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

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 ([sup.131]I)-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 [sup.131]I 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 [sup.131]I 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: polyethylenimine, pH-controlled cellular uptake, doxorubicin, iodine-131, SPECT imaging, chemo/radiotherapy