Abstract
In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium-based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple-negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced next-generation metallotherapeutics, with NAMI-A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well-known NAMI-A complex, information on non-nanostructured Ru-based anticancer agents have been included in a precise manner.
Highlights
Via specific interactions with protein targets such as members of the Bcl-2 family involved in the regulation of apoptosis, ruthenium complexes could selectively reactivate death pathways which are normally suppressed in cancer cells in response to tumorigenic metabolic adaptations promoting cell survival
dioleyl-3- trimethylammonium propane chloride (DOTAP) formulations can concurrently activate the extrinsic apoptotic pathway in triple negative breast cancer (TNBC), offering an additional possibility to block the growth of this breast cancer (BC) type
Specific molecular contacts with membrane components plus possible drug release might stimulate specific surface receptors involved in the early signaling of extrinsic apoptosis, as proven by some Ru-based chemotherapeutics whose action has been correlated to initiation of this apoptotic pathways [58,161]
Summary
The prevention, diagnosis, and treatment of neoplastic diseases are a major problem in developed countries [1]. Tumors overexpressing the human epidermal growth factor receptor-2 (HER-2 positive) tend to be more aggressive than luminal cancers but by chance are responsive to targeted therapy such as treatment with trastuzumab (Herceptin) aimed at the HER-2 protein. As the field of genomics has developed considerably, researchers can perform fast screening to examine gene sequences alterations with their protein products that might be correlated with precise BC subtypes. Many of these gene clusters mapped onto the four major biological markers described above [17]. Notwithstanding the progress in screening programs and the advancement in the therapeutic field, a considerable amount of BC patients will experience an invasive disease that, to this day, in an important percentage of cases remains incurable thereby justifying the search for new chemotherapeutic strategies
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