131I-Labeled Multifunctional Polyethylenimine/Doxorubicin Complexes with pH-Controlled Cellular Uptake Property for Enhanced SPECT Imaging and Chemo/Radiotherapy of Tumors

Jingyi Zhu; Junxing Yang; Lingzhou Zhao; Pingping Zhao; Jiqin Yang; Jinhua Zhao; Wenjun Miao

doi:10.2147/IJN.S312238

¹³¹I-Labeled Multifunctional Polyethylenimine/Doxorubicin Complexes with pH-Controlled Cellular Uptake Property for Enhanced SPECT Imaging and Chemo/Radiotherapy of Tumors

Int J Nanomedicine. 2021 Jul 30:16:5167-5183. doi: 10.2147/IJN.S312238. eCollection 2021.

Authors

Jingyi Zhu^#¹, Junxing Yang^#², Lingzhou Zhao^#³, Pingping Zhao¹, Jiqin Yang⁴, Jinhua Zhao³, Wenjun Miao¹

Affiliations

¹ School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, People's Republic of China.
² College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, People's Republic of China.
³ Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People's Republic of China.
⁴ Department of Nuclear Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Smart theranostic nanosystems own a favorable potential to improve internalization within tumor while avoiding nonspecific interaction with normal tissues. However, development of this type of theranostic nanosystems is still a challenge.

Methods: In this study, we developed the iodine-131 (¹³¹I)-labeled multifunctional polyethylenimine (PEI)/doxorubicin (DOX) complexes with pH-controlled cellular uptake property for enhanced single-photon emission computed tomography (SPECT) imaging and chemo/radiotherapy of tumors. Alkoxyphenyl acylsulfonamide (APAS), a typical functional group that could achieve improved cellular uptake of its modified nanoparticles, was utilized to conjugate onto the functional PEI pre-modified with polyethylene glycol (PEG) with terminal groups of monomethyl ether and N-hydroxysuccinimide (mPEG-NHS), PEG with terminal groups of maleimide and succinimidyl valerate (MAL-PEG-SVA) through sulfydryl of APAS and MAL moiety of MAL-PEG-SVA. This was followed by conjugation with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO), acetylating leftover amines of PEI, complexing DOX and labeling ¹³¹I to generate the theranostic nanosystems.

Results: The synthesized theranostic nanosystems exhibit favorable water solubility and stability. Every functional PEI can complex approximately 12.4 DOX, which could sustainably release of DOX following a pH-dependent manner. Remarkably, due to the surface modification of APAS, the constructed theranostic nanosystems own the capacity to achieve pH-responsive charge conversion and further lead to improved cellular uptake in cancer cells under slightly acidic condition. Above all, based on the coexistence of DOX and radioactive ¹³¹I in the single nanosystem, the synthesized nanohybrid system could afford enhanced SPECT imaging and chemo/radioactive combination therapy of cancer cells in vitro and xenografted tumor model in vivo.

Discussion: The developed smart nanohybrid system provides a novel strategy to improve the tumor theranostic efficiency and may be applied for different types of cancer.

Keywords: SPECT imaging; chemo/radiotherapy; doxorubicin; iodine-131; pH-controlled cellular uptake; polyethylenimine.

MeSH terms

Cell Line, Tumor
Chemoradiotherapy
Doxorubicin
Humans
Hydrogen-Ion Concentration
Iodine Radioisotopes
Neoplasms* / therapy
Polyethylene Glycols
Polyethyleneimine
Tomography, Emission-Computed, Single-Photon*

Substances

Iodine Radioisotopes
Iodine-131
Polyethylene Glycols
Doxorubicin
Polyethyleneimine