Redox-Sensitive Camptothecin Prodrug: A Promising Drug Delivery Strategy with Ultrahigh Drug Loading and Tunable Drug Release

Abstract

Small molecular drugs play a critical role in cancer therapy but face challenges like poor solubility, severe side effects, and inefficient delivery. Polymeric micellar-based drug delivery systems show promise but struggle with low drug loading, instability, and premature drug release partly due to the incompatible physicochemical properties. Here, we report a simple and efficient method to develop redox-sensitive camptothecin (CPT) prodrug by conjugating alkyl chains to CPT via a disulfide linker. By conjugating alkyl chains of varying lengths to CPT via a disulfide linker, we achieved high drug-loading efficiency and loading capacity, controlled responsive drug release, due to enhanced hydrophobic interaction and miscibility with the carrier. The prodrug loaded NPs exhibited slower drug release for more hydrophobic ones with longer alkyl chains. In vitro cytotoxicity assays against cancer cells confirmed the prodrugs' potency and the critical role of the disulfide bond in maintaining anticancer activity. These findings highlight the importance of tuning prodrug hydrophobicity and GSH sensitivity in drug delivery. This prodrug engineering strategy, which involves conjugating a hydrophobic alkyl chain to modulate the drug's physicochemical properties, offers a straightforward approach for designing and optimizing drug delivery systems for a wide range of therapeutic agents, whether hydrophilic or hydrophobic.

Keywords: Camptothecin; Chemotherapeutic agent; Drug delivery; Nanomedicine; Ultrahigh drug loading.

Fig. 1.

Synthesis of redox-sensitive CPT-based prodrugs toward improved drug delivery to the tumor.

Fig. 2

(A) ¹H NMR spectrum of redox-sensitive CPT-based prodrug CPT-ss-C₂₈; Hydrodynamic diameters (B) and zeta potential (C) of prodrug loaded nanoparticle (prodrug/polymer: 1:2, 10 μg/ ml) measured by dynamic light scattering

Fig. 3.

(A) HPLC traces of CPT prodrug NPs. (B) Intact CPT release from prodrug (CPT-ss-C₁₁, CPT-ss-C₁₈, CPT-ss-C₂₈, and CPT-cc-C₁₈ ) loaded NPs (10 μg/ ml) in PBS in the presence of GSH at different time points as monitored by HPLC. In vitro cytotoxicities of CPT-loaded and prodrug-loaded NPs against (C) 4T1 (n=3) and (D) PC3 cancer cells (n=3).