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Presently, there is clear evidence of a connection between this timing system and cancer development\/progression. Moreover, circadian rhythm consideration in the therapeutic action of anticancer drugs can enhance the effectiveness of cancer therapy. Nanosized drug delivery systems (DDS) have been demonstrated to be suitable engineered platforms for drug targeted\/sustained release. The investigation of the chronobiology-nanotechnology relationship, i.e., timing DDS performance according to a patient\u2019s circadian rhythm, may greatly improve cancer clinical outcomes. In the present work, we synthesized nanosystems based on an octa-arginine (R8)-modified poly(amidoamine) dendrimer conjugated with the anticancer drug paclitaxel (PTX), G4-PTX-R8, and its physicochemical properties were revealed to be appropriate for in vitro delivery. The influence of the circadian rhythm on its cellular internalization efficiency and potential therapeutic effect on human cervical cancer cells (HeLa) was studied. Cell-internalized PTX and caspase activity, as a measure of induced apoptosis, were monitored for six time points. Higher levels of PTX and caspase-3\/9 were detected at T8, suggesting that the internalization of G4-PTX-R8 into HeLa cells and apoptosis are time-specific\/-regulated phenomena. For a deeper understanding, the clock protein Bmal1\u2014the main regulator of rhythmic activity, was silenced by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. Bmal1 silencing was revealed to have an impact on both PTX release and caspase activity, evidencing a potential role for circadian rhythm on drug delivery\/therapeutic effect mediated by G4-PTX-R8.<\/jats:p>","DOI":"10.3390\/jfb14070362","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T01:01:41Z","timestamp":1689123701000},"page":"362","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Potential Effect of Circadian Rhythm in the Delivery\/Therapeutic Performance of Paclitaxel\u2013Dendrimer Nanosystems"],"prefix":"10.3390","volume":"14","author":[{"given":"T\u00e2nia","family":"Albuquerque","sequence":"first","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Ana Raquel","family":"Neves","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Milan","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Nanomedicine Research Laboratory, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-4206","authenticated-orcid":false,"given":"Swati","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Nanomedicine Research Laboratory, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3289-0605","authenticated-orcid":false,"given":"Elena","family":"Vuelta","sequence":"additional","affiliation":[{"name":"Servicio de Transg\u00e9nesis, Nucleus, Universidad de Salamanca, 37008 Salamanca, Spain"},{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Departamento de Medicina, Universidad de Salamanca, 37008 Salamanca, Spain"}]},{"given":"Ignacio","family":"Garc\u00eda-Tu\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8370-1336","authenticated-orcid":false,"given":"Manuel","family":"S\u00e1nchez-Martin","sequence":"additional","affiliation":[{"name":"Servicio de Transg\u00e9nesis, Nucleus, Universidad de Salamanca, 37008 Salamanca, Spain"},{"name":"Departamento de Medicina, Universidad de Salamanca, 37008 Salamanca, Spain"},{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-9858","authenticated-orcid":false,"given":"Telma","family":"Quintela","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"UDI-IPG-Unidade de Investiga\u00e7\u00e3o para o Desenvolvimento do Interior, Instituto Polit\u00e9cnico da Guarda, 6300-559 Guarda, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5049-4518","authenticated-orcid":false,"given":"Diana","family":"Costa","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pfeffer, C.M., and Singh, A.T.K. (2018). 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