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A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood\u2013brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug\u2019s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS = 5.75 \u00b1 0.932 L\u00b7Kg\u22121) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.<\/jats:p>","DOI":"10.3390\/pharmaceutics13060869","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T22:25:46Z","timestamp":1623709546000},"page":"869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6186-8696","authenticated-orcid":false,"given":"Andreia","family":"Almeida","sequence":"first","affiliation":[{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0870-039X","authenticated-orcid":false,"given":"Eduarda","family":"Fernandes","sequence":"additional","affiliation":[{"name":"CF-UM-UP, Centro de F\u00edsica das Universidades do Minho e Porto, Departamento de F\u00edsica da Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-7553","authenticated-orcid":false,"given":"Bruno","family":"Sarmento","sequence":"additional","affiliation":[{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"CESPU, Instituto de Investiga\u00e7\u00e3o e Forma\u00e7\u00e3o Avan\u00e7ada em Ci\u00eancias e Tecnologias da Sa\u00fade, Rua Central da Gandra 137, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2593-1672","authenticated-orcid":false,"given":"Marlene","family":"L\u00facio","sequence":"additional","affiliation":[{"name":"CF-UM-UP, Centro de F\u00edsica das Universidades do Minho e Porto, Departamento de F\u00edsica da Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"CBMA, Centro de Biologia Molecular e Ambiental, Departamento de Biologia, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1021\/ja00968a057","article-title":"Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminata1, 2","volume":"88","author":"Wall","year":"1966","journal-title":"J. Am. Chem. Soc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1749-6632.2000.tb07021.x","article-title":"Molecular and biological determinants of the cytotoxic actions of camptothecins: Perspective for the development of new topoisomerase I inhibitors","volume":"922","author":"Kohn","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.hoc.2012.03.002","article-title":"Topoisomerase 1 inhibitors and cancer therapy","volume":"26","author":"Moukharskaya","year":"2012","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.12693\/APhysPolA.118.99","article-title":"Fluorescence spectroscopy in Camptothecins studies","volume":"118","author":"Kruszewski","year":"2010","journal-title":"Acta Phys. Pol. B"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0168-3659(01)00343-1","article-title":"The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity","volume":"74","author":"Bom","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ijbiomac.2006.04.004","article-title":"Binding of anti-inflammatory drug cromolyn sodium to bovine serum albumin","volume":"39","author":"Hu","year":"2006","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.addr.2012.09.026","article-title":"Advanced drug delivery devices via self-assembly of amphiphilic block copolymers","volume":"64","author":"Vandermeulen","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"447","DOI":"10.2174\/157340606778250199","article-title":"Interactions between oxicams and membrane bilayers: An explanation for their different COX selectivity","volume":"2","author":"Ferreira","year":"2006","journal-title":"Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.2174\/092986710791111233","article-title":"Drug-membrane interactions: Significance for medicinal chemistry","volume":"17","author":"Lima","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1016\/j.addr.2013.09.004","article-title":"Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles","volume":"65","author":"Peetla","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.addr.2015.01.009","article-title":"The application of in silico drug-likeness predictions in pharmaceutical research","volume":"86","author":"Tian","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.2174\/15680266113139990033","article-title":"In silico ADMET prediction: Recent advances, current challenges and future trends","volume":"13","author":"Cheng","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12540","DOI":"10.1021\/bi00208a002","article-title":"Marked interspecies variations concerning the interactions of camptothecin with serum albumins: A frequency-domain fluorescence spectroscopic study","volume":"33","author":"Mi","year":"1994","journal-title":"Biochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0014-5793(97)00693-5","article-title":"Camptothecin-binding site in human serum albumin and protein transformations induced by drug binding","volume":"411","author":"Fleury","year":"1997","journal-title":"FEBS letters"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1021\/jm00027a005","article-title":"The structural basis of camptothecin interactions with human serum albumin: Impact on drug stability","volume":"37","author":"Burke","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_16","first-page":"721","article-title":"Camptothecins affinity to HSA and membranes determined by fluorescence anisotropy measurements","volume":"32","author":"Kruszweski","year":"2002","journal-title":"Opt. Appl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.saa.2011.10.017","article-title":"Binding interactions of water-soluble camptothecin derivatives with bovine serum albumin","volume":"86","author":"Li","year":"2012","journal-title":"Spectrochim. Acta A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1021\/acs.jctc.9b00541","article-title":"Interaction of Camptothecin with Model Cellular Membranes","volume":"16","author":"Tang","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s11095-007-9511-1","article-title":"Pharmaceutical quality by design: Product and process development, understanding, and control","volume":"25","author":"Lawrence","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, H. (2017). Thin-film hydration followed by extrusion method for liposome preparation. Liposomes, Springer.","DOI":"10.1007\/978-1-4939-6591-5_2"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1039\/B314551B","article-title":"Influence of some anti-inflammatory drugs in membrane fluidity studied by fluorescence anisotropy measurements","volume":"6","author":"Ferreira","year":"2004","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1038\/nprot.2010.137","article-title":"High-throughput microplate assay for the determination of drug partition coefficients","volume":"5","author":"Nunes","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"323","DOI":"10.3389\/fchem.2018.00323","article-title":"Spectroscopic studies as a toolbox for biophysical and chemical characterization of lipid-based nanotherapeutics","volume":"6","author":"Fernandes","year":"2018","journal-title":"Front. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fernandes, E., Soares, T.B., Gon\u00e7alves, H., Bernstorff, S., Real Oliveira, M.E.C., Lopes, C.M., and L\u00facio, M. (2018). A molecular biophysical approach to diclofenac topical gastrointestinal damage. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113411"},{"key":"ref_25","unstructured":"Lakowicz, J.R. (2013). Principles of fluorescence spectroscopy, Springer science & business media."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"119222","DOI":"10.1016\/j.ijpharm.2020.119222","article-title":"Prediction of paclitaxel pharmacokinetic based on in vitro studies: Interaction with membrane models and human serum albumin","volume":"580","author":"Carvalho","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_27","unstructured":"Di, L., and Kerns, E.H. (2015). Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization, Academic press."},{"key":"ref_28","unstructured":"Seydel, J.K., and Wiese, M. (2009). Drug-Membrane Interactions: Analysis, Drug Distribution, Modeling, John Wiley & Sons."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2533\/chimia.1992.299","article-title":"Hydrogen-bonding capacity and brain penetration","volume":"46","author":"Kansy","year":"1992","journal-title":"CHIMIA Int. J. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1124\/dmd.32.1.132","article-title":"Development of a computational approach to predict blood-brain barrier permeability","volume":"32","author":"Liu","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1007\/s11095-016-2086-y","article-title":"Drug distribution part 2. Predicting volume of distribution from plasma protein binding and membrane partitioning","volume":"34","author":"Korzekwa","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1021\/jm0200409","article-title":"Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data","volume":"45","author":"Lombardo","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Musteata, F.M. (2012). Clinical utility of free drug monitoring. Ther. Drug Monit. Newer Drugs Biomarkers, 75\u2013101.","DOI":"10.1016\/B978-0-12-385467-4.00004-X"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4586","DOI":"10.1002\/jps.21317","article-title":"Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding","volume":"97","author":"Waters","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1021\/js9804011","article-title":"Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption","volume":"88","author":"Clark","year":"1999","journal-title":"J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mandic, Z. (2012). Physico Chemical Methods in Drug Discovery and Development, IAPC Publishing.","DOI":"10.5599\/obp.7.0"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.ejpb.2019.01.009","article-title":"Covalently crosslinked organophosphorous derivatives-chitosan hydrogel as a drug delivery system for oral administration of camptothecin","volume":"136","author":"Bermejo","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1208\/s12248-011-9290-9","article-title":"BDDCS applied to over 900 drugs","volume":"13","author":"Benet","year":"2011","journal-title":"AAPS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0378-5173(02)00099-6","article-title":"Preformulation studies of a novel camptothecin anticancer agent, CKD-602: Physicochemical characterization and hydrolytic equilibrium kinetics","volume":"239","author":"Kim","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1208\/s12249-013-0046-y","article-title":"Physicochemical Characterization of 9-Aminocamptothecin in Aqueous Solutions","volume":"15","author":"Rahman","year":"2014","journal-title":"AAPS PharmSciTech"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S1741-8364(04)02388-1","article-title":"Simulation models for drug disposition and drug interactions","volume":"2","author":"Dickins","year":"2004","journal-title":"Drug Discov. Today: Biosilico"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Choi, G.-W., Lee, Y.-B., and Cho, H.-Y. (2019). Interpretation of non-clinical data for prediction of human pharmacokinetic parameters: In vitro-in vivo extrapolation and allometric scaling. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11040168"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/jps.10005","article-title":"Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution","volume":"91","author":"Poulin","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11157","DOI":"10.1021\/acsami.8b22487","article-title":"Acidic pH and high-H2O2 dual tumor microenvironment-responsive nanocatalytic graphene oxide for cancer selective therapy and recognition","volume":"11","author":"Lin","year":"2019","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4103\/0975-7406.76461","article-title":"Biomembrane models and drug-biomembrane interaction studies: Involvement in drug design and development","volume":"3","author":"Pignatello","year":"2011","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4875","DOI":"10.1021\/jp035260s","article-title":"Permeation of Small Molecules through a Lipid Bilayer: A Computer Simulation Study","volume":"108","author":"Bemporad","year":"2004","journal-title":"J. Phys. Chem. B"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejmech.2019.04.026","article-title":"Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents","volume":"174","author":"Oliveira","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1021\/cr60274a001","article-title":"Partition coefficients and their uses","volume":"71","author":"Leo","year":"1971","journal-title":"Chem. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4379","DOI":"10.1002\/jps.21314","article-title":"Physicochemical characterization and membrane binding properties of camptothecin","volume":"97","author":"Selvi","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1021\/je7003935","article-title":"Liquid phase behavior of ionic liquids with water and 1-octanol and modeling of 1-octanol\/water partition coefficients","volume":"52","author":"Chapeaux","year":"2007","journal-title":"J. Chem. Eng. Data"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1002\/jps.21244","article-title":"Alternative measures of lipophilicity: From octanol\u2013water partitioning to IAM retention","volume":"97","author":"Giaginis","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ijpharm.2012.12.030","article-title":"Imidazolium ionic liquids as solvents of pharmaceuticals: Influence on HSA binding and partition coefficient of nimesulide","volume":"443","author":"Azevedo","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.chemphyslip.2010.07.004","article-title":"Effects of resveratrol on membrane biophysical properties: Relevance for its pharmacological effects","volume":"163","author":"Brittes","year":"2010","journal-title":"Chem. Phys. Lipids"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12302-018-0176-7","article-title":"A comparison of log Kow (n-octanol\u2013water partition coefficient) values for non-ionic, anionic, cationic and amphoteric surfactants determined using predictions and experimental methods","volume":"31","author":"Hodges","year":"2019","journal-title":"Environ. Sci. Eur."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.bbamem.2016.11.012","article-title":"Distinct membrane properties are differentially influenced by cardiolipin content and acyl chain composition in biomimetic membranes","volume":"1859","author":"Pennington","year":"2017","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3389\/fphys.2011.00082","article-title":"FRET in membrane biophysics: An overview","volume":"2","author":"Loura","year":"2011","journal-title":"Front. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.bbamem.2007.02.001","article-title":"Monitoring the looping up of acyl chain labeled NBD lipids in membranes as a function of membrane phase state","volume":"1768","author":"Raghuraman","year":"2007","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"20131062","DOI":"10.1098\/rsif.2013.1062","article-title":"Amphiphilic drug interactions with model cellular membranes are influenced by lipid chain-melting temperature","volume":"11","author":"Casey","year":"2014","journal-title":"J. R. Soc. Interface"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.cplett.2009.02.047","article-title":"Effect of anti-inflammatory drugs in phosphatidylcholine membranes: A fluorescence and calorimetric study","volume":"471","author":"Nunes","year":"2009","journal-title":"Chem. Phys. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.chemphyslip.2005.09.003","article-title":"Determination of phase transition temperatures of lipids by light scattering","volume":"139","author":"Michel","year":"2006","journal-title":"Chem. Phys. Lipids"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/BF01870299","article-title":"Effect of small molecules on the dipalmitoyl lecithin liposomal bilayer: III. Phase transition in lipid bilayer","volume":"34","author":"Jain","year":"1977","journal-title":"J. Membr. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.chemphyslip.2003.09.002","article-title":"Lipid bilayers: Thermodynamics, structure, fluctuations, and interactions","volume":"127","author":"Nagle","year":"2004","journal-title":"Chem. Phys. Lipids"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.ejpb.2013.08.011","article-title":"Brain targeting effect of camptothecin-loaded solid lipid nanoparticles in rat after intravenous administration","volume":"85","author":"Martins","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Schanker, L. (1971). Absorption of drugs from the gastrointestinal tract. Concepts in Biochemical Pharmacology, Springer.","DOI":"10.1007\/978-3-642-65052-9_2"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ijpharm.2013.05.040","article-title":"Mucus as a barrier to lipophilic drugs","volume":"453","author":"Sigurdsson","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1002\/jps.23996","article-title":"The role of payload hydrophobicity in nanotherapeutic pharmacokinetics","volume":"103","author":"Norvaisas","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.addr.2015.03.011","article-title":"In vitro, in silico and integrated strategies for the estimation of plasma protein binding. A review","volume":"86","author":"Lambrinidis","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/S1367-5931(03)00055-3","article-title":"Pharmaceutical profiling in discovery research","volume":"7","author":"Di","year":"2003","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ballard, P., Brassil, P., Bui, K., Dolgos, H., Petersson, C., Tunek, A., and Webborn, P. (2012). Metabolism and pharmacokinetic optimization strategies in drug discovery. Drug Discovery and Development-E-Book: Technology in Transition, Elsevier.","DOI":"10.1016\/B978-0-7020-4299-7.00010-X"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/bjc.1996.130","article-title":"Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x 5 intravenous administration","volume":"73","author":"Gerrits","year":"1996","journal-title":"Br. J. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/j.1552-4604.1983.tb02753.x","article-title":"Is volume of distribution at steady state a meaningful kinetic variable?","volume":"23","author":"Greenblatt","year":"1983","journal-title":"J. Clin. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1021\/mp900243b","article-title":"Cancer therapies utilizing the camptothecins: A review of the in vivo literature","volume":"7","author":"Venditto","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"363","DOI":"10.20892\/j.issn.2095-3941.2017.0099","article-title":"Camptothecin-based nanodrug delivery systems","volume":"14","author":"Wen","year":"2017","journal-title":"Cancer Biol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ijpharm.2005.10.030","article-title":"Preparation of camptothecin-loaded polymeric micelles and evaluation of their incorporation and circulation stability","volume":"308","author":"Watanabe","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.jconrel.2006.03.012","article-title":"Enhanced antitumor effect of camptothecin loaded in long-circulating polymeric micelles","volume":"112","author":"Kawano","year":"2006","journal-title":"J. Control. Release"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"110920","DOI":"10.1016\/j.msec.2020.110920","article-title":"Novel amphiphilic chitosan micelles as carriers for hydrophobic anticancer drugs","volume":"112","author":"Almeida","year":"2020","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8318","DOI":"10.1021\/ja00047a069","article-title":"Liposomal stabilization of camptothecin\u2019s lactone ring","volume":"114","author":"Burke","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jconrel.2008.02.005","article-title":"In vivo antitumor activity of camptothecin incorporated in liposomes formulated with an artificial lipid and human serum albumin","volume":"127","author":"Watanabe","year":"2008","journal-title":"J. Control. Release"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.2217\/nnm-2019-0261","article-title":"Redox-sensitive dimeric camptothecin phosphatidylcholines-based liposomes for improved anticancer efficacy","volume":"14","author":"He","year":"2019","journal-title":"Nanomedicine"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"L\u00facio, M., Lopes, C.M., Fernandes, E., Gon\u1eb9alves, H., and Oliveira, M.E.C.R. (2021). Organic Nanocarriers for Brain Drug Delivery. Nanoparticles for Brain Drug Delivery, Jenny Stanford Publishing.","DOI":"10.1201\/9781003119326-6"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-019-0289-8","article-title":"Communication between mitochondria and other organelles: A brand-new perspective on mitochondria in cancer","volume":"9","author":"Xia","year":"2019","journal-title":"Cell Biosci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/6\/869\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:40Z","timestamp":1760163220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/6\/869"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":82,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["pharmaceutics13060869"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13060869","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202105.0480.v1","asserted-by":"object"}]},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,12]]}}}