Intracellular nanofiber formation triggers nuclear fragmentation to enhance chemotherapeutic effect of camptothecin

Nucleus-acting agents are efficient chemotherapeutic drugs for pancreatic cancer treatment. But immune clearance and small nuclear pore size significantly reduce delivery efficiency of the agents or their nanoformulations. Herein, we rationally design a drug-peptide conjugate Asp-Thr-Lys-Thr-Gly-Pro-Ala-Lys(SA-CPT)-Phe-Phe-Nap ( 1-CPT-Nap ) which, under the activations of fibroblast activation protein alpha and carboxylesterase, releases camptothecin (CPT) and forms Ala-Lys(SA)-Phe-Phe-Nap ( 2-Nap ) nanofibers intracellularly. In situ -formed 2-Nap nanofibers induce G2/M phase arrest and thereafter nuclear fragmentation, allowing more CPT to enter the nuclei. Cell experiments demonstrate that 2-Nap nanofiber-induced nuclear fragmentation leads to a 1.8-fold increase in CPT entry to the nuclei. In vivo experiments show that the antitumor efficacy of 1-CPT-Nap on MIA PaCa-2 pancreatic tumors is 1.5-times greater than that of CPT. This system of intracellularly enzymatic nanofiber formation offers a promising strategy for enhancing the delivery of chemotherapeutics into nuclei. We anticipate 1-CPT-Nap could be applied in clinical trial in the future.