Nanoparticle-Mediated Combination Therapy: Two-in-One Approach for Cancer

Abstract

Cancer represents a group of heterogeneous diseases characterized by uncontrolledgrowth and spread of abnormal cells, ultimately leading to death. Nanomedicine plays a significantrole in the development of nanodrugs, nanodevices, drug delivery systems and nanocarriers. Someof the major issues in the treatment of cancer are multidrug resistance (MDR), narrow therapeuticwindow and undesired side effects of available anticancer drugs and the limitations of anticancerdrugs. Several nanosystems being utilized for detection, diagnosis and treatment such as theranosticcarriers, liposomes, carbon nanotubes, quantum dots, polymeric micelles, dendrimers and metallicnanoparticles. However, nonbiodegradable nanoparticles causes high tissue accumulation andleads to toxicity. MDR is considered a major impediment to cancer treatment due to metastatictumors that develop resistance to chemotherapy. MDR contributes to the failure of chemotherapiesin various cancers, including breast, ovarian, lung, gastrointestinal and hematological malignancies.Moreover, the therapeutic efficiency of anticancer drugs or nanoparticles (NPs) used alone is lessthan that of the combination of NPs and anticancer drugs. Combination therapy has long beenadopted as the standard first-line treatment of several malignancies to improve the clinical outcome.Combination therapy with anticancer drugs has been shown to generally induce synergistic drugactions and deter the onset of drug resistance. Therefore, this review is designed to report andanalyze the recent progress made to address combination therapy using NPs and anticancer drugs.We first provide a comprehensive overview of the angiogenesis and of the different types of NPscurrently used in treatments of cancer; those emphasized in this review are liposomes, polymericNPs, polymeric micelles (PMs), dendrimers, carbon NPs, nanodiamond (ND), fullerenes, carbonnanotubes (CNTs), graphene oxide (GO), GO nanocomposites and metallic NPs used forcombination therapy with various anticancer agents. Nanotechnology has provided the convenienttools for combination therapy. However, for clinical translation, we need continued improvementsin the field of nanotechnology.

Keywords: anticancer drug; carbon nanoparticles; combination therapy; dendrimers; graphene oxide nanocomposites; liposomes; metallic nanoparticles; polymeric nanoparticles.

Figure 1

The worldwide percentage distribution of cancer types (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html, Accessed on 11 July 2018).

Figure 2

The angiogenesis process and treatment of tumors via nanoparticle delivery. (a) Angiogenesis; (b) Drug delivery through NPs; (c) Tumor reduction.

Figure 3

Central dogma of nanoparticles targeting in cancer cells.

Figure 4

Classification of liposomes based on the lamellarity: (a) Multilamellar vesicles (MLV) are composed of many lipid bilayers and range from 1–5 µm in size; (b) Large unilamellar vesicles (LUV) are in the size range of 100–250 nm with a single lipid bilayer; (c) Small unilamellar vesicles (SUV) consist of a single phospholipid bilayer surrounding an aqueous phase with a size range of 20–100 nm.

Figure 5

Drug delivery with and without Nanoparticles. Nanoparticle based targeted drug delivery enhanced the antitumor activity due to enhanced and sustained release of drug.

Figure 6

Encapsulation mechanism models: drug entrapped in, dissolved in, or dispersed within and adsorbed on: (a) nanocapsules and (b) nanospheres [67].

Figure 7

Different approaches to modify surfaces of nanoparticles (NPs) to target cancer cells.

Figure 8

Combined nano-therapy strategy of CaP nanoparticles containing siRNA and anticancer reagent and their therapeutic effect in cancerous cell. CaP nanoparticles which were assembled with siRNA targeting specific genes is coated with lipids, followed by co-incubation with anticancer drug. The obtained CaNPs/siRNA/DOX are encapsulated by polymers. Internalized CaNPs/siRNA/DOX into cancerous cell are dissolved in endosomal pH through endosomal/lysosomal escape and then released to cytoplasm. Then, siRNA is processed by dicer and RISC system in cytosol and recognize target mRNA to silence the gene expression. Simultaneously, anticancer drug released functions regarding its biological mechanism. Ultimately, both are purposed to induce cell death.

Figure 9

Combined nano-therapy strategy of MSN containing DOX and AgNPs in cancerous cell. MSNs are loaded with DOX then coated with AgNPs. The obtained DOX/AgNPs/MSN is internalized into cancerous cell via endocytosis and then released to cytosol by endosomal pH through endosomal/lysosomal escape. Released AgNPs resulted in mitochondrial dysfunction by inducing ROS production in mitochondria. DOX released accelerate ROS production, followed by induce oxidative stress in cytosol via DOX semiquinone. DOX also is intercalated into DNA that results in DNA damaging by poisoning of topoisomerase II. Both of AgNPs and DOX finally induce cancer cell death through oxidative stress by increasing ROS and DNA damaging in nucleus. Black colored indicates direction of pathway and red color indicates blocking function.