PEGylated Nanoscale Metal–Organic Frameworks for Targeted Cancer Imaging and Drug Delivery

Abstract

Nanoscale metal−organic frameworks (nMOFs) are a unique type of hybrid materials, which are broadly applicable as cargo delivery systems. However, the relatively low material stability and insufficient cancer cell interacting capacity have limited nMOFs' applications in cancer theranostics. Herein, a zirconium-based nMOF UiO-66-N 3 was synthesized, and its surface was covalently functionalized with alkyne-containing polyethylene glycol (PEG) via the azide−alkyne click chemistry. After that, F3 peptide was attached for targeting of cancer cells (the material was denoted as UiO-66-PEG-F3). Doxorubicin (DOX) served as a therapeutic drug and a fluorescent label in this study, and it was transported into UiO-66-PEG conjugates with sufficient drug loading efficiency. pH-responsive release of DOX from UiO-66 conjugates was witnessed. The structural integrity of UiO-66-N 3 was maintained post the surface modification process. Flow cytometry and confocal fluorescence microscopy revealed that DOX/UiO-66-PEG-F3 had stronger accumulation in MDA-MB-231 cells (nucleolin + ) compared with DOX/UiO-66-PEG. In order to track the pharmacokinetic behavior (organ distribution profile) in vivo, the positron-emitting zirconium-89 ( 89 Zr) was incorporated into UiO-66-N 3 . Similar PEGylation and F3 peptide conjugation resulted in the formation of 89 Zr-UiO-66-PEG-F3. Serial positron emission tomography (PET) imaging demonstrated that the preferential accumulation of 89 Zr-UiO-66-PEG-F3 in MDA-MB-231 tumors, and their liver clearance was faster than PEGylated UiO-66 using noncovalent methods. Thus, the PEGylated nMOFs using covalent strategies may find broad application in future cancer theranostics.

Trend in biodegradable porous nanomaterials for anticancer drug delivery

“…The schematic illustration of doxorubicin (DOX)/UiO‐66‐PEG‐F 3 for in vitro and in vivo experiment. Reprinted with permission from Zeng, Xiao, et al (2021). Copyright © 2021.…”

“…In addition, the primary persisting challenge of MOF‐based DDS was the undesired uptake in the internal organs. In the F3 peptide functionalized UiO‐66‐N3 study by Xu group, while the novel DDS exhibited more than fivefold the tumor uptake compared to DOX/UiO‐66‐PEG, the DDS uptake was significantly lower than in liver and spleen (Zeng, Xiao, et al, 2021). With the presence of the F3 peptide, the DDS could only achieve comparable uptake in the lung and slightly increased uptake in the blood.…”

A pH/ROS dual-responsive nanoparticle system for tumor targeting combined chemotherapy/phototherapy

“…TK-PEG-F3 was prepared by the Michael addition reaction between the F3 peptide modified by sulfhydryl (-SH) and the polymer TK-PEG-OCH 3 /MAL modified by -MAL. 31,35 The 1 H-NMR spectrum is shown in Fig. 2(C).…”

“…Under a nitrogen atmosphere, 30 mg of F3 peptide and 5 mg of tris(2-carboxyethyl) phosphine were dispersed in 5 mL of HEPES buffer (pH = 7.4) and stirred at 30 °C for 1 h. Then, TK-PEG-OCH 3 /MAL (120 mg) was added to the above solution and stirred for 4 h. 31 The reaction mixture was placed in a dialysis bag ( M cut off = 4000) and dialyzed against pure water for 48 h, and TK-PEG-OCH 3 /F3 was collected by lyophilization.…”

F3‐functionalized nanoscale metal–organic frameworks for tumor‐targeting combined chemotherapy and chemodynamic therapy

“…According to previous reports, 30 we covalently bound the polymer Alkyne‐PLA‐PEG‐F3 to the surface of nanocarriers via a click chemistry reaction between alkyne and azide groups. DOX/MIL‐101(Fe)‐N 3 (10 mg) was dispersed evenly in 10 ml pure water by sonication for 6 min, Then Alkyne‐PLA‐PEG (14 mg) and Alkyne‐PLA‐PEG‐F3 (6 mg) were added to the above dispersion and mixed well.…”