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cancer necessitate the adoption of intelligent materials that respond to environmental stimuli. Therefore, we developed and optimized pH-triggered drug delivery nanoassemblies that exhibit an increased release of doxorubicin (DOX) in acidic conditions typical of cancer tissues and endosomal vesicles (pH 5.5) while exhibiting significantly lower release under normal physiological conditions (pH 7.5), indicating the potential to reduce cytotoxicity in healthy cells. The hybrid (polymeric\/lipid) composition of the lyotropic non-lamellar liquid crystalline (LNLCs) nanoassemblies demonstrated high encapsulation efficiency of the drug (&gt;90%) and high drug loading content (&gt;7%) with colloidal stability lasting at least 4 weeks. Confocal microscopy revealed cancer cellular uptake and DOX-loaded LNLCs accumulation near the nucleus of human hepatocellular carcinoma cells, with a large number of cells appearing to be in apoptosis. DOX-loaded LNLCs have also shown higher citotoxicity in cancer cell lines (MDA-MB 231 and HepG2 cell lines after 24 h and in NCI-H1299 cell line after 48 h) when compared to free drug. After 24 h, free DOX was found to have higher cytotoxicity than DOX-loaded LNLCs and empty LNLCs in the normal cell line. Overall, the results demonstrate that DOX-loaded LNLCs have the potential to be explored in cancer therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics15020326","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T03:45:16Z","timestamp":1674099916000},"page":"326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["pH-Responsive Hybrid Nanoassemblies for Cancer Treatment: Formulation Development, Optimization, and In Vitro Therapeutic Performance"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0335-0159","authenticated-orcid":false,"given":"Patr\u00edcia V.","family":"Teixeira","sequence":"first","affiliation":[{"name":"CF-UM-UP\u2014Centro de F\u00edsica das Universidades do Minho e Porto, Departamento de F\u00edsica, Universidade do Minho, 4710-057 Braga, Portugal"},{"name":"DNA & RNA Sensing Lab, Department of Genetics and Biotechnology, University of Tr\u00e1s-os-Montes and Alto Douro, Blocos Laboratoriais Ed, 5000-801 Vila Real, Portugal"}]},{"given":"Filomena","family":"Adega","sequence":"additional","affiliation":[{"name":"CAG\u2014Laboratory of Cytogenomics and Animal Genomics, Department of Genetics and Biotechnology, University of Tr\u00e1s-os-Montes e Alto Douro, 5000-801 Vila Real, Portugal"},{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8229-0117","authenticated-orcid":false,"given":"Paula","family":"Martins-Lopes","sequence":"additional","affiliation":[{"name":"DNA & RNA Sensing Lab, Department of Genetics and Biotechnology, University of Tr\u00e1s-os-Montes and Alto Douro, Blocos Laboratoriais Ed, 5000-801 Vila Real, Portugal"},{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9477-9945","authenticated-orcid":false,"given":"Raul","family":"Machado","sequence":"additional","affiliation":[{"name":"CBMA\u2014Center of Molecular and Environmental Biology, Departamento de Biologia, Universidade do Minho, 4710-057 Braga, Portugal"},{"name":"IB-S\u2014Institute of Science and Innovation for Bio-Sustainability, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5080-032X","authenticated-orcid":false,"given":"Carla M.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o, Inova\u00e7\u00e3o e Desenvolvimento (FP-I3ID), Biomedical and Health Sciences Research Unit (FP-BHS), Faculdade de Ci\u00eancias da Sa\u00fade, Universidade Fernando Pessoa, Rua Carlos da Maia 296, 4200-150 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2593-1672","authenticated-orcid":false,"given":"Marlene","family":"L\u00facio","sequence":"additional","affiliation":[{"name":"CF-UM-UP\u2014Centro de F\u00edsica das Universidades do Minho e Porto, Departamento de F\u00edsica, Universidade do Minho, 4710-057 Braga, Portugal"},{"name":"CBMA\u2014Center of Molecular and Environmental Biology, Departamento de Biologia, Universidade do Minho, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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