International Journal of Drug Delivery Technology
Volume 15, Issue 3

Design, Synthesis, and Evaluation of Erlotinib–Metal Complexes for Enhanced Anticancer Efficacy

Sumithra Devi1*, M Kumar2 

1Department of Pharmaceutics, Vinayaka Mission’s College of Pharmacy, Salem, Tamil Nadu-522601, India

2Department of Pharmaceutical Chemistry, Vinayaka Mission’s College of Pharmacy, Salem, Tamil Nadu-522601, India 

Received: 29th May, 2025; Revised: 30th Jul, 2025; Accepted: 7th Aug, 2025; Available Online: 25th Sep, 2025 

ABSTRACT

Erlotinib, a known tyrosine kinase inhibitor (TKI), has played a vital role in the management of non-small cell lung cancer (NSCLC) and pancreatic cancer. Despite its therapeutic success, challenges such as low aqueous solubility, reduced bioavailability, and emerging drug resistance limit its long-term clinical use. In response to these concerns, the present study explores a novel approach—forming metal complexes of Erlotinib with selected transition metals—to potentially improve its pharmacological profile. The drug was initially characterized through UV-visible and FTIR spectroscopy to ensure structural integrity and purity. Metal complexation was achieved by reacting a mildly alkaline ethanolic solution of Erlotinib with ethanolic solutions of metal chlorides, namely CuCl₂, FeCl₃, ZnCl₂, MgCl₂, and MnCl₂. The process involved dropwise addition of metal solutions with continuous stirring, followed by an incubation period that facilitated the formation of stable complexes. Shifts in λmax values and unique mass spectral fragmentation patterns confirmed the successful coordination of metal ions with Erlotinib. By altering the drug’s electronic environment through metal binding, the study demonstrates a promising pathway to enhance Erlotinib’s physicochemical and therapeutic characteristics. The outcomes encourage further pharmacological exploration and suggest that metal complexation may help address some of the limitations associated with Erlotinib monotherapy.

Keywords: Erlotinib, Metal Complex, EGFR Inhibitor, UV Spectroscopy, Mass Spectrometry, Anticancer Drug Design

How to cite this article: Sumithra Devi, M Kumar. Design, Synthesis, and Evaluation of Erlotinib–Metal Complexes for Enhanced Anticancer Efficacy. International Journal of Drug Delivery Technology. 2025;15(3):1146-53. doi: 10.25258/ijddt.15.3.33

REFERENCES

  1. Herbst RS, Fukuoka M, Baselga J. Gefitinib—a novel targeted approach to treating cancer. Nat Rev Cancer. 2004;4(12):956–65.
  2. Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 2005;10(7):461–6.
  3. Alsayad HH, Aziz Alibeg AA, Rad Oleiwi ZK. Molecular Docking, Synthesis, Characterization, and Preliminary Cytotoxic Study of Novel 1, 2, 3-Triazole-Linked Metronidazole Derivatives. Adv J Chem Sect A. 2024;7(6):797–809.
  4. Durgawale TP, Singh LP, Shamim M, Ranajit SK, Dash S, Masih M, et al. Chemistry , Molecular Mechanisms , and Potential of Curcumin in Cancer Therapy Therapeutic. J Chem Rev. 2025;7(3):452–511.
  5. Permana KR, Al Fauzi A, Haq IBI, Parenrengi MA, Purwati P, Utomo B, et al. Growth factor receptor as angiogenesis targetting therapy of electric Field-Based management for glioblastoma: From laboratory to clinical perspective. J Med Pharm Chem Res. 2025;7(4):681–90.
  6. Wang X, Guo Z. Targeting and delivery of platinum-based anticancer drugs. Chem Soc Rev. 2013;42(1):202–24.
  7. Mjos KD, Orvig C. Metallodrugs in medicinal inorganic chemistry. Chem Rev. 2014;114(10):4540–63.
  8. Theophanides T, Anastassopoulou J. Metal–drug interactions: molecular recognition and therapeutic applications. Curr Top Med Chem. 2016;16(3):241–60.
  9. Kostova I. Platinum complexes as anticancer agents. Recent Pat Anticancer Drug Discov. 2006;1(1):1–22.
  10. Zhang C, Chen W, Zhang H, Liu H. Design and evaluation of metal-based erlotinib analogues with improved anticancer activity. J Inorg Biochem. 2019;193:108–17.
  11. Kundu S, Roy S, Dey D, et al. Copper(II) complex of erlotinib exhibits enhanced anticancer activity via EGFR inhibition and ROS generation. Eur J Med Chem. 2020;190:112110.
  12. Aliyu AB, Ibrahim MA, Kolawole AO, et al. Zinc(II)-erlotinib complex induces apoptosis in resistant lung cancer cells via mitochondrial pathways. Biometals. 2021;34(2):307–18.
  13. Shahabadi N, Falsafi M. DNA-binding and anticancer activity of a novel ruthenium(II) complex of erlotinib: Spectroscopic and molecular docking studies. Spectrochim Acta A Mol Biomol Spectrosc. 2022;266:120424.
  14. Ghosh S, Das D, Das P. Synthesis and characterization of metal complexes of a quinazoline-based tyrosine kinase inhibitor. J Coord Chem. 2020;73(8):1091–1105.
  15. Bhat S, Madyastha K. Spectroscopic studies on the complexation of anticancer drugs with transition metals. Spectrochim Acta A Mol Biomol Spectrosc. 2015;134:360–368.
  16. Amr AE-GE, El-Tabl AS, Hagar M. Metal complexes of Erlotinib: synthesis, characterization, and anticancer evaluation. J Mol Struct. 2019;1198:126903.
  17. Baraga WM, Shtewia FA, Ulsalam Tarrousha AA, Al-Adiwisha WM, Altounsib MK. Green Synthesis of Silver Nanowires Using Aqueous Brassica Tournefortii Leaves Extract and Evaluation of Their Antibacterial and Antioxidant Activities. J Appl Organomet Chem. 2025;5(1):13–27.
  18. Ashindortiang OI, Anyama CA, Ayi AA. Phytosynthesis, Characterization and Antimicrobial Studies of Silver Nanoparticles Using Aqueous Extracts of Olax Subscorpioidea. Adv J Chem Sect A. 2022;5(3):215–25.
  19. Alabady AA, Al-Majidi SMH. Synthesis, characterization, and evaluation of molecular docking and experimented antioxidant activity of some new chloro azetidine-2-one and diazetine-2-one derivatives from 2-phenyl-3-amino-quinazoline-4(3H)-one. J Med Pharm Chem Res. 2023;5(1):1–18.
  20. Kovala-Demertzi D, Katsaros N, Coluccia M, Demertzis MA, Papageorgiou A. Platinum(II) complexes with biologically active ligands: synthesis, structural characterization and antitumor activity. J Inorg Biochem. 2001;86(3):555–563.
  21. Li Y, Liu S, Xie H, Wu C. Spectral characterization and DNA-binding studies of transition metal–drug complexes. J Photochem Photobiol B. 2017;173:273–280.
  22. Abdel-Rahman LH, Abu-Dief AM, El-Khatib RM, Ismail MA. Synthesis, characterization, and cytotoxicity studies of new metal-based anticancer drugs derived from bioactive ligands. Eur J Med Chem. 2014;76:508–520.
  23. Preeti N. Yadav, Chhalotiya Usmangani K, Patel Kesha M, Tandel Jinal N. Quantification of A β Adrenergic Receptor Drug Mirabegron by Stability Indicating LC Method andUv–visible Spectroscopic Method in Bulk and Pharmaceutical Dosage Form. Chem Methodol [Internet]. 2020;4(53):340–58. Available from: http://chemmethod.com
  24. Reddy KTK, Haque MA. Development and Validation of Aducanumab by Bioanalytical Method Using Liquid Chromatography-Tandem Mass Spectroscopy. Adv J Chem Sect A. 2025;8(3):456–68.
  25. Haribabu J, Chaitanya K, Raju RR. Complexes of metal ions with anticancer drugs: synthesis and bioinorganic approach. Bioorg Chem. 2020;102:104058.
  26. Aliaga-Alcalde N, Sanchiz J, Muñoz MC, Julve M. Synthesis and characterization of metal complexes with N-donor anticancer ligands. Dalton Trans. 2010;39(16):3941–3950.
  27. Chandramore KR, Sonawane SS, Ahire RS, Reddy H, Ahire SB, Jadhav PB, et al. Development and Validation of Stability Indicating LC Method for Selexipag : In-Silico Toxicity Study and Characterization of its Degradation Products. Chem Methodol. 2025;9:427–47.
  28. Ukwubile CA, Mathias SN, Pisagih PS. Acute and Subchronic Toxicity Evaluation and GC-MS Profiling of Ajumbaise: A Traditional Nigerian Polyherbal Formulation for Labor Enhancement and Pain Relief. J Pharm Sci Comput Chem. 2025;1(2):154–73.
  29. Elumalai S, Sharma M, Dantinapalli VLS, Palanisamy M. Novel Stability Indicating UPLC Method Development and Validation for Simultaneous Quantification of Perindopril Arginine and Bisoprolol Fumarate in Pure and Pharmaceutical Dosage Form. Adv J Chem Sect A. 2025;8(9):1488–507.
  30. Hani U, Al-Qahtani EH, Albeeshi FF, Alshahrani SS. Exploring the Landscape of Drug-Target Interactions: Molecular Mechanisms, Analytical Approaches, and Case Studies. J Pharm Sci Comput Chem. 2025;1(1):12–25.