Facile fabrication of multi-pocket nanoparticles with stepwise size transition for promoting deep penetration and tumor targeting

Xingyu Hou,Hu Zhang,Hongli Mao,Kui Luo,Qiyong Gong,Zhongwei Gu,Dan Zhong,Jun Yang,Yunkun Li

doi:10.1186/s12951-021-00854-z

Abstract

BackgroundNanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy.ResultsThe multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. Furthermore, MPNs exhibited not only an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm3) bearing mice with reduced side effect.ConclusionsOur facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy.Graphic

Highlights

Nanoscale supramolecular assemblies have been extensively exploited as drug carriers for cancer therapy over the last decades due to their improved drug solubility and pharmacokinetics, enhanced permeability and retention (EPR) at tumor site, and reduced systemic side effects [1,2,3]
Preparation and characterization of multi-pocket nanoparticles (MPNs) The amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates were readily prepared by treating mPEG with lipoic acid. 1H NMR spectrum in Additional file 1: Fig. S1 revealed that lipoic acid was successfully conjugated onto mPEG, and in the matrix-assisted laser desorption/ionization time-of-flight mass spectrum (MALDI-TOF MS) the peaks corresponded to the theoretical [M + Na]+ ions, where M = 264.09 + 44.03n and n = number of repeat units (Fig. 1a)
The amphiphilic mPEG-LA self-assembled into uniform-nanosized spheres in aqueous medium with an average size of 40 nm and a negative surface charge of -18.1 mV (Additional file 1: Fig. S2)

Summary

Results

The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. Once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. MPNs exhibited an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm3) bearing mice with reduced side effect

Conclusions

Introduction

Results and discussion