Bispecific antibodies (anti-mPEG/anti-HER2) for active tumor targeting of docetaxel (DTX)-loaded mPEGylated nanocarriers to enhance the chemotherapeutic efficacy of HER2-overexpressing tumors

Chia-Yu Su,Michael Chen,Ling-Chun Chen,Yuan-Soon Ho,Hsiu-O Ho,Shyr-Yi Lin,Kuo-Hsiang Chuang,Ming-Thau Sheu

doi:10.1080/10717544.2018.1466936

Chia-Yu Su, Michael Chen + Show 6 more

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https://doi.org/10.1080/10717544.2018.1466936

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Abstract

Anti-mPEG/anti-human epidermal growth factor receptor 2 (HER2) bispecific antibodies (BsAbs) non-covalently bound to a docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micellar drug delivery system (LsbMDDs) were endowed with active targetability to improve the chemotherapeutic efficacy of DTX. DTX-loaded mPEGylated LsbMDDs formulations were prepared using lecithin/DSPE-PEG(2K or 5K) nanosuspensions to hydrate the thin film, and then they were subjected to ultrasonication. Two BsAbs (anti-mPEG/anti-DNS or anti-HER2) were simply mixed with the LsbMDDs to form BsAbs-LsbMDDs formulations, respectively, referred as the DNS-LsbMDDs and HER2-LsbMDDs. Results demonstrated that the physical characteristics of the BsAbs-LsbMDDs were similar to those of the plain LsbMDDs but more slowly released DTX than that from the LsbMDDs. Results also showed that the HER2-LsbMDDs suppressed the growth of HER2-expressing MCF-7/HER2 tumors, increasing the amount taken up via an endocytosis pathway leading to high drug accumulation and longer retention in the tumor. In conclusion, the BsAbs-LsbMDDs preserved the physical properties of the LsbMDDs and actively targeted tumors with a drug cargo to enhance drug accumulation in tumors leading to greater antitumor activity against antigen-positive tumors.

Highlights

In the past few decades of rapidly evolving drug research, numerous high-potency chemotherapeutic drugs have been discovered
To introduce mPEGylation to robust and previously developed promising delivery systems known as the lecithin-stabilized micellar drug delivery system (LsbMDDs) (Chen et al, 2015; Chen et al, 2016), the thin film of selfassembling micelles was hydrated with a lecithin/DSPE-polyethylene glycol (PEG) (2K or 5K) nanosuspension in this study
The micellar core of the so-obtained LsbMDDs was composed of DTX and DSPEPEG2K, while the lipid shell consisted of lecithin and DSPEPEG (2K or 5K) at a ratio of 40:15 (w/w)

Summary

Introduction

In the past few decades of rapidly evolving drug research, numerous high-potency chemotherapeutic drugs have been discovered. For the success of chemotherapeutic agents in clinical applications, a durable and specific drug delivery system is required to carry and release the drugs into the right pathological site (Peer et al, 2007; Brigger et al, 2012) For this purpose, numerous nanocarrier (NC) types like liposomes, micelles, polymeric nanoparticles (NPs), dendrimers, solid-lipid nanoparticles (SLNs), and gold NPs have been investigated for controlled drug release applications (Davis et al, 2008; Wang et al, 2012). Numerous nanocarrier (NC) types like liposomes, micelles, polymeric nanoparticles (NPs), dendrimers, solid-lipid nanoparticles (SLNs), and gold NPs have been investigated for controlled drug release applications (Davis et al, 2008; Wang et al, 2012) These NCs delivery systems can through a leaky tumor blood vasculature via an enhanced permeability and retention (EPR) effect. Those advances in nanomedicine have demonstrated obvious advantages, including preferential drug accumulation in tumor sites, decreased side effects, better drug tolerance, and improved patient compliance in clinical practice (Zhong et al, 2014; Hare et al, 2017)

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