Smart Nanocarriers Based on Cyclodextrin Derivatives for Controlled Anticancer Drug Release

We engineered redox-responsive cyclodextrin (CD) nanogels for doxorubicin (DOX) and benchmarked them against β-CD inclusion complexes. Nanogels were formed by EDC/NHS coupling of carboxymethyl-β-CD with cystamine, optionally PEGylated and HA-targeted via adamantane–β-CD host–guest; DOX was loaded overnight and formulations characterized (DLS/TEM) and tested by dialysis release (pH 7.4/5.5 ± 10 mM GSH), MTT uptake/viability (MCF-7, MDA-MB-231, HeLa, MCF-7/ADR), MCF-7 xenografts (5 mg/kg i.v., q4d×4), and satellite PK; stats used one-way ANOVA with Tukey (p<0.05). CD-SS nanogels achieved DL 8.2±0.9% and EE 78±6% with 112±14 nm size; solubility rose 165× versus free DOX (β-CD complexes 60–80×) and stability improved (48 h remaining 88±3% vs 52±5% free; t½ 72±6 h vs 29±3 h, p<0.01). Release was minimal at pH 7.4 (38.2±2.7%/48 h) but strongly triggered at pH 5.5+10 mM GSH (97.8±1.4%/48 h; t50 6.2 h). In vivo, tumor volumes fell to 380±90 mm³ (PEG-nanogel; TGI 76%) and 260±75 mm³ (HA-nanogel; TGI 83%) vs 820±140 mm³ (free DOX); ANOVA p<0.001, Tukey p<0.05, with higher intratumoral DOX (7.9–10.4 vs 2.8–3.5 µg/g) and improved safety (CK-MB 182–198 vs 318 U/L; troponin I 0.024–0.028 vs 0.067 ng/mL; 100% survival). Overall, CD-SS nanogels provide pH/redox-responsive release, better PK, greater efficacy, and reduced cardiotoxicity at equal dose.