Modulating the\nSelf-Assembly of a Camptothecin Prodrug\nwith Paclitaxel for Anticancer Combination Therapy: A Molecular Dynamics\nApproach

Camptothecin (CPT) and paclitaxel (PTX), derived from\nnatural products,\nare recognized for their significant efficacy in clinical cancer treatments.\nDespite its therapeutic advantages, CPT is challenged by issues of\ntoxicity and solubility, necessitating its use in conjugation with\nother compounds for enhanced compatibility. This study delves into\nthe coassembly mechanism of Evans blue-conjugated camptothecin (EB-CPT)\nwith PTX, aiming to elucidate their synergistic potential in combination\ntherapy applications, employing all-atom molecular dynamics simulations.\nThe EB-CPT prodrug is reported to form a self-aggregated cluster.\nOur findings suggest that increasing the PTX concentration induces\na dispersion of EB-CPT clusters, thereby disrupting their inherent\nself-assembly. This disruption is explained to be facilitated by the\ncoassembly of EB-CPT and PTX. With increasing concentration of PTX,\na lengthening of the coassembled structures is observed, supporting\nthe experimental findings of tube-like coassembled structures at higher\nweight ratios of PTX. Hydrophobic interactions and π–π\nstacking are the primary forces responsible for the formation of both\nself- and coassembled structures. Interestingly, the structural analysis\nreveals that the CPT moiety of EB-CPT is less involved in assemblies\ndue to steric hindrances. Instead, the interaction and coassembly\nprocesses are predominantly mediated by the EB derivative component\nof the prodrug. This research underscores the critical role of the\nsolubilizing agent, EB derivative, in mediating the flexibility and\ninteraction of CPT in combination therapy strategies, particularly\nwith PTX, thus emphasizing the importance of conjugates for therapeutic\ndevelopments. Furthermore, the molecular insights into the interaction\nsites and mechanisms facilitating coassembly between EB-CPT and PTX\ncontribute valuable knowledge to the field, highlighting the potential\nof these nanomedicine combinations in advancing cancer treatment modalities.