{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:24:15Z","timestamp":1793651055337,"version":"4.5.1"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100018785","name":"Gastro-Intestinal Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018785","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharm Res"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Colorectal cancer (CRC) is a leading cause of cancer mortality with current chemotherapeutic strategies often limited by systemic side effects and suboptimal tumor targeting. This study aimed to enhance the delivery and efficacy of paclitaxel (PTX) for CRC therapy by engineering nanoparticles (NPs) actively targeted to the folate receptor-\u03b1 (FR\u03b1) using pemetrexed, an FDA-approved antifolate with high FR\u03b1 affinity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A novel FR\u03b1-targeted polymer (PLGA-PEG-pemetrexed) was synthesized by ring-opening polymerization and used to prepare tumor-targeted nanoparticles (TTNPs). The physical characteristics of TTNPs and non-targeted NPs (NTNPs) were evaluated by dynamic light scattering and TEM. Cellular uptake was assessed in FR\u03b1-expressing CT26 colorectal cancer cells by flow cytometry and confocal imaging. Cytotoxicity was evaluated using PrestoBlue\u2122 assays.\n                      <jats:italic>In vivo<\/jats:italic>\n                      tumor targeting and therapeutic efficacy were assessed in a syngeneic CT26 tumor-bearing BALB\/c mouse model using IVIS imaging, tumor accumulation and growth measurements.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The synthesized PLGA-PEG-pemetrexed formed uniform, negatively charged NPs with a hydrodynamic diameter of 140\u2013170 nm. TTNPs demonstrated significantly enhanced uptake in FR\u03b1-expressing CT26 cells compared to NTNPs, which was abrogated by folic acid pre-treatment.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , PTX-loaded TTNPs exhibited greater cytotoxicity against CT26 cells than free PTX.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , TTNPs showed superior tumor accumulation compared to NTNPs, resulting in significantly greater tumor growth inhibition and increased intratumoral PTX concentrations. All treatments were well tolerated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results demonstrate that active targeting of chemotherapy-loaded NPs with a FR\u03b1 ligand, pemetrexed, enhances tumor targeting and antitumor efficacy in a CRC model.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-025-03940-1","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T18:35:59Z","timestamp":1763490959000},"page":"2339-2351","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Active Targeting of Colorectal Cancer Using Chemotherapy-Loaded Nanoparticles Functionalized with a Folate Receptor-\u03b1 (FR\u03b1) Ligand, Pemetrexed"],"prefix":"10.1007","volume":"42","author":[{"given":"Mohammad","family":"Alnatour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramkrishna","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leela Sai Lokesh","family":"Janardhanam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Meraj","family":"Anjum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean M.","family":"Geary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-6633","authenticated-orcid":false,"given":"Aliasger K.","family":"Salem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"issue":"3","key":"3940_CR1","first-page":"233","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233\u201354.","journal-title":"CA Cancer J Clin"},{"issue":"2","key":"3940_CR2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1177\/1758834011431592","volume":"4","author":"B Chibaudel","year":"2012","unstructured":"Chibaudel B, Tournigand C, Andr\u00e9 T, de Gramont A. Therapeutic strategy in unresectable metastatic colorectal cancer. Ther Adv Med Oncol. 2012;4(2):75\u201389.","journal-title":"Ther Adv Med Oncol"},{"key":"3940_CR3","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.colsurfb.2018.11.088","volume":"175","author":"X Wu","year":"2019","unstructured":"Wu X, Liu J, Yang L, Wang F. Photothermally controlled drug release system with high dose loading for synergistic chemo-photothermal therapy of multidrug resistance cancer. Colloids Surf B Biointerfaces. 2019;175:239\u201347.","journal-title":"Colloids Surf B Biointerfaces"},{"issue":"1","key":"3940_CR4","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1021\/acsami.8b17958","volume":"11","author":"RK Singh","year":"2019","unstructured":"Singh RK, Patel KD, Mahapatra C, Parthiban SP, Kim TH, Kim HW. Combinatory cancer therapeutics with nanoceria-capped mesoporous silica nanocarriers through ph-triggered drug release and redox activity. ACS Appl Mater Interfaces. 2019;11(1):288\u201399.","journal-title":"ACS Appl Mater Interfaces"},{"key":"3940_CR5","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.jconrel.2016.07.028","volume":"238","author":"R Ngoune","year":"2016","unstructured":"Ngoune R, Peters A, von Elverfeldt D, Winkler K, P\u00fctz G. Accumulating nanoparticles by EPR: a route of no return. J Control Release. 2016;238:58\u201370.","journal-title":"J Control Release"},{"issue":"20","key":"3940_CR6","doi-asserted-by":"publisher","first-page":"19810","DOI":"10.1021\/acsnano.3c04037","volume":"17","author":"Q Chen","year":"2023","unstructured":"Chen Q, Yuan L, Chou WC, Cheng YH, He C, Monteiro-Riviere NA, et al. Meta-analysis of nanoparticle distribution in tumors and major organs in tumor-bearing mice. ACS Nano. 2023;17(20):19810\u201331.","journal-title":"ACS Nano"},{"issue":"10","key":"3940_CR7","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1021\/acs.bioconjchem.6b00437","volume":"27","author":"Y Nakamura","year":"2016","unstructured":"Nakamura Y, Mochida A, Choyke PL, Kobayashi H. Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjug Chem. 2016;27(10):2225\u201338.","journal-title":"Bioconjug Chem"},{"key":"3940_CR8","doi-asserted-by":"publisher","first-page":"101722","DOI":"10.1016\/j.jddst.2020.101722","volume":"57","author":"RS Prabhuraj","year":"2020","unstructured":"Prabhuraj RS, Bomb K, Srivastava R, Bandyopadhyaya R. Selection of superior targeting ligands using PEGylated PLGA nanoparticles for delivery of curcumin in the treatment of triple-negative breast cancer cells. J Drug Deliv Sci Technol. 2020;57:101722.","journal-title":"J Drug Deliv Sci Technol"},{"key":"3940_CR9","doi-asserted-by":"publisher","first-page":"101380","DOI":"10.1016\/j.jddst.2019.101380","volume":"54","author":"H Tonbul","year":"2019","unstructured":"Tonbul H, Sahin A, Tavukcuoglu E, Esendagli G, Capan Y. Combination drug delivery with actively-targeted PLGA nanoparticles to overcome multidrug resistance in breast cancer. J Drug Deliv Sci Technol. 2019;54:101380.","journal-title":"J Drug Deliv Sci Technol"},{"issue":"1","key":"3940_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-06803-7","volume":"20","author":"P Wu","year":"2020","unstructured":"Wu P, Zhou Q, Zhu H, Zhuang Y, Bao J. Enhanced antitumor efficacy in colon cancer using EGF functionalized PLGA nanoparticles loaded with 5-fluorouracil and perfluorocarbon. BMC Cancer. 2020;20(1): 354.","journal-title":"BMC Cancer"},{"issue":"3","key":"3940_CR11","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/bjc.2012.605","volume":"108","author":"JP Tiernan","year":"2013","unstructured":"Tiernan JP, Perry SL, Verghese ET, West NP, Yeluri S, Jayne DG, et al. Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting. Br J Cancer. 2013;108(3):662\u20137.","journal-title":"Br J Cancer"},{"key":"3940_CR12","doi-asserted-by":"crossref","unstructured":"Ly P-D, Ly K-N, Phan H-L, Nguyen HHT, Duong V-A, Nguyen HV. Recent advances in surface decoration of nanoparticles in drug delivery. Front Nanotechnol. 2024;6:1456939.","DOI":"10.3389\/fnano.2024.1456939"},{"issue":"1","key":"3940_CR13","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1080\/10717544.2018.1440447","volume":"25","author":"D Bi","year":"2018","unstructured":"Bi D, Zhao L, Yu R, Li H, Guo Y, Wang X, et al. Surface modification of doxorubicin-loaded nanoparticles based on polydopamine with pH-sensitive property for tumor targeting therapy. Drug Deliv. 2018;25(1):564\u201375.","journal-title":"Drug Deliv"},{"issue":"8","key":"3940_CR14","doi-asserted-by":"publisher","first-page":"3284","DOI":"10.1021\/acs.analchem.3c03593","volume":"96","author":"T Mochizuki","year":"2024","unstructured":"Mochizuki T, Sampei S, Suga K, Watanabe K, Welling TAJ, Nagao D. A quantitative approach to characterize the surface modification on nanoparticles based on localized dielectric environments. Anal Chem. 2024;96(8):3284\u201390.","journal-title":"Anal Chem"},{"key":"3940_CR15","doi-asserted-by":"crossref","unstructured":"Chen CI, Li WS, Chen HP, Liu KW, Tsai CJ, Hung WJ, et al. High expression of Folate receptor alpha (FOLR1) is associated with aggressive tumor behavior, poor response to chemoradiotherapy, and worse survival in rectal cancer. Technol Cancer Res Treat. 2022;21:15330338221141796.","DOI":"10.1177\/15330338221141795"},{"key":"3940_CR16","doi-asserted-by":"crossref","unstructured":"D\u2019Angelica M, Ammori J, Gonen M, Klimstra DS, Low PS, Murphy L, et al. Folate receptor-\u03b1 expression in resectable hepatic colorectal cancer metastases: patterns and significance. Mod Pathol. 2011;24(9):1221\u20138.","DOI":"10.1038\/modpathol.2011.82"},{"issue":"2","key":"3940_CR17","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1158\/1535-7163.MCT-06-0343","volume":"6","author":"S Chattopadhyay","year":"2007","unstructured":"Chattopadhyay S, Moran RG, Goldman ID. Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther. 2007;6(2):404\u201317.","journal-title":"Mol Cancer Ther"},{"issue":"2","key":"3940_CR18","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1586\/14737140.3.2.145","volume":"3","author":"AA Adjei","year":"2003","unstructured":"Adjei AA. Pemetrexed (Alimta): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther. 2003;3(2):145\u201356.","journal-title":"Expert Rev Anticancer Ther"},{"key":"3940_CR19","doi-asserted-by":"crossref","unstructured":"Einzig AI, Neuberg D, Wiernik PH, Grochow LB, Ramirez G, O\u2019Dwyer PJ, et al. Phase II trial of paclitaxel in patients with advanced colon cancer previously untreated with cytotoxic chemotherapy: an eastern cooperative oncology group trial (PA286). Am J Ther. 1996;3(11):750\u20134.","DOI":"10.1097\/00045391-199611000-00003"},{"issue":"13","key":"3940_CR20","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.3748\/wjg.v30.i13.1780","volume":"30","author":"K Kita","year":"2024","unstructured":"Kita K, Burdowski A. Recent clinical trials and optical control as a potential strategy to develop microtubule-targeting drugs in colorectal cancer management. World J Gastroenterol. 2024;30(13):1780\u201390.","journal-title":"World J Gastroenterol"},{"issue":"1","key":"3940_CR21","doi-asserted-by":"publisher","first-page":"674175","DOI":"10.1155\/2015\/674175","volume":"2015","author":"HN Ho","year":"2015","unstructured":"Ho HN, Tran TH, Tran TB, Yong CS, Nguyen CN. Optimization and characterization of artesunate-loaded chitosan-decorated poly(D,L-lactide-co-glycolide) acid nanoparticles. J Nanomater. 2015;2015(1):674175.","journal-title":"J Nanomater"},{"issue":"4","key":"3940_CR22","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1039\/C8MD00565F","volume":"10","author":"J Kazi","year":"2019","unstructured":"Kazi J, Mukhopadhyay R, Sen R, Jha T, Ganguly S, Debnath MC. Design of 5-fluorouracil (5-FU) loaded, folate conjugated peptide linked nanoparticles, a potential new drug carrier for selective targeting of tumor cells. Medchemcomm. 2019;10(4):559\u201372.","journal-title":"Medchemcomm"},{"issue":"7","key":"3940_CR23","doi-asserted-by":"publisher","first-page":"6458","DOI":"10.1021\/acsnano.8b02881","volume":"12","author":"F Meng","year":"2018","unstructured":"Meng F, Wang J, Ping Q, Yeo Y. Quantitative assessment of nanoparticle biodistribution by fluorescence imaging, revisited. ACS Nano. 2018;12(7):6458\u201368.","journal-title":"ACS Nano"},{"issue":"3","key":"3940_CR24","first-page":"3763","volume":"17","author":"XY Li","year":"2018","unstructured":"Li XY, Xu L, Li HL, Du J, Liu XS, Li FH. Au-poly(lactic-co-glycolic) acid complex nanoparticles as ultrasound contrast agents: preparation, characterization and in vitro study. Mol Med Rep. 2018;17(3):3763\u20138.","journal-title":"Mol Med Rep"},{"issue":"33","key":"3940_CR25","doi-asserted-by":"publisher","first-page":"28806","DOI":"10.1021\/acsomega.2c01660","volume":"7","author":"MA Al-natour","year":"2022","unstructured":"Al-natour MA, Abdelrazig S, Ghaemmaghami AM, Alexander C, Kim D-H. Metabolic signatures of surface-modified poly(lactic-co-glycolic acid) nanoparticles in differentiated THP-1 cells derived with liquid chromatography-mass spectrometry-based metabolomics. ACS Omega. 2022;7(33):28806\u201319.","journal-title":"ACS Omega"},{"key":"3940_CR26","doi-asserted-by":"crossref","unstructured":"Al-Natour MA, Yousif MD, Cavanagh R, Abouselo A, Apebende EA, Ghaemmaghami A, et al. Facile dye-initiated polymerization of lactide-glycolide generates highly fluorescent poly(lactic-co-glycolic acid) for enhanced characterization of cellular delivery. ACS Macro Lett. 2020;9(3):431\u20137.","DOI":"10.1021\/acsmacrolett.9b01014"},{"key":"3940_CR27","doi-asserted-by":"publisher","first-page":"708593","DOI":"10.1155\/2014\/708593","volume":"2014","author":"J Varshosaz","year":"2014","unstructured":"Varshosaz J, Hassanzadeh F, Sadeghi-Aliabadi H, Firozian F. Uptake of etoposide in CT-26 cells of colorectal cancer using folate targeted dextran stearate polymeric micelles. Biomed Res Int. 2014;2014:708593.","journal-title":"Biomed Res Int"},{"key":"3940_CR28","doi-asserted-by":"crossref","unstructured":"Kwon S, Meng F, Tamam H, Gadalla HH, Wang J, Dong B, et al. Systemic delivery of paclitaxel by find-me nanoparticles activates antitumor immunity and eliminates tumors. ACS Nano. 2024;18(4):3681\u201398.","DOI":"10.1021\/acsnano.3c11445"},{"issue":"7","key":"3940_CR29","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.3390\/ma11071154","volume":"11","author":"L Guerrini","year":"2018","unstructured":"Guerrini L, Alvarez-Puebla RA, Pazos-Perez N. Surface modifications of nanoparticles for stability in biological fluids. Materials. 2018;11(7):1154.","journal-title":"Materials"},{"issue":"2","key":"3940_CR30","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1021\/bm0343040","volume":"5","author":"TI Croll","year":"2004","unstructured":"Croll TI, O\u2019Connor AJ, Stevens GW, Cooper-White JJ. Controllable surface modification of poly(lactic-co-glycolic acid) (PLGA) by hydrolysis or aminolysis I: physical, chemical, and theoretical aspects. Biomacromol. 2004;5(2):463\u201373.","journal-title":"Biomacromol"},{"issue":"4","key":"3940_CR31","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1016\/j.apsb.2021.02.019","volume":"11","author":"S Mazumdar","year":"2021","unstructured":"Mazumdar S, Chitkara D, Mittal A. Exploration and insights into the cellular internalization and intracellular fate of amphiphilic polymeric nanocarriers. Acta Pharm Sin B. 2021;11(4):903\u201324.","journal-title":"Acta Pharm Sin B"},{"issue":"3","key":"3940_CR32","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41565-021-00858-8","volume":"16","author":"JJ Rennick","year":"2021","unstructured":"Rennick JJ, Johnston APR, Parton RG. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat Nanotechnol. 2021;16(3):266\u201376.","journal-title":"Nat Nanotechnol"},{"key":"3940_CR33","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.addr.2013.11.009","volume":"66","author":"N Bertrand","year":"2014","unstructured":"Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014;66:2\u201325.","journal-title":"Adv Drug Deliv Rev"},{"key":"3940_CR34","doi-asserted-by":"publisher","unstructured":"Wang L, Hu D, Xu J, Hu J, Wang Y. Complex in vitro model: a transformative model in drug development and precision medicine. Clin Transl Sci. 2023. https:\/\/doi.org\/10.1111\/cts.13695.","DOI":"10.1111\/cts.13695"},{"key":"3940_CR35","doi-asserted-by":"crossref","unstructured":"Prabhakar U, Maeda H, Jain RK, Sevick-Muraca EM, Zamboni W, Farokhzad OC, et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 2013;73(8):2412\u20137.","DOI":"10.1158\/0008-5472.CAN-12-4561"},{"key":"3940_CR36","doi-asserted-by":"crossref","unstructured":"Zhang J, Wang S, Zhang D, He X, Wang X, Han H, et al. Nanoparticle-based drug delivery systems to enhance cancer immunotherapy in solid tumors. Front Immunol. 2023;14:1230893.","DOI":"10.3389\/fimmu.2023.1230893"},{"key":"3940_CR37","doi-asserted-by":"crossref","unstructured":"Cheung A, Bax HJ, Josephs DH, Ilieva KM, Pellizzari G, Opzoomer J, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016;7(32):52553\u201374.","DOI":"10.18632\/oncotarget.9651"}],"container-title":["Pharmaceutical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03940-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11095-025-03940-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03940-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T16:50:54Z","timestamp":1768927854000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11095-025-03940-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,18]]},"references-count":37,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["3940"],"URL":"https:\/\/doi.org\/10.1007\/s11095-025-03940-1","relation":{},"ISSN":["0724-8741","1573-904X"],"issn-type":[{"value":"0724-8741","type":"print"},{"value":"1573-904X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,18]]},"assertion":[{"value":"4 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}