The tumour microenvironment regulates tumour progression and the spread of cancer in the body. Targeting the stromal cells that surround cancer cells could, therefore, improve the effectiveness of existing cancer treatments. Here, we show that magnetic nanoparticle clusters encapsulated inside a liposome can, under the influence of an external magnet, target both the tumour and its microenvironment. We use the outstanding T2 contrast properties (r2=5731286 s(1) mM(1)) of these ferriliposomes, which are cca 95 nm in diameter, to noninvasively monitor drug delivery in vivo. We also visualize the targeting of the tumour microenvironment by the drugloaded ferriliposomes and the uptake of a model probe by cells. Furthermore, we used the ferriliposomes to deliver a cathepsin protease inhibitor to a mammary tumour and its microenvironment in a mouse, which substantially reduced the size of the tumour compared with systemic delivery of the same drug.
COBISS.SI-ID: 25057831
Protease research has undergone a major expansion in the last decade, largely due to the extremely rapid development of new technologies, such as quantitative proteomics and in vivo imaging, as well as an extensive use of in vivo models. These have led to identification of physiological substrates and resulted in a paradigm shift from the concept of proteases as proteindegrading enzymes to proteases as key signalling molecules. However, we are still at the beginning of an understanding of protease signalling pathways. We have only identified a minor subset of true physiological substrates for a limited number of proteases, and their physiological regulation is still not well understood. Similarly, links with other signalling systems are not well established. Herein, we highlight current challenges in protease research.
COBISS.SI-ID: 25737767
In this paper we describe the procedure of allosteric site prediction in papain-like cysteine peptidases by computational methods, using cathepsin K as the model enzyme. Compound libraries were screened in silico to identify compound NSC13345 as the first lowmolecularweight allosteric inhibitor of cathepsin K. THe compound was thoroughly characterized from the functional and structural perspectives. The crystal structure of the cathepsin K/NSC13345 complex showed that the compound indeed binds at the computationally anticipated site, which was thereby identified as a novel allosteric site in cathepsin K. The compound was characterized as a partial inhibitor of the hydrolysis of synthetic substrates and azocasein and a full inhibitor of type I collagen hydrolysis. These results qualify compound NSC1334 as an excellent candidate for the design of drugs for the treatment of osteoporosis.
COBISS.SI-ID: 1678895
Lipidated protease FRET probes were previously shown to get internalized by target cells releasing the protease of interest. Here we introduce a lipidated, nonpeptidic FRET probe for cathepsin S, a protease secreted by macrophages in the tumor environment. We show that in cultured cells as well as in a grafted tumor mouse model, the probe is successfully cleaved and in the mouse is accumulated in the tumor tissue with little signal in organs such as liver and lung. The probe is therefore a promising prototype tool for detecting tumors in humans in the future.
COBISS.SI-ID: 27739175
Cathepsin B is a lysosomal cysteine proteinase that is specifically translocated to the extracellular milieu during cancer progression. The development of a lipidated CtsB inhibitor incorporated into the envelope of a liposomal nanocarrier (LNC-NS-629) is described in this work. Ex vivo and in vivo studies confirmed selective targeting and internalization of LNC-NS-629 by tumor and stromal cells, thus validating CtsB targeting as a highly promising approach to cancer diagnosis and treatment.
COBISS.SI-ID: 27932455