Novel Tamoxifen Nanoformulations for Improving Breast Cancer Treatment: Old Wine in New Bottles

Abstract

Breast cancer (BC) is one of the leading causes of death from cancer in women; second only to lung cancer. Tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA for hormone therapy of BC. Despite having striking efficacy in BC therapy, concerns regarding the dose-dependent carcinogenicity of TAM still persist, restricting its therapeutic applications. Nanotechnology has emerged as one of the most important strategies to solve the issue of TAM toxicity, owing to the ability of nano-enabled-formulations to deliver smaller concentrations of TAM to cancer cells, over a longer period of time. Various TAM-containing-nanosystems have been successfully fabricated to selectively deliver TAM to specific molecular targets found on tumour membranes, reducing unwanted toxic effects. This review begins with an outline of breast cancer, the current treatment options and a history of how TAM has been used as a combatant of BC. A detailed discussion of various nanoformulation strategies used to deliver lower doses of TAM selectively to breast tumours will then follow. Finally, a commentary on future perspectives of TAM being employed as a targeting vector, to guide the delivery of other therapeutic and diagnostic agents selectively to breast tumours will be presented.

Keywords: breast cancer; drug delivery systems; nanotechnology; tamoxifen; targeted therapy.

Figure 1

Tamoxifen (TAM) (PubChem CID: 2733526).

Figure 2

Passive delivery of TAM-loaded-nanosystems to tumours via the enhanced permeability and retention (EPR) effect. The explanation for this concept is that, as tumour cells grow quickly, their needs for nutrients and oxygen supply also increase rapidly, simulating the production of new tumour blood vessels with abnormal architectures, or angiogenic blood vessels. These rapidly formed and premature tumour vessels are made up of poorly aligned endothelial cells with large gaps (usually about 100 to 800 nm) between them, allowing TAM-loaded-nanoformulations with appropriate sizes to enter [54,55,56]. In addition to this, these nanosystems are retained inside tumour tissues for days and even weeks, due to the lack of effective lymphatic drainage, allowing TAM molecules sufficient time to be released from carriers and take effect [54,55,56]. Image adapted from Dai et al. [55].

Figure 3

Graphic illustration of TAM/ gemcitabine (GEM) liposome and their localisation inside the multidrug (MD) carrier. TAM was incorporated into the lipid bilayer of liposomes; while GEM molecules were loaded inside the hydrophilic central core of liposomes, allowing the co-loading of two therapeutic agents to occur. Image taken from Cosco et al. [61].

Figure 4

Schematic illustration of the synthesis of α-tocopherol succinate-g-carboxymethyl-chitosan via carbodiimide chemistry. The carboxyl group of α-tocopherol succinate was conjugated with the amine group of chitosan (Cmc) of low molecular weights, with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) employed as coupling agents. In the final step, Cmc-TS were obtained by lyophilization. Image taken from Jena and Sangamwar [72].

Figure 5

Schematic illustrating the fabrication of My-g-G5/TAM complex: (1) The terminal carboxyl groups (–COOH) of myristic acid (My) chains were activated by the addition of EDC/NHS, and magnetically stirred for 12 h in light-sealed condition. (2) Resulting solution was added drop-wise into the G5 PAMAM–DMSO solution under N2 atmosphere, and left undisturbed for 24 h at room temperature to form My-g-G5. (3) TAM containing solution was slowly added into My-g-G5, resulting in the formation of My-g-G5/TAM complex. Image taken from Matai and Gopinath [113].

Figure 6

TAM-conjugated-SWCNT: N-desmethyltamoxifen was reacted with carboxylic acid groups (-COOH) present on SWCNT surface. This conjugation was induced by the addition of N,N′-diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (DMAP) as solvents, in the presence of diisopropylethylamine (DIEA). The resulting solution was filtered and washed with N,N-dimethylformamide and dichloromethane to remove impurities. Image adapted from Oskoueian A., et al. [121].

Figure 7

The internalization of TAM-guided nanosystems into breast tumour: TAM is employed as an active/targeting vector due to its ability to recognize and bind specifically to ERs locating on the membrane of tumours, namely membrane-localized-ER. By conjugating TAM at the distal end of various nanosystems containing other therapeutic materials (including different drugs), selective delivery and receptor-mediated cellular internalisation of incorporated materials can be initiated [132,133,134]. Image adapted from Barclay et al. [134].

Figure 8

Examples of TAM conjugates [135,136,137].