Ayşe ÜNAL, Şenay Hamarat ŞANLIER
European Journal of Therapeutics - 2026;32(2):154-164
Objective: Albumin, a biodegradable, biocompatible, and non-toxic plasma protein, is widely used as a nanocarrier in drug delivery systems. Pemetrexed, a potent thymidylate synthase inhibitor for non-small cell lung cancer (NSCLC), is limited by severe systemic side effects. Embedding magnetite within albumin carriers enables external-field guidance (magnetic targeting), which enhances tumor accumulation while reducing off-target exposure. Additionally, employing genipin as a natural, biodegradable, and low-cytotoxicity crosslinker stabilizes the albumin matrix while eliminating the use of toxic aldehyde-based agents. This study introduces a genipin-crosslinked, magnetically targetable albumin nanoparticle platform for enhanced and controlled delivery of pemetrexed to lung cancer cells. Unlike previous pemetrexed-albumin systems, this dual design-combining genipin crosslinking with magnetite-mediated targeting-offers improved structural stability, biocompatibility, and site-specific delivery potential. Methods: Bovine serum albumin (BSA) nanoparticles were prepared via desolvation using genipin as the crosslinker and magnetite for magnetic responsiveness. Key formulation parameters-BSA concentration, genipin content, magnetite ratio, reaction time, and drug loading-were systematically optimized. Drug release from free pemetrexed and nanoparticle formulations was evaluated at pH 7.4 and 5.5. Nanoparticles were characterized by SEM, FTIR, and zeta potential; cytotoxic efficacy was assessed in A549-luc-C8 and CRL-5807 lung cancer cells. Results: The nanoparticle yielded spherical, negatively charged nanoparticles with sustained, pH-responsive release. In vitro, the genipin-crosslinked, magnetite-containing nanoparticles demonstrated improved antitumor efficacy versus free drug. Conclusion: Magnetite provides a handle for external magnetic guidance, supporting targeted delivery, while genipin crosslinking minimizes residual crosslinker toxicity and stabilizes the carrier network. Together, genipin crosslinking + magnetic targeting define the novelty and translational potential of this system, with the prospect of reducing systemic exposure via controlled, site-directed delivery.
