Natural Compounds: Co-Delivery Strategies with Chemotherapeutic Agents or Nucleic Acids Using Lipid-Based Nanocarriers

Abstract

Cancer is one of the leading causes of death, and latest predictions indicate that cancer- related deaths will increase over the next few decades. Despite significant advances in conventional therapies, treatments remain far from ideal due to limitations such as lack of selectivity, non-specific distribution, and multidrug resistance. Current research is focusing on the development of several strategies to improve the efficiency of chemotherapeutic agents and, as a result, overcome the challenges associated with conventional therapies. In this regard, combined therapy with natural compounds and other therapeutic agents, such as chemotherapeutics or nucleic acids, has recently emerged as a new strategy for tackling the drawbacks of conventional therapies. Taking this strategy into consideration, the co-delivery of the above-mentioned agents in lipid-based nanocarriers provides some advantages by improving the potential of the therapeutic agents carried. In this review, we present an analysis of the synergistic anticancer outcomes resulting from the combination of natural compounds and chemotherapeutics or nucleic acids. We also emphasize the importance of these co-delivery strategies when reducing multidrug resistance and adverse toxic effects. Furthermore, the review delves into the challenges and opportunities surrounding the application of these co-delivery strategies towards tangible clinical translation for cancer treatment.

Keywords: cancer; combined therapy; conventional therapy; lipid-based nanocarriers; natural compounds.

Figure 1

Problems associated with the classical single-delivery therapy (i.e., administration of each of the therapeutic agents in their free form). Nucleic acids, if delivered in the free form, would face different pharmacokinetic challenges, including inactivation by nucleases (A), lack of serum stability due to the immune system (B) and serum proteins (C), extravasation difficulties (D), non-specific distribution in target cells (E), difficulties entering the cell (F), and degradation if not able to escape endosomes (G). Chemotherapeutic drugs, when delivered in the free form, have a nonspecific distribution in cancer cells and healthy cells causing serious adverse side effects, commonly affecting hair follicles, the digestive tract, blood cells and nerves. Furthermore, several MDR mechanisms, such as drug efflux by multidrug resistance protein 1 (MRP1), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP), or inactivation of apoptotic pathways by B cell leukemia protein (Bcl2), can impair their efficiency. Natural compounds, when administered in their free form, exhibit a number of pharmacokinetic issues that affect their biodistribution and efficacy (1–6).

Figure 2

Schematic illustration of lipid-based nanocarriers and advantages of their use for the co-delivery of natural compounds and chemotherapeutic drugs or nucleic acids. Adapted from [36,37], and from [38,39] with permission from Elsevier.

Figure 3

Main natural compounds considered chemosensitizing agents, according to their chemical family [47].

Figure 4

Potential targets associated with Curcumin anticancer activity. This natural compound induces a reduction in its target genes by inhibiting NF-kβ signaling. Bcl-2-B-cell limphoma-2; COX-2-ciclo-oxigenase-2; IL-6-interleukin 6; IL-10-interleukin 10; IL-18-interleukin 18; MMP9-matrix metallopeptidase 9; NF-kβ-nuclear factor kappa B; VEGF-vascular endothelial growth factor; XIAP-X-linked inhibitor of apoptosis protein.