Nanoparticle-mediated targeted drug delivery for breast cancer treatment

Abstract

Breast cancer (BC) is the most common malignancy in women worldwide, and one of the deadliest after lung cancer. Currently, standard methods for cancer therapy including BC are surgery followed by chemotherapy or radiotherapy. However, both chemotherapy and radiotherapy often fail to treat BC due to the side effects that these therapies incur in normal tissues and organs. In recent years, various nanoparticles (NPs) have been discovered and synthesized to be able to selectively target tumor cells without causing any harm to the healthy cells or organs. Therefore, NPs-mediated targeted drug delivery systems (DDS) have become a promising technique to treat BC. In addition to their selectivity to target tumor cells and reduce side effects, NPs have other unique properties which make them desirable for cancer treatment such as low toxicity, good compatibility, ease of preparation, high photoluminescence (PL) for bioimaging in vivo, and high loadability of drugs due to their tunable surface functionalities. In this study, we summarize with a critical analysis of the most recent therapeutic studies involving various NPs-mediated DDS as alternatives for the traditional treatment approaches for BC. It will shed light on the significance of NPs-mediated DDS and serve as a guide to seeking for the ideal methodology for future targeted drug delivery for an efficient BC treatment.

Introduction

Cancer is a class of diseases resulting from unregulated cell growth and these abnormal cells are able to spread or invade other parts of the body. Based on the presumed origin of the tumor cells, cancers are classified into carcinoma, sarcoma, lymphoma, leukemia, germ cell tumor and blastoma. Among them, carcinoma indicates cancer that derive from the epithelial cells and it includes nearly all cancers in breast, prostate, lung, pancreas and colon [1]. Considering the damage various cancers incur, skin and lung cancers are the most common malignancies worldwide. In addition, breast cancer (BC) is the most common cancer type among women accounting for nearly 30% of all cancers [2]. In 2018, about 266,120 new cases of invasive BC have been diagnosed that will potentially cause 40,920 cases of death according to the statistics of the American Cancer Society [2]. In contrast, BC in men accounts only for 1% of all malignant breast neoplasms [3]. Also compared to women, men tend to be diagnosed for BC at an older age as 67 years [4]. Although it is the most common cancer type in women, it is considered as treatable if diagnosed at an early stage [5,6]. However, if metastasis is achieved, it can spread through blood and lymph systems to distant organs, increasing treatment difficulties and the fatality rates rapidly.

Similar to other cancers, the traditional treatment approaches for BC include surgery, chemotherapy and radiotherapy. The primary goal of these therapies is to eradicate tumors while prolonging the survival of patients. Nonetheless, these standard methods are challenged by the advanced and metastatic tumors in terms of tumor recurrence and drug resistance. For instance, surgery is not effective in case of tumor recurrence and metastases to distant organs including bone, lung and liver. In contrast, the goal of chemotherapy is to use cytotoxic chemotherapeutic drugs either after or without surgery to interfere with tumor cell division and growth. Radiotherapy involves delivering powerful waves of energy to disrupt the tumor cell division, which results in the shrinkage or eradication of tumors. Although chemotherapy and radiotherapy are powerful cancer treatment techniques to increase the survival rate, these techniques could lead to acute and long-term adverse effects on the patients' healthy organs [7,8]. For instance, the chemotherapeutic agent; trastuzumab, a monoclonal antibody used to treat BC, has shown toxicity assisted with cardiac dysfunction in long-term use [9]. Furthermore, multidrug resistance is also a challenging issue caused by over-expression of certain proteins in the tumor cells. The effect of chemotherapy is often drastically reduced in this case. Radiation therapy is a local treatment that only affects the area of the tumor location. But side effects can occur due to the damages caused on the neighboring healthy tissues. Considering these adverse effects present in the classic cancer treatment approaches, novel effective alternatives need to be well sought.

Alternatively, the use of nanomaterials as an effective drug delivery method for the cancer treatment has recently gained specific interest, and ongoing investigations are aiming to optimize this method to ultimately reduce the adverse effects caused by the conventional approaches. To date, such NPs commonly used in research for drug delivery to treat BC include liposomes, mesoporous silica NPs, viral NPs, polymer-, metal- or carbon-based NPs and different drug loading techniques are used depending on the NPs such as encapsulation, covalent or electrostatic binding and adsorption. There are numerous advantages of using NPs for drug delivery: i) it solves issues related to the poor solubility and bioavailability of the drug; ii) it enhances targeted drug permeability to cancer cells and administer slow release of the drug; and iii) NPs are small (1–100 nm), nontoxic, biodegradable and highly photoluminescent particles on to which the cancer drugs can be easily loaded. The PL could endow the in vivo drug tracking ability to determine drug delivery efficacy during treatment. For the studies of targeted DDS, different types of breast tumor cell lines have been used in vitro including MDA-MB-231, MDA-MB-453, SkBr3 and MCF-7 [5,7,[10], [11], [12], [13], [14]]. Besides, doxorubicin (Dox) is the most popular chemotherapeutic agent for NPs mediated delivery for BC and it has also been used together with siRNAs and miRNAs in co-delivery systems. Other chemotherapeutic agents, namely paclitaxel (PTX), cisplatin, trastuzumab, fulvestrant, anastrozole, and carboplatin are also often used for phase II and III clinical trials [[14], [15], [16], [17]]. Furthermore, several combinations among these therapeutics have shown synergistic effects against BC [14].

Administering drugs using a targeted DDS can help reduce the doses because the pharmacologically effective concentrations can be achieved at lower concentrations compared to untargeted administering of drugs. Side effects resulting from toxicity and damages to healthy cells and tissues could also be significantly reduced through a targeted delivery method compared to the standard chemotherapy approach. Therefore, the development of new treatment methods such as NPs-based targeted DDS as well as combination therapy has the potential to alleviate the side effects. Usage of a DDS is also of crucial importance in treatments using drug combinations or oligonucleotides, due to the needs such as delivery without premature decay and simultaneous drug administration.