Cyclodextrin-Based Chemically Modified pH-Responsive New Kind of Aldehyde-Functionalized Nanosponge Nanoparticles for Doxorubicin Hydrochloride Delivery

Abstract

This study aimed to develop and assess ALD-NS nanoparticles (NPs) as pH-responsive drug delivery systems. Functionalized beta-cyclodextrin derivatives (OX-beta-CDs) containing aldehyde (CHO) groups were synthesized and crosslinked with pyromellitic dianhydride (PMDA) to form water-soluble ALD-NS-NPs. Doxorubicin hydrochloride (DOX & sdot;HCl), containing an NH2 side group, was incorporated bidirectionally into ALD-NS through the reflux method, forming pH-sensitive Schiff base (C=N) bonds and integrating into the hydrophilic portion of ALD-NS. Characterization of the ALD-NS + DOX complex confirmed successful drug loading, with a particle size of 372.7 +/- 8.21 nm, a negative zeta potential of -12.8 +/- 1.54 mV, and a high encapsulation efficiency of 85.5 %. In vitro drug release studies conducted under three distinct buffer conditions revealed a higher release rate at pH 5.2 compared to pH 7.4, which was attributed to the hydrolysis of Schiff base bonds and crosslinker in the acidic environment. Cytotoxicity and cellular uptake assays performed on A549 cancer cells demonstrated doseand time-dependent responses. ALD-NS + DOX displaying higher cell viability and increased drug accumulation within cells when compared to free DOX at equivalent concentrations. Drug release kinetics, assessed using the Korsmeyer-Peppas model (R2 = 0.97), revealed a release mechanism that involves both dissolution (hydrolysis) and non-Fickian diffusion, with diffusion coefficients of 0.622 in PBS and 0.71 in NaOAc at pH 5.2. These findings suggest that the ALD-NS-NP system is a promising candidate for targeted drug delivery, particularly for drugs with NH2 functional groups in acidic environments.