G2B-002

The development of carrier-free drug delivery systems (CDDS) for tailored drug combinations posed a significant challenge, particularly in achieving efficient co-assembly while maintaining therapeutic efficacy. Herein, we proposed a co-assembly strategy based on molecular engineering. Paclitaxel (PTX) and 7-ethyl-10-hydroxycamptothecin (SN38) were chemically modified with tert-butoxycarbonyl (BOC) groups. The successful incorporation of the BOC groups was confirmed by proton nuclear magnetic resonance and mass spectrometry analyses. Further characterization using polarized light microscopy and X-ray diffraction revealed that this modification significantly reduced the crystallinity of both drugs, while simultaneously disrupting their original ordered stacking structure. Molecular dynamics simulations indicated that BOC modification increased molecular spacing, reduced stacking density, and expanded molecular volume, resulting in a looser molecular packing arrangement. This structural alteration enabled the modified drug molecules to efficiently coassemble with α-tocopherol succinate (α-TOS) into spherical nanoparticles at a nearly predefined mass ratio. The resulting nanoparticles exhibited a high drug loading capacity of 52.66% and remained stable at 4 °C for over 50 days. Notably, these nanoparticles displayed controllable release characteristics at pH 5.0. Both in vitro and in vivo studies demonstrated the BOC-modified drugs retained their bioactivity. When co-assembled with α-TOS, the nanoparticles exhibited a significant synergistic antitumor effect and suppressed tumor metastasis through downregulation of matrix metalloproteinase-9 (MMP-9) expression. This study provided a solid theoretical foundation and innovative approach for the development of CDDS, utilizing molecular-scale regulation for drug co-assembly.

Chemotherapy of lethal colorectal peritoneal metastases (PM) is notoriously challenged by poor drug delivery efficiency in PM tumors. Inspired by the histopathological examinations of PM tumors from colon cancer patients, a C[RGDfK] peptide-modified bioinspired lipoprotein (R-BLP) system was optimized from 8 formulations with profound penetrating ability in PM tumors of colorectal cancers. Then, a chemotherapeutic 7-ethyl-10-hydroxy-camptothecin (SN38)-loaded R-BLP (termed SR-BLP) was designed to promote their penetration in PM tumors and improve the chemotherapeutic efficacy. In CT26-induced PM models, SR-BLP exhibited better penetration profiles in PM tumors over a counterpart liposomal formulation. SR-BLP treatment produced an 80.03% suppression of PM incidence with obvious DNA damage and topoisomerase I (TOP I) downregulation and caused a 1.78-fold prolongation of survival time. Therefore, the histopathological features-inspired R-BLP provides an encouraging tumor-penetrating delivery platform for the effective chemotherapy of colorectal PM.