Integrated prodrug micelles with two-photon bioimaging and pH-triggered drug delivery for cancer theranostics.

Yunbing Wang,Weihua Zhuang,Rongrong Peng,Hong Xu,Gaocan Li,Sutong Xiao,Boxuan Ma,Jizhou Jiang

doi:10.1093/rb/rbz035

Yunbing Wang, Weihua Zhuang + Show 6 more

Open Access

https://doi.org/10.1093/rb/rbz035

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Abstract

Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging, less side effect, better drug utilization as well as the good bioimaging ability. However, traditional nanocarriers still suffer from unexpectable drug leakage, unsatisfactory tumor-targeted drug delivery and shallow imaging depth, which limit their further application in cancer theranostics. In this study, an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging, charge reversal and drug delivery triggered by acidic pH. The prodrug micelles can be self-assembled by the TP-PEI (DA/DOX)-PEG prodrug polymer, which consists of the two-photon fluorophore (TP), dimethylmaleic anhydride (DA) grafted polyethyleneimine (PEI) and polyethylene glycol (PEG). The PEG segment, DOX and DA are bridged to polymer by acid cleavable bonds, which provides the micelles a ‘stealth’ property and a satisfactory stability during blood circulation, while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment, thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery. The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo. Meanwhile, these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 μm in depth. The great antitumor efficacy, reduced side effect and deep two-photon tissue imaging make the TP-PEI (DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.

Highlights

In recent years, chemotherapy is deemed to be one of the most important methods for cancer treatment [1, 2], while it suffers from poor targeting, rapid clearance and severe side effects of antitumor drugs [3, 4]
Micelle solution was treated by 1 M HCl for 24 h and lyophilized to measure the drug loading content (DLC) and drug loading efficacy (DLE) of the micelles by using UV-vis at 480 nm, where the lyophilized prodrug micelles were dissolved in methanol and DMF solution (1/1, v/v)
two-photon fluorophore (TP)-PEI (DA/DOX)-polyethylene glycol (PEG) prodrug polymer was synthesized via several steps shown in Fig. 2. 1H NMR spectrum of TP-PEI was shown in Supplementary Fig. S1

Summary

Introduction

Chemotherapy is deemed to be one of the most important methods for cancer treatment [1, 2], while it suffers from poor targeting, rapid clearance and severe side effects of antitumor drugs [3, 4]. To this perspective, drug-loaded nanocarriers, such as polymeric micelles, are utilized to achieve an efficient tumor inhibition with significantly reduced toxicity [5, 6].

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