Modulating the Self-Assembly of a Camptothecin Prodrug with Paclitaxel for Anticancer Combination Therapy: A Molecular Dynamics Approach

Camptothecin (CPT) and paclitaxel (PTX), derived from natural products, are recognized for their significant efficacy in clinical cancer treatments. Despite its therapeutic advantages, CPT is challenged by issues of toxicity and solubility, necessitating its use in conjugation with other compounds for enhanced compatibility. This study delves into the coassembly mechanism of Evans blue-conjugated camptothecin (EB-CPT) with PTX, aiming to elucidate their synergistic potential in combination therapy applications, employing all-atom molecular dynamics simulations. The EB-CPT prodrug is reported to form a self-aggregated cluster. Our findings suggest that increasing the PTX concentration induces a dispersion of EB-CPT clusters, thereby disrupting their inherent self-assembly. This disruption is explained to be facilitated by the coassembly of EB-CPT and PTX. With increasing concentration of PTX, a lengthening of the coassembled structures is observed, supporting the experimental findings of tube-like coassembled structures at higher weight ratios of PTX. Hydrophobic interactions and π-π stacking are the primary forces responsible for the formation of both self- and coassembled structures. Interestingly, the structural analysis reveals that the CPT moiety of EB-CPT is less involved in assemblies due to steric hindrances. Instead, the interaction and coassembly processes are predominantly mediated by the EB derivative component of the prodrug. This research underscores the critical role of the solubilizing agent, EB derivative, in mediating the flexibility and interaction of CPT in combination therapy strategies, particularly with PTX, thus emphasizing the importance of conjugates for therapeutic developments. Furthermore, the molecular insights into the interaction sites and mechanisms facilitating coassembly between EB-CPT and PTX contribute valuable knowledge to the field, highlighting the potential of these nanomedicine combinations in advancing cancer treatment modalities.