Blood TfR+ exosomes separated by a pH-responsive method deliver chemotherapeutics for tumor therapy

Abstract

Blood transferrin receptor-positive (TfR+) exosomes are a kind of optimized drug delivery vector compared with other kinds of exosomes due to their easy access and high bio-safety. Their application facilitates the translation from bench to bedside of exosome-based delivery vehicles.Methods: In this study, a pH-responsive superparamagnetic nanoparticles cluster (denoted as SMNC)-based method was developed for the precise and mild separation of blood TfR+ exosomes. Briefly, multiple superparamagnetic nanoparticles (SPMNs) labeled with transferrins (Tfs) could precisely bind to blood TfR+ exosomes to form an exosome-based cluster due to the specific recognition of TfR by Tf. They could realize the precise magnetic separation of blood TfR+ exosomes. More importantly, the pH-responsive dissociation characteristic of Tf and TfR led to the mild collapse of clusters to obtain pure blood TfR+ exosomes.Results: Blood TfR+ exosomes with high purity and in their original state were successfully obtained through the pH-responsive SMNC-based method. These can load Doxorubicin (DOX) with a loading capacity of ~10% and dramatically increase the tumor accumulation of DOX in tumor-bearing mice because of their innate passive-targeting ability. In addition, blood TfR+ exosomes changed the biodistribution of DOX leading to the reduction of side effects. Compared with free DOX, DOX-loaded blood TfR+ exosomes showed much better tumor inhibition effects on tumor-bearing mice.Conclusion: Taking advantage of the pH-responsive binding and disaggregation characteristics of Tf and TfR, the SMNC-based method can precisely separate blood TfR+ exosomes with high purity and in their original state. The resulting blood TfR+ exosomes showed excellent bio-safety and enable the efficient delivery of chemotherapeutics to tumors, facilitating the clinical translation of exosome-based drug delivery systems.

Advances in Exosomes‐Based Drug Delivery Systems

“…Recently, microfluidic devices are used in exosome isolation [ 99,100 ] ( Figure 5 ). Their basis is the controlled handling of the sample through capillary tubes associated to different isolation mechanisms.…”

“…Some authors studied the possibility of encapsulating doxorubicin into exosomes to mitigate its side effects and increase its benefits as a therapeutic drug by comparing the results obtained when it is administrated free and when it is encapsulated. In this kind of research, some premises were proved: when doxorubicin was encapsulated in bone marrow MSCs for the treatment of osteosarcoma, there was an increase in tumor accumulation, [ 100 ] better cellular uptake and antitumor effects and no cytotoxicity for the osteosarcoma cell line. [ 126 ] Moreover, their rapid cellular uptake, redistribution and enhanced potency were proved.…”

“…[98] Finally antibodies linked to a column allow for exosomes separation by immunoaffinity chromatography. [92] Recently, microfluidic devices are used in exosome isolation [99,100] (Figure 5). Their basis is the controlled handling of the sample through capillary tubes associated to different isolation mechanisms.…”

Blood TfR+ exosomes separated by a pH-responsive method deliver chemotherapeutics for tumor therapy: Erratum

“…1. In our paper 1 , the label of Figure 6C was reversed. The correct version of the figure appears below.…”

“…2. In our paper 1 , the images of experimental groups in Figure S6 have misused that of the Control group. The correct version of the figure appears below.…”