A Cleverly Designed Novel Lipid Nanosystem: Targeted Retention, Controlled Visual Drug Release, and Cascade Amplification Therapy for Mammary Carcinoma in vitro

Abstract

Xiang-Zhi Zhao,1,2 Wei Zhang,1 Yang Cao,1,3 Shuai-Shuai Huang,4 Yi-Zhen Li,5 Dan Guo,1 Xing-Yue Wang,1 Hai-Tao Ran1,3 1Ultrasound Department of the Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400016, People’s Republic of China; 2Department of Cardiovascular Ultrasound, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, People’s Republic of China; 3Ultrasound Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 4Department of Renal Disease, Urology and Nephrology Hospital of Ningbo University, Ningbo 315100, Zhejiang, People’s Republic of China; 5Department of Cardiovascular Ultrasound and Noninvasive Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, People’s Republic of ChinaCorrespondence: Hai-Tao RanUltrasound Department of the Second Affiliated Hospital of Chongqing Medical University,  No. 76, Linjiang Road, Chongqing, Yuzhong District 400010, People’s Republic of ChinaEmail [email protected]: To construct an ideal theranostic nanoplatform (LIP3); to clarify its physicochemical properties; to confirm its characteristics of dual-modality imaging, active-targeting, and cascade amplification therapy for mammary carcinoma; and to perform a preliminary exploration of the cytotoxicity mechanism.Design: A self-prepared liposome nanosystem, LIP3, can actively target 4T1 cells because the surface is linked with C-RGD. Haematoporphyrin monomethyl ether (HMME), an excellent sonosensitizer entrapped in the lipid bilayer, can function in photoacoustic imaging. Low-intensity focused ultrasound (LIFU) of ultrasound-targeted microbubble destruction (UTMD) promotes localized drug delivery into tumours because PFH, a phase-change substance, is loaded in the LIP3 core, achieving visualization of targeted drug release, and sonodynamic therapy (SDT) can kill tumour cells. SDT provides a favourable environment for AQ4N, resulting in amplification of LIP3 treatment. Therefore, LIP3 shows targeted aggregation and targeted release, integrating dual-mode imaging and precise treatment.Results: The self-prepared lipid nanosystem, LIP3, meets the above expectations and has ideal physicochemical properties, with a regular sphere with uniform distribution. Contrast-enhanced ultrasound (CEUS), photoacoustic imaging, and bimodal imaging were effective in vitro. In 4T1 cell experiments, the cell capacity was as high as 42.9%, and the cytotoxicity to 4T1 was more than 5 times that of LIP1 (containing AQ4N only) and more than 2 times that of LIP2 (containing only HMME), achieving comparable results as cascade therapy for mammary cancer.Conclusion: LIP3, a theranostic nanoplatform, was successfully constructed and conformed to the physicochemical characterization of ideal nanoparticles, with active-targeting, dual-modality imaging, visualized drug release, and precise treatment under the action of LIFU. SDT provides a favourable environment for AQ4N, resulting in amplification of LIP3 treatment. Therefore, LIP3 shows targeted aggregation and targeted release, integrating dual-mode imaging, and precise cascade treatment. This unique theranostic NPS with multiple capabilities is expected to be a favourable anti-cancer method in the future.Keywords: LIFU, SDT, HMME, AQ4N

Keywords

• lifu
• sdt
• hmme
• aq4n