Variation in tumor pH affects pH-triggered delivery of peptide-modified magnetic nanoparticles

Alexandra G Pershina; Olga Ya Brikunova; Alexander M Demin; Maxim A Abakumov; Alexander N Vaneev; Victor A Naumenko; Alexander S Erofeev; Peter V Gorelkin; Timur R Nizamov; Albert R Muslimov; Alexander S Timin; Dina Malkeyeva; Elena Kiseleva; Sergey V Vtorushin; Irina V Larionova; Elena A Gereng; Artem S Minin; Aidar M Murzakaev; Victor P Krasnov; Alexander G Majouga; Ludmila M Ogorodova

doi:10.1016/j.nano.2020.102317

Variation in tumor pH affects pH-triggered delivery of peptide-modified magnetic nanoparticles

Nanomedicine. 2021 Feb:32:102317. doi: 10.1016/j.nano.2020.102317. Epub 2020 Oct 21.

Authors

Alexandra G Pershina¹, Olga Ya Brikunova², Alexander M Demin³, Maxim A Abakumov⁴, Alexander N Vaneev⁵, Victor A Naumenko⁶, Alexander S Erofeev⁵, Peter V Gorelkin⁷, Timur R Nizamov⁴, Albert R Muslimov⁸, Alexander S Timin⁹, Dina Malkeyeva¹⁰, Elena Kiseleva¹⁰, Sergey V Vtorushin¹¹, Irina V Larionova¹², Elena A Gereng², Artem S Minin¹³, Aidar M Murzakaev¹⁴, Victor P Krasnov¹⁵, Alexander G Majouga¹⁶, Ludmila M Ogorodova²

Affiliations

¹ Siberian State Medical University, Tomsk, Russia; Research School of Chemical and Biomedical Engineering, National Research Tomsk Polytechnic University, Tomsk, Russia. Electronic address: allysyz@mail.ru.
² Siberian State Medical University, Tomsk, Russia.
³ Postovsky Institute of Organic Synthesis UB RAS, Yekaterinburg, Russia.
⁴ National University of Science and Technology MISiS, Moscow, Russia.
⁵ National University of Science and Technology MISiS, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia.
⁶ National University of Science and Technology MISiS, Moscow, Russia; V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow, Russia.
⁷ National University of Science and Technology MISiS, Moscow, Russia; Medical Nanotechnology LLC, Moscow, Russia.
⁸ Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia.
⁹ Research School of Chemical and Biomedical Engineering, National Research Tomsk Polytechnic University, Tomsk, Russia; Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia.
¹⁰ Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
¹¹ Siberian State Medical University, Tomsk, Russia; Cancer Research Institute, Tomsk National Research Medical Center RAS, Tomsk, Russia.
¹² Cancer Research Institute, Tomsk National Research Medical Center RAS, Tomsk, Russia; National Research Tomsk State University, Tomsk, Russia.
¹³ Mikheev Institute of Metal Physics UB RAS, Yekaterinburg, Russia.
¹⁴ Institute of Electrophysics UB RAS, Yekaterinburg, Russia; Ural Federal University, Yekaterinburg, Russia.
¹⁵ Postovsky Institute of Organic Synthesis UB RAS, Yekaterinburg, Russia; Ural Federal University, Yekaterinburg, Russia.
¹⁶ National University of Science and Technology MISiS, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia; Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia.

PMID: 33096245
DOI: 10.1016/j.nano.2020.102317

Abstract

Acidification of the extracellular matrix, an intrinsic characteristic of many solid tumors, is widely exploited for physiologically triggered delivery of contrast agents, drugs, and nanoparticles to tumor. However, pH of tumor microenvironment shows intra- and inter-tumor variation. Herein, we investigate the impact of this variation on pH-triggered delivery of magnetic nanoparticles (MNPs) modified with pH-(low)-insertion peptide (pHLIP). Fluorescent flow cytometry, laser confocal scanning microscopy and transmission electron microscopy data proved that pHLIP-conjugated MNPs interacted with 4T1 cells in two-dimensional culture and in spheroids more effectively at pH 6.4 than at pH 7.2, and entered the cell via clathrin-independent endocytosis. The accumulation efficiency of pHLIP-conjugated MNPs in 4T1 tumors after their intravenous injection, monitored in vivo by magnetic resonance imaging, showed variation. Analysis of the tumor pH profiles recorded with implementation of original nanoprobe pH sensor, revealed obvious correlation between pH measured in the tumor with the amount of accumulated MNPs.

Keywords: Endocytosis; Iron oxide magnetic nanoparticles; MRI; pH profile; pHLIP.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Drug Delivery Systems*
Endocytosis / drug effects
Female
Hydrogen-Ion Concentration
Magnetic Resonance Imaging
Magnetite Nanoparticles / chemistry*
Magnetite Nanoparticles / ultrastructure
Membrane Proteins / pharmacology*
Mice
Mice, Inbred BALB C
Neoplasms / diagnostic imaging
Neoplasms / pathology*
Polyethylene Glycols / chemistry
Spheroids, Cellular / drug effects
Tumor Microenvironment*

Substances

Magnetite Nanoparticles
Membrane Proteins
pHLIP protein
Polyethylene Glycols