Journal of Cancer Research and Pharmacology

Journal of Cancer Research and Pharmacology

Targeted PLGA-PAMAM Nanocarrier for efficient Doxorubicin Delivery against Pancreatic Cancer: An In Vitro Evaluation

Document Type : Original Article

Author
Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Background and Aims: Pancreatic cancer's poor prognosis necessitates advanced therapeutic strategies. This study aimed to develop a folic acid (FA)-decorated, poly(lactic-co-glycolic acid) (PLGA)-polyamidoamine (PAMAM) nanocarrier for the active targeting and enhanced delivery of doxorubicin (Dox) to folate receptor-overexpressing pancreatic cancer cells.
Methods: The PLGA-PAMAM-FA nanocarrier was synthesized via EDC/NHS chemistry and characterized using FT-IR, DLS, and SEM. Dox was loaded into the nanocarrier, and its release profile was evaluated in PBS (pH 7.4). The cytotoxic effects and selectivity of the formulation (PLGA-Dox-PAMAM-FA) were assessed against PANC1 cancer cells and MSC normal cells using the MTT assay.
Results: The fabricated nanocarrier exhibited a nanometric size (281.7 ± 17.2 nm), a near-neutral surface charge (+2.6 ± 1.0 mV), and a high drug loading capacity (28 ± 3.2%). It demonstrated a controlled, sustained release of Dox (19.9% at 4 h) compared to free drug (74.7%). The targeted nanocarrier showed potent and selective cytotoxicity, with a 4-fold lower IC₅₀ (28.78 nM) in PANC1 cells than free Dox. Notably, at 100 nM, it achieved 12% cancer cell viability while maintaining 80% viability in normal cells.
Conclusion: The FA-decorated PLGA-PAMAM nanocarrier significantly enhances the potency and selectivity of Dox against pancreatic cancer cells in vitro. Its optimal physicochemical properties and promising antitumor efficacy position it as a highly promising platform for the targeted treatment of pancreatic cancer.
Keywords

  1. Yousefi M, Narmani A, Jafari SM. Dendrimers as efficient nanocarriers for the protection and delivery of bioactive phytochemicals. Adv Colloid Interface Sci. 2020;278:102125. doi:10.1016/j.cis.2020.102125 PMid:32109595
  2. Filho AM, Soerjomataram I, Dsouza JP, Weiderpass E, Bray F. The GLOBOCAN 2022 cancer estimates: data sources, methods, and a snapshot of the cancer burden worldwide. Int J Cancer. 2025;156(7):1336-1346. doi:10.1002/ijc.35278 PMid:39688499
  3. Soerjomataram I, Bray F. Planning for tomorrow: global cancer incidence and the role of prevention 2020-2070. Nat Rev Clin Oncol. 2021;18(10):663-672. doi:10.1038/s41571-021-00514-z PMid:34079102
  4. Narmani A, Farhood B, Haghi-Aminjan H, Mortezazadeh T, Aliasgharzadeh A, Mohseni M, et al. Dual targeting of breast cancer by chitosan/poly lactic-co-glycolic acid nanodelivery systems: Surface activation with folic acid/aptamers, and co-encapsulated with Sorafenib and quercetin. Carbohydr Polym Technol Appl. 2025;9:100695. doi:10.1016/j.carpta.2025.100695
  5. Bandi P, Islami F, Cahan S, Drope J, Goding Sauer A, Nargis N, et al. Prevalence and review of major modifiable cancer risk factors, HPV vaccination, and cancer screenings in the United States: 2025 update. Cancer Epidemiol Biomarkers Prev. 2025;34(6):836-849. doi:10.1158/1055-9965.EPI-24-1835 PMid:40266051
  6. Zhao X, Li L, Li Y, Zhang L, Wang J, Li J, et al. Penetration cascade of size switchable nanosystem in desmoplastic stroma for improved pancreatic cancer therapy. ACS Nano. 2021; 15(9):14149-14161. doi:10.1021/acsnano.0c08860 PMid:34478262
  7. Bazeed AY, Day CM, Garg S. Pancreatic cancer: challenges and opportunities in locoregional therapies. Cancers (Basel). 2022; 14 (17):4257. doi:10.3390/cancers14174257 PMid:36077794 PMCid:PMC9454856
  8. Yu Q, Zhang B, Li M, Wang F, Liu J, Zhang Y, et al. Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy. J Control Release. 2020;321:564-575. doi:10.1016/j.jconrel.2020.02.040 PMid:32112854
  9. Narmani A, Kamali M, Amini B, Koohi M, Salimi A. Gadolinium nanoparticles as diagnostic and therapeutic agents: Their delivery systems in magnetic resonance imaging and neutron capture therapy. J Drug Deliv Sci Technol. 2018;44:457-466. doi:10.1016/j.jddst.2018.01.011
  10. Liu G, McEnnis K. Glass transition temperature of PLGA particles and the influence on drug delivery applications. Polymers (Basel). 2022;14(5):993. doi:10.3390/polym14050993 PMid:35267816 PMCid:PMC8912735
  11. Mundekkad D, Cho WC. Nanoparticles in clinical translation for cancer therapy. Int J Mol Sci. 2022;23(3):1685. doi:10.3390/ijms23031685 PMid:35163607 PMCid:PMC8835852
  12. Narmani A, Jafari SM. Chitosan-based nanodelivery systems for cancer therapy: Recent advances. Carbohydr Polym. 2021; 272:118464. doi:10.1016/j.carbpol.2021.118464 PMid:34420724
  13. Moletta L, Serafini S, Valmasoni M, Pierobon ES, Ponzoni A, Sperti C, et al. Surgery for recurrent pancreatic cancer: is it effective? Cancers (Basel). 2019;11(7):991. doi:10.3390/cancers11070991 PMid:31315222 PMCid:PMC6679234
  14. Narmani A, Rezvani M, Farhood B, Darkhor P, Mohammadnejad J, Amini B, et al. Folic acid functionalized nanoparticles as pharmaceutical carriers in drug delivery systems. Drug Dev Res. 2019;80(4):404-424. doi:10.1002/ddr.21545 PMid:31140629
  15. Farokh A, Narmani A, Ebrahimi S, Jafari SM. Assessment of synthesized chitosan/halloysite nanocarrier modified by carbon nanotube for pH-sensitive delivery of curcumin to cancerous media. Int J Biol Macromol. 2023;237:123937. doi:10.1016/j.ijbiomac.2023.123937 PMid:36882143
  16. Mortezaee K, Narmani A, Salehi M, Bagheri H, Farhood B, Haghi-Aminjan H, et al. Synergic effects of nanoparticles-mediated hyperthermia in radiotherapy/chemotherapy of cancer. Life Sci. 2021;269:119020. doi:10.1016/j.lfs.2021.119020 PMid:33450258
  17. Alamdari SG, Narmani A, Farhood B, Mohammadnejad J, Pakniya E, Monfared LK, et al. Recent advances in nanoparticle-based photothermal therapy for breast cancer. J Control Release. 2022; 349:269-303. doi:10.1016/j.jconrel.2022.06.050 PMid:35787915
  18. Khakinahad Y, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Ahangari N, et al. Margetuximab conjugated-PEG-PAMAM G4 nano-complex: A smart nano-device for suppression of breast cancer. Biomed Eng Lett. 2022;12(3):317-329. doi:10.1007/s13534-022-00225-z PMid:35892030 PMCid:PMC9308845
  19. Narmani A, Mohammadnejad J, Yavari K. Synthesis and evaluation of polyethylene glycol-and folic acid-conjugated polyamidoamine G4 dendrimer as nanocarrier. J Drug Deliv Sci Technol. 2019; 50:278-286. doi:10.1016/j.jddst.2019.01.037
  20. Pelaz B, Alexiou C, Alvarez-Puebla RA, Alves F, Andrews AM, Ashraf S, et al. Diverse applications of nanomedicine. ACS Nano. 2017;11(3):2313-2381. doi:10.1021/acsnano.6b06040 PMid:28290206 PMCid:PMC5371978
  21. Elkomy MH, Ali AA, Eid HM. Chitosan on the surface of nanoparticles for enhanced drug delivery: A comprehensive review. J Control Release. 2022;351:923-940. doi:10.1016/j.jconrel.2022.10.005 PMid:36216174
  22. You T, Zhang S. Recent advances in PLGA polymer nanocarriers for ovarian cancer therapy. Front Oncol. 2025;15:1526718. doi:10.3389/fonc.2025.1526718 PMid:40196734 PMCid:PMC11973302
  23. Aghanejad A, Narmani A, Farhood B, Mohammadnejad J, Ebrahimi-Kalan A, Sharifi S, et al. Targeted co-delivery nanosystem based on methotrexate, curcumin, and PAMAM dendrimer for improvement of the therapeutic efficacy in cervical cancer. Sci Rep. 2025;15(1):1813. doi:10.1038/s41598-024-82074-7 PMid:39805840 PMCid:PMC11730290
  24. Rosales-Barrios C, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. PSMA-targeted delivery of docetaxel in prostate cancer using small-sized PDA-based micellar nanovectors. J Control Release. 2025;379:890-905. doi:10.1016/j.jconrel.2025.01.062 PMid:39864631
  25. Narmani A, Kamali M, Amini B, Salimi A. Highly sensitive and accurate detection of Vibrio cholera O1 OmpW gene by fluorescence DNA biosensor based on gold and magnetic nanoparticles. Process Biochem. 2018;65:46-54. doi:10.1016/j.procbio.2017.10.009
  26. Alkhamach D, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Nanostructured lipid carriers in cancer Therapy: Advances in passive and active targeting strategies. Int J Pharm. 2025:125736. doi:10.1016/j.ijpharm.2025.125736 PMid:40389069
  27. Narmani A, Mohammadnejad J, Yavari K, Farhood B, Haghi-Aminjan H, Mortezazadeh T, et al. Targeting delivery of oxaliplatin with smart PEG-modified PAMAM G4 to colorectal cell line: In vitro studies. Process Biochem. 2018;69:178-187. doi:10.1016/j.procbio.2018.01.014
  28. Narmani A, Rezvani M, Mohammadi Samani S, Farhood B, Mohammadnejad J, Jafari SM, et al. Breast tumor targeting with PAMAM-PEG-5FU-99mTc as a new therapeutic nanocomplex: in in-vitro and in-vivo studies. Biomed Microdevices. 2020; 22(2):31. doi:10.1007/s10544-020-00485-5 PMid:32335724
  29. Kim J, Lee Y, Singha K, Kim HW, Park JH, Kim WJ. Sustained and long-term release of doxorubicin from PLGA nanoparticles for eliciting anti-tumor immune responses. Pharmaceutics. 2022; 14 (3):474. doi:10.3390/pharmaceutics14030474 PMid:35335852 PMCid:PMC8954063
  30. Payamifar S, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Cyclodextrin-based nanocarriers as promising scaffolds for overcoming challenges of doxorubicin delivery in cancer chemotherapy. Carbohydr Polym Technol Appl. 2025:100677. doi:10.1016/j.carpta.2025.100677
  31. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 2013;65(2):157-170. doi:10.1111/j.2042-7158.2012.01567.x PMid:23278683
  32. Salem D, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Natural Nanoparticles for Drug Delivery: Proteomic Insights and Anticancer Potential of Doxorubicin-Loaded Avocado Exosomes. Pharmaceuticals (Basel). 2025; 18 (6): 844. doi:10.3390/ph18060844 PMid:40573239 PMCid:PMC12195682
  33. Imantay A, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Doxorubicin-conjugated nanoparticles for potential use as drug delivery systems. Nanomaterials (Basel). 2025; 15(2):133. doi:10.3390/nano15020133 PMid:39852748 PMCid:PMC11768029
  34. Zhu J, Zheng L, Wen S, Tang Y, Shen M, Zhang G, et al. Encapsulation of doxorubicin within multifunctional gadolinium-loaded dendrimer nanocomplexes for targeted theranostics of cancer cells. RSC Adv. 2015;5(38):30286-30296. doi:10.1039/C5RA01215E
  35. Rajapaksha W, Guller A, Lozano N, Ebrahimi D, Sikder T, Ebrahimi M, et al. Novel alginate nanoparticles for the simultaneous delivery of iron and folate: a potential nano-drug delivery system for anaemic patients. RSC Pharm. 2024; 1(2):259-271. doi:10.1039/D3PM00068K
  36. Ramezani F, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Folic Acid-Decorated Chitosan-PLGA Nanobiopolymers for Targeted Drug Delivery to Acute Lymphoblastic Leukemia Cells: In Vitro Studies. Technol Cancer Res Treat. 2024;23: 15330338241308077. doi:10.1177/15330338241308077 PMid:39711084 PMCid:PMC11672380
  37. Al-Nemrawi NK, Altawabeyeh RM, Darweesh RS. Preparation and characterization of docetaxel-PLGA nanoparticles coated with folic acid-chitosan conjugate for cancer treatment. J Pharm Sci. 2022; 111(2):485-494. doi:10.1016/j.xphs.2021.10.034 PMid:34728172
  38. Khan I, Yousaf S, Subramanian S, Albed Alhnan M, Ahmed W, Elhissi A, et al. Nano-co-delivery of berberine and anticancer drug using PLGA nanoparticles: exploration of better anticancer activity and in vivo kinetics. Pharm Res. 2019;36(10):149. doi:10.1007/s11095-019-2677-5 PMid:31420752
  39. Li J, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Advances in polysaccharide‐based materials for biomedical and pharmaceutical applications: A comprehensive review. Arch Pharm (Weinheim). 2025;358(1): e2400854. doi:10.1002/ardp.202400854 PMid:39651831
  40. Saadh MJ, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Recent advances of hyaluronic acid‐based materials in drug delivery systems and regenerative medicine: A review. Arch Pharm (Weinheim). 2025;358(3):e2400903. doi:10.1002/ardp.202400903 PMid:40091562
  41. Hsu C-Y, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Recent advances in polysaccharide-based drug delivery systems for cancer therapy: a comprehensive review. Artif Cells Nanomed Biotechnol. 2024;52(1):564-586. doi:10.1080/21691401.2024.2436350 PMid:39639430
  42. Belyaev IB, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Beyond the EPR effect: Intravital microscopy analysis of nanoparticle drug delivery to tumors. Adv Drug Deliv Rev. 2025:115550. doi:10.1016/j.addr.2025.115550 PMid:40021012
  43. Mekuria SL, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Dendrimer nanoclusters loaded with gold nanoparticles for enhanced tumor CT imaging and chemotherapy via an amplified EPR effect. J Mater Chem B. 2024;12(38):9524-9532. doi:10.1039/D4TB01747A PMid:39301737
  44. Pyrak B, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Exploring Cyclodextrin-Based Nanosponges as Drug Delivery Systems: Understanding the Physicochemical Factors Influencing Drug Loading and Release Kinetics. Int J Mol Sci. 2024;25(6):3527. doi:10.3390/ijms25063527 PMid:38542499 PMCid:PMC10971266
  45. Zhou H, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Prodrug-designed nanocarrier co-delivering chemotherapeutic and vascular disrupting agents with exceptionally high drug loading capacity. J Control Release. 2025;382:113628. doi:10.1016/j.jconrel.2025.113628 PMid:40088979
  46. Almajidi YQ, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Advances in chitosan-based hydrogels for pharmaceutical and biomedical applications: A comprehensive review. Int J Biol Macromol. 2023;253:127278. doi:10.1016/j.ijbiomac.2023.127278 PMid:37806412
  47. Narmani A, Yavari K, Mohammadnejad J. Imaging, biodistribution and in vitro study of smart 99mTc-PAMAM G4 dendrimer as novel nano-complex. Colloids Surf B Biointerfaces. 2017;159:232-240. doi:10.1016/j.colsurfb.2017.07.089 PMid:28800462
  48. Ren Y, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Dual-responsive nanoparticles for enhanced drug delivery in breast Cancer chemotherapy. J Control Release. 2025;377:146-161. doi:10.1016/j.jconrel.2024.11.026 PMid:39549730
  49. Narmani A, Farhood B, Haghi-Aminjan H, Mortezazadeh T, Aliasgharzadeh A, Mohseni M, et al. Biomedical applications of PLGA nanoparticles in nanomedicine: advances in drug delivery systems and cancer therapy. Expert Opin Drug Deliv. 2023; 20 (7):937-954. doi:10.1080/17425247.2023.2223941 PMid:37294853
  50. Sadeghi S, Narmani A, Jafari SM, Farhood B, Mohammadnejad J, Aghanejad A, et al. Biocompatible PLGA-PCL nanobeads for efficient delivery of curcumin to lung cancer. Cancer Nanotechnol. 2024; 15 (1): 34. doi:10.1186/s12645-024-00272-4
Volume 1, Issue 1
Summer 2025
Pages 27-37

  • Receive Date 23 July 2025
  • Revise Date 30 July 2025
  • Accept Date 10 September 2025