Published May 15, 2024 | Version v1
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Coating methotrexate-PLGA nanoparticles with folic acid-chitosan conjugate for cancer targeting

  • 1. Jordan University of Science and Technology, Irbid, Jordan

Description

Background: Loading Methotrexate, a chemotherapeutic agent, in a nanocarrier can improve its efficacy and lower its side effects. Both PLGA and chitosan were used to formulate Methotrexate nanoparticles. Folate acts as a targeting ligand for anticancer medications. Therefore, folate, chitosan, and PLGA were used to deliver methotrexate.

Methods: Folic acid and Chitosan (FA-CS) were conjugated and used to coat Methotrexate-PLGA nanoparticles. The conjugate and the nanoparticles were characterized using Zetasizer to test particle size, polydispersity and charge, SEM was used to test particles' morphology. Both %EE and %LC of MTX in the NPs were measured. Finally, MTX release and the system cytotoxicity were tested in vitro.

Results: FTIR, NMR, and XRD proved the successful formation of FA-CS, and the formation of the coated nanoparticles. The particles were spherical with a size ~385 nm, a disparity ~0.27, and a charge ~+15 mV. The %EE and the % LC were 79% and 21.2%, respectively. In vitro release studies revealed nearly complete MTX release after 48 h. In vitro cytotoxicity testing demonstrated that the formulation components are safe and that the incorporation of MTX within the nanoparticles enhanced the drug's cytotoxic effect in comparison to the free drug.

Conclusion: loading of MTX in the NPs enhances its chemotherapeutic effect, hence, this system can be used to target carcinogenic cells.

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References

  • Akbari E, Mousazadeh H, Sabet Z, Fattahi T, Dehnad A, Akbarzadeh A, Alizadeh E (2021) Dual drug delivery of trapoxin A and methotrexate from biocompatible PLGA-PEG polymeric nanoparticles enhanced antitumor activity in breast cancer cell line. Journal of Drug Delivery Science and Technology 61: 102294. https://doi.org/10.1016/j.jddst.2020.102294
  • Al-Nemrawi NK, Altawabeyeh RM, Darweesh RS (2022) Preparation and Characterization of docetaxel-PLGA nanoparticles coated with folic acid-chitosan conjugate for cancer treatment. Journal of Pharmaceutical Sciences 111: 485–494. https://doi.org/10.1016/j.xphs.2021.10.034
  • Anon (2021a) A549 | ATCC. https://www.atcc.org/products/ccl-185 [July 27, 2021a]
  • Anon (2021b) Calu-3 | ATCC. https://www.atcc.org/products/htb-55 [July 27, 2021b]
  • Anon (2021c) RPMI 2650 | ATCC. https://www.atcc.org/products/ccl-30 [July 27, 2021c]
  • Anon (2021d) Table 4: FTIR peaks of functional groups of PLGA. ResearchGate. https://www.researchgate.net/figure/FTIR-peaks-of-functional-groups-of-PLGA_tbl3_269808442 [January 12, 2021d]
  • Ashwanikumar N, Kumar NA, Nair SA, Kumar GSV (2014) Dual drug delivery of 5-fluorouracil (5-FU) and methotrexate (MTX) through random copolymeric nanomicelles of PLGA and polyethylenimine demonstrating enhanced cell uptake and cytotoxicity. Colloids and Surfaces B: Biointerfaces 122: 520–528. https://doi.org/10.1016/j.colsurfb.2014.07.024
  • Barbosa AI, Costa Lima SA, Reis S (2019) Development of methotrexate loaded fucoidan/chitosan nanoparticles with anti-inflammatory potential and enhanced skin permeation. International Journal of Biological Macromolecules 124: 1115–1122. https://doi.org/10.1016/j.ijbiomac.2018.12.014
  • Cohen IJ (2017) Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue. Cancer Chemotherapy and Pharmacology 79: 1057–1065. https://doi.org/10.1007/s00280-017-3304-y
  • Coutinho A, Costa Lima S, Afonso C, Reis S (2020) Mucoadhesive and pH responsive fucoidan-chitosan nanoparticles for the oral delivery of methotrexate. International Journal of Biological Macromolecules 158. https://doi.org/10.1016/j.ijbiomac.2020.04.233
  • Dhanaraj SA, Muralidharan S, Venugopal V, Kanniappan P, Sze Hui WT, Qi LL (2016) Formulation and Evaluation of Chitosan Nanospheres Containing Methotrexate Targeted Drug Delivery System. Journal of Young Pharmacists 8: 330–334. https://doi.org/10.5530/jyp.2016.4.7
  • Dhas NL, Ige PP, Kudarha RR (2015) Design, optimization and in-vitro study of folic acid conjugated-chitosan functionalized PLGA nanoparticle for delivery of bicalutamide in prostate cancer. Powder Technology 283: 234–245. https://doi.org/10.1016/j.powtec.2015.04.053
  • Ebrahimnejad P, Sodagar Taleghani A, Asare-Addo K, Nokhodchi A (2022) An updated review of folate-functionalized nanocarriers: A promising ligand in cancer. Drug Discovery Today 27: 471–489. https://doi.org/10.1016/j.drudis.2021.11.011
  • Esim O, Oztuna A, Sarper M, Hascicek C (2022) Chitosan-coated bovine serum albumin nanocarriers mediate efficient delivery of methotrexate in breast cancer therapeutics. Journal of Drug Delivery Science and Technology 77: 103906. https://doi.org/10.1016/j.jddst.2022.103906
  • Essa D, Kondiah PPD, Choonara YE, Pillay V (2020) The design of poly(lactide-co-glycolide) nanocarriers for medical applications. Frontiers in Bioengineering and Biotechnology, Vol. 8. https://doi.org/10.3389/fbioe.2020.00048 [October 31, 2023]
  • Gomes C, Moreira RG, Castell-Perez E (2011) Poly (DL-lactide-co-glycolide) (PLGA) Nanoparticles with entrapped trans-cinnamaldehyde and eugenol for antimicrobial delivery applications. Journal of Food Science 76: N16–N24. https://doi.org/10.1111/j.1750-3841.2010.01985.x
  • Hamed KM, Dighriri IM, Baomar AF, Alharthy BT, Alenazi FE, Alali GH, Alenazy RH, Alhumaidi NT, Alhulayfi DH, Alotaibi YB, Alhumaidan SS, Alhaddad ZA, Humadi AA, Alzahrani SA, Alobaid RH (2022) Overview of methotrexate toxicity: A comprehensive literature review. Cureus 14(9): e29518. https://doi.org/10.7759/cureus.29518
  • Hassan M, Farid D, Mahdi A, Masood K, Hossein A, Morteza K (2017) Methotrexate-loaded plga nanoparticles: Preparation, characterization and their cytotoxicity effect on human glioblastoma U87MG cells. International Journal of Medical Nano Research 4: 020. https://doi.org/10.23937/2378-3664/1410020
  • Ji J, Wu D, Liu L, Chen J, Xu Y (2012) Preparation, characterization, and in vitro release of folic acid-conjugated chitosan nanoparticles loaded with methotrexate for targeted delivery. Polymer Bulletin 68: 1707–1720. https://doi.org/10.1007/s00289-011-0674-x
  • Liu G, Li D-C, Li P-P, Li R-R, Chen S-Y (2017) Nanoparticle methotrexate delivery system for the treatment of paediatric patients with inflammatory bowel disease. Biomedical Research 28. https://www.alliedacademies.org/abstract/nanoparticle-methotrexate-delivery-system-for-the-treatment-of-paediatric-patients-with-inflammatory-bowel-disease-7110.html [February 17, 2021]
  • Madani F, Mujokoro B, Khosravani M, Adabi M (2018) Preparation of Methotrexate loaded PLGA nanoparticles coated with PVA and Poloxamer188. Nanomedicine Research Journal 3: 19–24. https://doi.org/10.22034/nmrj.2018.01.003
  • Madani F, Esnaashari SS, Bergonzi MC, Webster TJ, Younes HM, Khosravani M, Adabi M (2020) Paclitaxel/methotrexate co-loaded PLGA nanoparticles in glioblastoma treatment: Formulation development and in vitro antitumor activity evaluation. Life Sciences 256: 117943. https://doi.org/10.1016/j.lfs.2020.117943
  • Maksimovic V, Pavlovic-Popovic Z, Vukmirovic S, Cvejic J, Mooranian A, Al-Salami H, Mikov M, Golocorbin-Kon S (2020) Molecular mechanism of action and pharmacokinetic properties of methotrexate. Molecular Biology Reports 47: 4699–4708. https://doi.org/10.1007/s11033-020-05481-9
  • Manna S, Donnell AM, Kaval N, Al-Rjoub MF, Augsburger JJ, Banerjee RK (2018) Improved design and characterization of PLGA/PLA-coated Chitosan based micro-implants for controlled release of hydrophilic drugs. International Journal of Pharmaceutics 547: 122–132. https://doi.org/10.1016/j.ijpharm.2018.05.066
  • Naghibi Beidokhti HR, Ghaffarzadegan R, Mirzakhanlouei S, Ghazizadeh L, Dorkoosh FA (2017) Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery. AAPS PharmSciTech 18: 115–129. https://doi.org/10.1208/s12249-015-0445-3
  • Nagulu M, Kiran VU, Reddy YN, Krishna DR (2009) Development and Validation of Rapid and Sensitive HPLC Method for the Determination of Methotrexate in Human Serum. Stamford Journal of Pharmaceutical Sciences 2: 8–13. https://doi.org/10.3329/sjps.v2i1.1693
  • Nezhad-Mokhtari P, Arsalani N, Javanbakht S, Shaabani A (2019) Development of gelatin microsphere encapsulated Cu-based metal-organic framework nanohybrid for the methotrexate delivery. Journal of Drug Delivery Science and Technology 50: 174–180. https://doi.org/10.1016/j.jddst.2019.01.020
  • Salar R, Kumar N (2016) Synthesis and characterization of vincristine loaded folic acid–chitosan conjugated nanoparticles. Resource-Efficient Technologies 2: 199–214. https://doi.org/10.1016/j.reffit.2016.10.006
  • Samra ZQ, Ahmad S, Javeid M, Dar N, Aslam MS, Gull I, Ahmad MM (2013) Anticancer medicines (doxorubicin and methotrexate) conjugated with magnetic nanoparticles for targeting drug delivery through iron. Preparative Biochemistry & Biotechnology 43: 781–797. https://doi.org/10.1080/10826068.2013.782042
  • Singla AK, Chawla M (2001) Chitosan: some pharmaceutical and biological aspects - an update. Journal of Pharmacy and Pharmacology 53: 1047–1067. https://doi.org/10.1211/0022357011776441
  • Vakilinezhad MA, Amini A, Dara T, Alipour S (2019) Methotrexate and Curcumin co-encapsulated PLGA nanoparticles as a potential breast cancer therapeutic system: In vitro and in vivo evaluation. Colloids and Surfaces B: Biointerfaces 184: 110515. https://doi.org/10.1016/j.colsurfb.2019.110515
  • Wang Y, Yang X, Yang J, Wang Y, Chen R, Wu J, Liu Y, Zhang N (2011) Self-assembled nanoparticles of methotrexate conjugated O-carboxymethyl chitosan: Preparation, characterization and drug release behavior in vitro. Carbohydrate Polymers 86: 1665–1670. https://doi.org/10.1016/j.carbpol.2011.06.080
  • Wu Z, Xu K, Min J, Chen M, Shen L, Xu J, Jiang Q, Han G, Pan L, Li H (2020) Folate-conjugated hydrophobicity modified glycol chitosan nanoparticles for targeted delivery of methotrexate in rheumatoid arthritis. Journal of Applied Biomaterials & Functional Materials 18: 2280800020962629. https://doi.org/10.1177/2280800020962629