Engineered a dual-targeting HA-TPP/A nanoparticle for combination therapy against KRAS-TP53 co-mutation in gastrointestinal cancers

Yong Mei; Xiaohua Qin; Zhenyu Yang; Shiyao Song; Xiaoting Liu; Chong Wu; Jieying Qian; Xiaowan Huang; Yunjiao Zhang; Weiling He

doi:10.1016/j.bioactmat.2023.10.003

Engineered a dual-targeting HA-TPP/A nanoparticle for combination therapy against KRAS-TP53 co-mutation in gastrointestinal cancers

Bioact Mater. 2023 Oct 14:32:277-291. doi: 10.1016/j.bioactmat.2023.10.003. eCollection 2024 Feb.

Authors

Yong Mei¹, Xiaohua Qin², Zhenyu Yang², Shiyao Song¹, Xiaoting Liu¹, Chong Wu¹, Jieying Qian², Xiaowan Huang², Yunjiao Zhang^{2

3}, Weiling He^{1

4}

Affiliations

¹ Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
² School of Biomedical Science and Engineering, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China.
³ National Engineering Research Centre for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, Guangdong, 510006, China.
⁴ Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China.

Abstract

KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers. Therefore, a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53. Herein, we present a novel self-assembled nanoparticle (HA-TPP/A) that are functionalized nano-carrier hyaluronic acid (HA)-TPP conjugate (HA-TPP) to degrade mutant p53 proteins (mutp53) and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways. The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria. Furthermore, these nanoparticles abrogated the gain-of-function (GOF) phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing, thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation. The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model, particularly in KRAS-TP53 double mutant expressing cancer cells, compared with single drug and combined free drug groups. Notably, HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53, providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.

Keywords: Co-mutation; Dual-targeting; Gastrointestinal cancer; HA-TPP/A nanoparticle; KRAS; Mitochondrial targeting; TP53.