A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer

doi:10.1016/j.biopha.2017.09.059

Biomedicine & Pharmacotherapy

Volume 95, November 2017, Pages 1209-1218

https://doi.org/10.1016/j.biopha.2017.09.059 Get rights and content

Abstract

In metastatic breast cancer (MBC), the conventional doxorubicin (DOX) has various problems due to lack of selectivity with subsequent therapeutic failure and adverse effects. DOX- induced cardiotoxicity is a major problem that necessitates the presence of new forms to decrease the risk of associated morbidity.

Nanoparticles (NPs) are considered an important approach to selectively increase drug accumulation inside tumor cells and thus decreasing the associated side effects. Tumor cells develop resistance to chemotherapeutic agents through multiple mechanisms, one of which is over expression of efflux transporters. Various NPs have been investigated to overcome efflux mediated resistance.

To date, only liposomal doxorubicin (LD) and pegylated liposomal doxorubicin (PLD) have entered phase II and III clinical trials and FDA- approved for clinical use in MBC. This review addresses the effects of LD and PLD on the hematological and palmar-plantar erythrodysesthesia (PPE) in anthracycline naïve and pretreated MBC patients. For evidence, studies to be included in this review were identified through PubMed, Cochrane and Google scholar databases. The results derived from: four phase III clinical trials that compared LD with the conventional DOX in naïve MBC patients, and ten non-comparative clinical trials investigated LD and PLD as monotherapy or combination in pretreated MBC. This work confirmed the cardiac tolerability profile of LD and PLD versus DOX, while hematological and skin toxicities were more common.

Other DOX-NPs in preclinical trials were discussed in a chronological order. Finally, the modern preclinical development framework for DOX includes exosomal DOX (exo-DOX). Exosomal NPs are non-toxic, non-immunogenic, and can be engineered to have high cargo loading capacity and targeting specificity. These NPs have not been investigated clinically. Our study shows that the full clinical potentiality of DOX-NPs remains to be addressed to move the field forward.

Graphical abstract

Introduction

The progressively increasing incidence of breast cancer is a major public health problem. It is the most common malignant disease affecting females by approximately 26% compared with other cancer types [1]. In Egypt, incidence rates in females reached 38.8% [2]. Doxorubicin (DOX) is one of the main treatments for early and advanced breast cancer. The induced cardiotoxicity necessitates the presence of new forms to decrease the risk of drug associated morbidity [3].

In early-stage breast cancer, surgery alone can cure the patient, later adjuvant chemotherapeutic agents are planned to treat micro-metastatic stages [4]. Metastatic breast cancer (MBC) and recurrent cases were approached systemically to target the areas affected by the disease. Hormonal therapy and chemotherapy are the main systemic interventions [5]. Hormonal therapy is for estrogen and/or progesterone–positive diseased patients without a life-threatening metastasis. Patients who develop resistance to hormonal treatment become candidates for cytotoxic chemotherapy [5].

The therapeutic goal in treating MBC is to prolong the survival while maintaining a good quality of life. Chemotherapy is usually initiated as a monotherapy, but combination therapy is preferred as it has higher response rates (RR) and early onset of clinical benefits [6].

The aim of the present review is to take a journey through the history of different doxorubicin nanoparticles (DOX-NPs) passing through the conventional DOX and exploring the potential new DOX-NPs based therapy for treating MBC. Nanotechnology is a promising alternative that has been developed to overcome limitations in cancer therapy.

This review includes an updated summary of the clinical and preclinical studies with various DOX-NPs based therapy in metastatic breast cancer, presented in a chronological order. Previous systematic reviews have demonstrated the efficacy and cardiac safety of LD (liposomal doxorubicin) and PLD (pegylated liposomal doxorubicin) [8]. To our knowledge, there are currently no available reviews to address the effects of LD and PLD on the hematological and palmar plantar erythrodysesthesia (PPE) in anthracycline naïve and pretreated MBC. For evidence, the current review involved studies that were identified through PubMed, Cochrane and Google scholar database.

Section snippets

Conventional doxorubicin and its limitation

Doxorubicin (DOX) is one of anthracycline family of antibiotics [9]. Two proposed mechanisms for DOX anticancer effect are confirmed. First mechanism is by intercalation into DNA and the subsequent disruption of topoisomerase-II-mediated DNA repair for which candidate pharmacogenes are TOP2A, MLH1, MSH2, TP53, and ERCC2 genes [10] (Fig. 1). Second mechanism involves oxidative stress to cellular membranes, DNA and proteins [11] for which candidate genes involve NADH dehydrogenases, nitric oxide

Nanoparticle doxorubicin-based therapy in metastatic cancer

Nanotechnology is a promising alternative to overcome different limitations in cancer therapy. Several nanoparticles (NPs; diameter 1–100 nm) carrying multiple drugs have been investigated regarding anticancer activities. NPs are characterized by the presence of high ligand density on the surface due to their high surface-area-to-volume ratio. They also increase local drug concentration by carrying the drug within and control its release upon reaching the targets [20], [21].

As illustrated in

Effects of DOX-NPs on drug resistance in preclinical studies

MDR in tumor cells is still one of the major limitations in the clinical treatment of cancer breast. MDR cancer cells can facilitate the efflux of drugs through up-regulating efflux transporters that are either located at the plasma membrane or at the nuclear membrane, with a decrease in intracellular drug concentration [81]. To enhance chemotherapeutic effect, high drug doses should be used which always causes severe systemic toxicity [82]. Adding chemosensitizers is often unsatisfactory. NPs

Lack of clinical trial with other NPs and recommendation

Studying the potential toxicity of NPs on cells and organism has not been done yet. So evaluation of the potential toxicity of nanoparticles holds excellent prospect for research and clinical applications in the future. The supposed advantages of NPs include longer circulation and enhanced drug delivery to tumor tissue; however, these factors did not translate into clinical practice. This might be due to dosing regimen being optimized for the conventional DOX rather than the Nano-carrier

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

None.

Acknowledgment

We appreciate Dr Nesreen Nabil, lecturer of Biochemistry, Faculty of Pharmacy, Modern University for technology and Information for manuscript editing.

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ReviewA review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer

Abstract

Graphical abstract

Introduction

Section snippets

Conventional doxorubicin and its limitation

Nanoparticle doxorubicin-based therapy in metastatic cancer

Effects of DOX-NPs on drug resistance in preclinical studies

Lack of clinical trial with other NPs and recommendation

Funding

Conflict of interest

Acknowledgment

J. Mol. Cell. Cardiol.

Prog. Cardiovasc. Dis.

Int. J. Pharm.

Ann. Oncol.

Ann. Oncol.

Clin. Breast Cancer

Clin. Breast Cancer

Clin. Breast Cancer

Ann. Oncol.

Nanomed. Nanotechnol. Biol. Med.

Carbohydr. Polym.

J. Control. Release

Adv. Drug Deliv. Rev.

Eur. J. Cancer Part A

Biomaterials

J. Surg. Res.

Adv. Drug Deliv. Rev.

Int. J. Pharm.

Int. J. Pharm.

Cancer Lett.

Biomaterials

FEBS Lett.

Cancer Lett.

Nanomed. Nanotechnol. Biol. Med.

Lancet

Lancet Oncol.

Incidence and mortality and epidemiology of breast cancer in the world

Asian Pac. J. Cancer Prev.

Cancer incidence in egypt: results of the national population-based cancer registry program

J. Cancer Epidemiol.

Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

Nat. Med.

Prognostic and predictive factors in early-stage breast cancer

Oncologist

Fluorouracil, doxorubicin, and cyclophosphamide followed by tamoxifen as adjuvant treatment for patients with stage IV breast cancer with no evidence of disease 831

Breast J.

International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured?

J. Natl. Cancer Inst.

Nanoparticle delivery strategies to target doxorubicin to tumor cells and reduce side effects

Ther. Deliv.

Efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized controlled trials

PLoS One

The comparison of cytotoxicity of the anticancer drugs doxorubicin and ellipticine to human neuroblastoma cells

Interdiscip. Toxicol.

Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II

Science

Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase

Oncol. Res.

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials

Cancer

Risk factors for doxorubicin-induced congestive heart failure

Ann. Intern. Med.

Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer

N. Engl. J. Med.

NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity

Circulation

Anthracyclines in the treatment of cancer. An overview

Drugs

The anthracyclines: will we ever find a better doxorubicin?

Semin. Oncol.

Cancer nanotechnology: opportunities and challenges

Nat. Rev. Cancer

Review
A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer