Erlotinib-Guided Self-Assembled Trifunctional Click Nanotheranostics for Distinguishing Druggable Mutations and Synergistic Therapy of Nonsmall Cell Lung Cancer

Abstract

The outcome of molecular targeted therapies is restricted by the ambiguous molecular subtypes of nonsmall cell lung cancer (NSCLC), which are difficult to be defined with druggable mutations, and the inevitable emergence of drug-resistance. Here we used the Cu-catalyzed click chemistry to synthesize a chitosan-based self-assembled nanotheranostics (CE7Ns) composed of a near-infrared (NIR) fluorescent photosensitizer Cy7 and molecular targeted drug erlotinib. The wellcharacterized CE7Ns can release erlotinib and Cy7 fast under acidic condition in the presence of lysozyme, distinguish three molecular subtypes of NSCLC, and specifically bind to the erlotinib-sensitive epidermal growth factor receptor (EGFR)-mutated PC-9 cells. The uptake of CE7Ns is much more in PC-9 cells than in other NSCLC cells, thus generating a notable fluorescence signal in PC-9 cells. Upon NIR irradiation, Cy7 in CE7Ns produces high reactive oxygen species in PC-9 cells. The synergistic effect between erlotinib-targeted therapy and photodynamic therapy significantly up-regulates cancer suppressor p53 and inhibits Survivin, which results in more apoptosis and cell cycle arrest. Upon intravenous administration, the erlotinib-guided CE7Ns significantly accumulate in PC-9-seeded mouse lungs and produce strong fluorescence. Upon NIR irradiation, CE7Ns significantly inhibit the subcutaneously implanted PC-9 tumor growth. This study provides, for the first time, a novel strategy to synthesize a multifunctional theranostic entity to simultaneously distinguish and image druggable mutations and combine targeted therapy with photodynamic therapy to overcome drug resistance.

Carrier‐Free Nanoassembly of Curcumin–Erlotinib Conjugate for Cancer Targeted Therapy

“…There is a triple bond in the chemical structure of ELT, which allows for introducing modifications to ELT through click chemistry. [ 16 ] We utilized a hydrophilic bifunctional PEG, which bears an azido group and a carboxylic acid group on either end, to link ELT and CCM via click chemistry and esterification reaction, respectively. The resulted compound EPC is composed of both hydrophilic and hydrophobic moieties, which renders it capable of self‐assembling into nanoassemblies through a one‐step nanoprecipitation process.…”

EGFR-Targeted Photodynamic Therapy

“…A chitosan derivative for targeting EGFR-overexpressing cells was created by chemically linking the Cy7 photosensitizer and erlotinib to chitosan, exploiting the reactive amine and hydroxyl groups that are naturally present on the chitosan backbone. Eventually, the polymeric chitosan derivative self-assembled to form theranostic nanoparticles [130]. Alternative formulations using the chitosan-erlotinib derivative as a targeting agent were also developed.…”

“…In all of these formulations, the nanoparticles specifically bind to the erlotinib-sensitive EGFR-overexpressing cells and release their cargo (erlotinib and photosensitizer) under specific conditions. The synergistic effect between the erlotinib-targeted therapy and photodynamic therapy resulted in the activation of the apoptotic pathway and cell cycle arrest [130]. Upon intravenous administration, the erlotinib-guided nanoparticles accumulated in EGFR-overexpressing cells, producing strong fluorescence, while upon NIR irradiation they significantly inhibited the growth of subcutaneously implanted EGFR-responsive tumors [130].…”

Reshaping Tumor Blood Vessels to Enhance Drug Penetration with a Multistrategy Synergistic Nanosystem

“…These factors, together with other pro-angiogenic factors, they promote the growth of excessive tumor vasculature in tumors. Erlotinib (ERL), a tyrosine inhibitor that specifically targets tumor cells, , has been shown to normalize tumor vasculature. − …”

“…These factors, together with other pro-angiogenic factors, they promote the growth of excessive tumor vasculature in tumors. Erlotinib (ERL), a tyrosine inhibitor that specifically targets tumor cells, 11,12 has been shown to normalize tumor vasculature. 13−16 Normalization of blood vessels can repair the structure and function of tumor vasculature by correcting angiogenesis signals.…”