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Drug Targeting to Tumors: Principles, Pitfalls and (Pre-) Clinical Progress
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Twan Lammers, Fabian Kiessling, Wim E. Hennink, Gert Storm
There are several ways to overcome this penetration barrier. These for instance include the use of inherently unstable or stimuli-sensitive nanomedicines (see above; Section 6.2.4), which either already in the tumor (micro-) circulation, or relatively fast upon extravasation, release their contents in the peri-vascular space, thereby setting free their low-molecular-weight payload, which can then penetrate deeply into the tumor. In addition, pharmacological treatments can be implemented, including besides the abovementioned extravasation- and penetration-enhancing inflammatory mediators TNF-α and histamine, e.g. also inhibitors of fibrosis and matrix-degrading enzymes. Regarding the former, Miyazono, Kataoka and colleagues have recently shown that a low dose of a transforming growth factor-β (TGF-β) inhibitor, which reduces fibrosis in the tumor microenvironment and the pericyte coverage of tumor blood vessels, can be used to substantially enhance both the extravasation and the penetration of both liposomal and micellar doxorubicin [49], as well as of iron oxide nanoparticles [50]. They demonstrated this in two xenograft models of pancreas cancer, which is notorious for its poor penetration, and also convincingly showed that co-treatment with the TGF-β inhibitor substantially improved the antitumor efficacy of micellar doxorubicin [49]. Regarding the latter, i.e. matrix-modifying agents, Jain and colleagues have shown that by pre-treating tumors with the enzyme collagenase (which degrades collagen; a major matrix component in tumors), caused a 2–3-fold increase in the penetration of antibodies and viral nanoparticles [51–53]. Similarly, pre-treatment of tumors with the hormone relaxin, which changes the structure of collagen, resulted in a 2–3-fold increase in the delivery of antibodies and macromolecules [51, 54]. An alternative non-pharmacological means to improve tumor penetration might be based on combinations with radiotherapy, which is known to be able to increase both the extravasation (via inducing the expression of VEGF and FGF) and the penetration (via lowering of the interstitial fluid pressure) of nanomedicines [38, 55–58]. A final elegant approach to improve the penetration and the intratumoral distribution of drug delivery systems relies on the development of ∼100 nm-sized “multistage” nanoparticles, which initially profit from their relatively large size to ensure prolonged circulation times, but which upon extravasation are degraded to 10 nm-sized “sub-particles” by tumor-associated proteases, such ∼ as matrix metalloproteinases, thereby enabling enhanced tumor penetration and improved intratumoral distribution [59].
Physical fitness and maternal body composition indices during pregnancy and postpartum: the GESTAFIT project
Published in European Journal of Sport Science, 2023
Nuria Marín-Jiménez, Marta Flor-Alemany, Laura Baena-García, Irene Coll-Risco, José Castro-Piñero, Virginia A. Aparicio
Finally, our results indicate that greater levels of flexibility were associated with lower GWG and lower total fat mass in the postpartum period. Greater flexibility levels during pregnancy, especially in late pregnancy to facilitate labour, are mandatory since relaxin is an important vasodilatory hormone during pregnancy (Petersen et al., 1995). Although the mechanisms are not fully understood yet, it plausible that overweight status induces relaxin-resistance (van Drongelen et al., 2012). Therefore, those pregnant women with greater fat mass indices are more likely to have reduced vascular responses, in addition to the possible vasoconstriction phenotype present in overweight status (van Drongelen et al., 2012). On the other hand, those pregnant women with greater flexibility during pregnancy could also present higher levels of relaxin, and relaxin seems to contribute to weight reduction (van Drongelen et al., 2012). Altogether could partially explain our results.