell lines accompanied by a time- and concentration-dependent reduction (6, 12, and 24 h; 10-50 µM) in metabolic activity and compromised cell plasma membrane integrity. This study demonstrates an apoptosis pathway for cytotoxicity of FBP, an endogenous serum protein, in cancer cell lines with widely varying levels of FR expression. Furthermore, in vivo tumor growth suppression for xenograft KB tumors in SCID mice was observed. These studies suggest novel strategies for the elimination of cancer cells employing endogenous, serum transport proteins.
Assuntos
Proteínas de Transporte , Ácido Fólico , Animais , Proteínas de Transporte/metabolismo , Receptores de Folato com Âncoras de GPI , Ácido Fólico/metabolismo , Humanos , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Camundongos , Camundongos SCIDRESUMO
Serum proteins play a critical role in the transport, uptake, and efficacy of targeted drug therapies, and here we investigate the interactions between folic acid-polymer conjugates and serum folate binding protein (FBP), the soluble form of the cellular membrane-bound folate receptor. We demonstrate that both choice of polymer and method of ligand conjugation affect the interactions between folic acid-polymer conjugates and serum FBP, resulting in changes in the folic acid-induced protein aggregation process. We have previously demonstrated that individual FBP molecules self-aggregate into nanoparticles at physiological concentrations. When poly(amidoamine) dendrimer-folic acid conjugates bound to FBP, the distribution of nanoparticles was preserved. However, the dendritic conjugates produced larger nanoparticles than those formed in the presence of physiologically normal human levels of folic acid, and the conjugation method affected particle size distribution. In contrast, poly(ethylene glycol)-folic acid conjugates demonstrated substantially reduced binding to FBP, did not cause folic acid-induced aggregation, and fully disrupted FBP self-aggregation. On the basis of these results, we discuss the potential implications for biodistribution, trafficking, and therapeutic efficacy of targeted nanoscale therapeutics, especially considering the widespread clinical use of poly(ethylene glycol) conjugates. We highlight the importance of considering specific serum protein interactions in the rational design of similar nanocarrier systems. Our results suggest that prebinding therapeutic nanocarriers to serum FBP may allow folate-specific metabolic pathways to be exploited for delivery while also affording benefits of utilizing an endogenous protein as a vector.
Assuntos
Dendrímeros/metabolismo , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/metabolismo , Polietilenoglicóis/metabolismo , Animais , Bovinos , Dendrímeros/química , Ácido Fólico/química , Humanos , Microscopia de Força Atômica , Polietilenoglicóis/química , Agregados Proteicos , Ligação Proteica , Espectrometria de FluorescênciaRESUMO
This data article presents a compilation of mechanical properties of 630 multi-principal element alloys (MPEAs). Built upon recently published MPEA databases, this article includes updated records from previous reviews (with minor error corrections) along with new data from articles that were published since 2019. The extracted properties include reported composition, processing method, microstructure, density, hardness, yield strength, ultimate tensile strength (or maximum compression strength), elongation (or maximum compression strain), and Young's modulus. Additionally, descriptors (e.g. grain size) not included in previous reviews were also extracted for articles that reported them. The database is hosted and continually updated on an open data platform, Citrination. To promote interpretation, some data are graphically presented.
RESUMO
Blood serum proteins play a critical role in the transport, biodistribution, and efficacy of systemically-delivered therapeutics. Here, we have investigated the concentration- and ligand-dependent aggregation of folate binding protein (FBP), focusing in particular on folic acid, an important vitamin and targeting agent; methotrexate, an antifolate drug used to treat cancer and rheumatoid arthritis; and leucovorin which is used to decrease methotrexate toxicity. We employed atomic force microscopy to characterize, on a particle-by-particle basis, the volumes of the FBP nanoparticles that form upon ligand binding. We measured the distribution of FBP nanoparticle volumes as a function of ligand concentration over physiologically- and therapeutically-relevant ranges. At physiologically-relevant concentrations, significant differences in particle volume distributions exist that we hypothesize are consistent with different trafficking mechanisms for folic acid and methotrexate. In addition, we hypothesize leucovorin is trafficked and delivered like folic acid at therapeutically-relevant concentrations. We propose that changes in dosing procedures could improve the delivery and therapeutic index for methotrexate and other folic acid-targeted drug conjugates and imaging agents. Specifically, we suggest pre-binding the drugs to FBP may provide a better formulation for drug delivery of methotrexate for both cancer and rheumatoid arthritis. This would be analogous to pre-binding paclitaxel to albumin, which is already used in the clinic.