Hybride nanoparticles composed of SN38-modified [12]aneN3 and biotinylated lipids for targeted and synergistic lung Cancer therapy

  • Bioorg Chem. 2025 Jun 15:160:108411. doi: 10.1016/j.bioorg.2025.108411.
De-Zhong Xu  1 ,  Jing-Bo Yang  2 ,  Xi Zhang  1 ,  Zhi-Xuan Ren  1 ,  Rui Liu  1 ,  Quan Tang  3 ,  Zhong-Lin Lu  4 ,  Yang Liu  5
Affiliations
  • 1. Key Laboratory of Radiopharmaceutics, Ministry of Education; College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China.
  • 2. Key Laboratory of Radiopharmaceutics, Ministry of Education; College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China; Institute of Chemical Drug Control, National Institute for Food and Drug Control, HuaTuo Road 29, Beijing 100050, China.
  • 3. Key Laboratory of Radiopharmaceutics, Ministry of Education; College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China. Electronic address: [email protected].
  • 4. Key Laboratory of Radiopharmaceutics, Ministry of Education; College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China. Electronic address: [email protected].
  • 5. Institute of Chemical Drug Control, National Institute for Food and Drug Control, HuaTuo Road 29, Beijing 100050, China. Electronic address: [email protected].
PMID: 40239402 DOI: 10.1016/j.bioorg.2025.108411
Abstract

The combination of chemo- and gene-therapy for Lung Cancer therapy has attracted continuous attention due to its high synergistic therapeutic efficiency. Here, three novel esterase-responsive prodrug-based amphiphiles, SCN1 ∼ SCN3, composed of 7-ethyl-10-hydroxycamptothecin (SN38, S) and di-(triazole-[12]aneN3, N) moiety through different length of carbon chain (C, 5, 7, 11‑carbon alkyl chains, respectively) were designed and synthesized. The amphiphiles displayed excellent self-assembly capabilities and the ability to effectively condense and release siRNA, and SCN2 showed the most effective in inhibiting proliferation of A549 cells. Furthermore, SCN2, siRNA, DOPE (D) and DSPE-PEG2000-Biotin (B) were co-assembled into hybrid nanoparticles (SCN2-DB/siRNA) with an average size of 198 nm, outstanding serum tolerance, high targeting capability, and biocompatibility. Additionally, the release of SN38 (80 %) and siPLK1 (abundant) were observed clearly in the presence of esterase. In vitro experiments verified that SCN2-DB/siPLK1 NPs could efficiently suppress the proliferation, migration, and invasion of A549 cells. In vivo experiments demonstrated that SCN2-DB/siPLK1 NPs efficiently inhibited tumor growth (90 %) with negligible toxic side effects. The results showed that the combination of SN38 and siPLK1 through esterase-responsive amphiphile provided a strategy for Lung Cancer therapy that combined chemotherapy, gene therapy, and targeted delivery.

Keywords
Chemotherapy; Gene therapy; Lung Cancer; SN38; [12]aneN(3); siPLK1.
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