Liposome Delivery of Natural STAT3 Inhibitors for the Treatment of Cancer

Abstract

In the tumor microenvironment, cytokines, growth factors, and oncogenes mediate constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in both cancer cells and infiltrating immune cells. STAT3 activation in cancer cells drives tumorigenic changes that allow for increased survival, proliferation, and resistance to apoptosis. The modulation of immune cells is more complicated and conflicting. STAT3 signaling drives the myeloid cell phenotype towards an immune suppressive state, which mediates T cell inhibition. On the other hand, STAT3 signaling in T cells leads to proliferation and T cell activity required for an anti-tumor response.Targeted delivery of STAT3 inhibitors to cancer cells and myeloid cells could therefore improve therapeutic outcomes. Many compounds that inhibit the STAT3 pathways for cancer treatment include peptide drugs, small molecule inhibitors, and natural compounds. However, natural compounds that inhibit STAT3 are often hydrophobic, which reduces their bioavailability and leads to unfavorable pharmacokinetics. This review focuses specifically on liposome-encapsulated natural STAT3 inhibitors and their ability to target cancer cells and myeloid cells to reduce tumor growth and decrease STAT3-mediated immune suppression. Many of these liposome formulations have led to profound tumor reduction and examples of combination formulations have been shown to eliminate tumors through immune modulation.

Towards the Development of Delivery Systems of Bioactive Compounds With Eyes Set on Pharmacokinetics

“…Natural bioactive compounds may present several properties that complicate their therapeutic use: The first of these points are well-known limitations of some natural compounds, and delivery systems are capable to stabilize active formulations, increase absorption and, therefore, favor their oral bioavailability (Kullberg et al, 2019;Lagoa et al, 2020a;Nasery et al, 2020;Peng et al, 2018).…”

“…Liposomal systems are one of the most successful reaching the clinics, including anticancer products with doxorubicin (Doxil®), vincristine and the irinotecan camptothecin (Bobo et al, 2016;Lagoa et al, 2020a;Tiwari et al, 2012). Liposomal and phytosomal formulations of curcumin have also been trialed in cancer patients, while those of resveratrol and several other potential drugs are being studied in animal models (Kullberg et al, 2019;Lagoa et al, 2020a). Liposomes encapsulating amphotericin B with reduced side effects and morphine with prolonged release were approved for fungal infections and analgesia, respectively (Bobo et al, 2016;Tiwari et al, 2012).…”