Cancer-Targeted Controlled Delivery of Chemotherapeutic Anthracycline Derivatives Using Apoferritin Nanocage Carriers

Katarzyna Kurzątkowska,Maria Hepel,Manuel A Pazos,Jason I Herschkowitz

doi:10.3390/ijms22031362

Abstract

The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs in APO-based controlled drug delivery systems. The encapsulation enables mitigating the drugs’ side effects, collateral damage to healthy cells, and adverse immune reactions. Herein, the interactions of anthracycline drugs with APO were studied to assess the effect of drug lipophilicity on their encapsulation excess n and in vitro activity. Anthracycline drugs, including doxorubicin (DOX), epirubicin (EPI), daunorubicin (DAU), and idarubicin (IDA), with lipophilicity P from 0.8 to 15, were investigated. We have found that in addition to hydrogen-bonded supramolecular ensemble formation with n = 24, there are two other competing contributions that enable increasing n under strong polar interactions (APO(DOX)) or under strong hydrophobic interactions (APO(IDA) of the highest efficacy). The encapsulation/release processes were investigated using UV-Vis, fluorescence, circular dichroism, and FTIR spectroscopies. The in vitro cytotoxicity/growth inhibition tests and flow cytometry corroborate high apoptotic activity of APO(drugs) against targeted MDA-MB-231 adenocarcinoma and HeLa cells, and low activity against healthy MCF10A cells, demonstrating targeting ability of nanodrugs. A model for molecular interactions between anthracyclines and APO nanocarriers was developed, and the relationships derived compared with experimental results.

Highlights

Recent advances in cancer treatment, achieved through the development of precision guided surgical techniques, novel drugs, and modern technologies for cancer detection and monitoring [1,2,3,4], have resulted in considerable deceleration of the disease progression and spread
There is a growing body of evidence that these antagonistic effects can largely be prevented by developing controlled drug delivery (CDD) systems [1,13,14,15] based on biocompatible drug nanocarriers with the targeting ability to act upon cancer cells
We have addressed some of these issues by investigating the capability of a biogenic nanocage carrier, apoferritin (APO), to encapsulate anthracycline (ANTR) chemotherapeutic drugs for safe, controlled delivery directly to the cancer cells, mitigating most of the adverse effects encountered in a systemic drug delivery in classical chemotherapy [2,3,4,5,12,16]

Summary

Introduction

Recent advances in cancer treatment, achieved through the development of precision guided surgical techniques, novel drugs, and modern technologies for cancer detection and monitoring [1,2,3,4], have resulted in considerable deceleration of the disease progression and spread. A great effort is still being paid to solve key challenges in cancer therapy by focusing on early detection [5], nanotechnology-assisted theranostics [4], overcoming multi-drug resistance (MDR) [6,7,8,9,10], control of proliferation and metastasis, and activation of immunodefenses [11]. The advantages of using chemotherapeutic agents with high cytotoxicity and an ability to kill cancer cells are often offset by harmful side effects, MDR, and DNA damage to healthy cells [12], which may preclude prolonged treatment due to organ failure or systemic collapse. There is a growing body of evidence that these antagonistic effects can largely be prevented by developing controlled drug delivery (CDD) systems [1,13,14,15] based on biocompatible drug nanocarriers with the targeting ability to act upon cancer cells. We have addressed some of these issues by investigating the capability of a biogenic nanocage carrier, apoferritin (APO), to encapsulate anthracycline (ANTR) chemotherapeutic drugs for safe, controlled delivery directly to the cancer cells, mitigating most of the adverse effects encountered in a systemic drug delivery in classical chemotherapy [2,3,4,5,12,16]

Methods

Results

Conclusion