Combinatorial therapeutic effect of liposomes in inhibiting prostate cancer aggressiveness and targeting cancer-associated fibroblast.

Prostate cancer has the second-highest incidence cancer and is the fifth leading cause of mortality in males. Cancer-associated fibroblasts (CAFs), the abundant stromal cells in the tumor microenvironment (TME), play vital roles in secreting soluble factors and remodeling the extracellular matrix to enhance tumor aggressiveness. This work proposes a novel combinatorial drug delivery system for modulating CAFs and eliminating prostate cancer. Two different liposomes were developed, consisting of docetaxel-loaded pH-responsive liposomes to inhibit cancer growth (pSLip/DTX) and fibroblast activation protein (FAP) antibody conjugated with resveratrol-loaded liposomes (Lip/Res/anti-FAPs) to target and normalize activated fibroblasts. The obtained liposomes were spherical and monodisperse, with a diameter of less than 200 nm. The encapsulation efficiency of DTX and Res in pSLip/DTX and Lip/Res/anti-FAPs was 40.40 ± 6.70% and 80.70 ± 3.40%, respectively. An in vitro release experiment revealed the pH-responsiveness of pSLip/DTX and sustained release of Lip/Res. In vitro cytotoxicity against prostate cancer and fibroblasts was investigated. Lip/Res/anti-FAPs demonstrated their ability to convert phenotype of prostate cancer-activated fibroblasts (Act-MRC-5) toward normal fibroblast by reducing the protein expression of α-smooth muscle actin, FAP, interleukin-6, and matrix metalloproteinase-2 expression. Taken together, Act-MRC-5 inactivated by Lip/Res/anti-FAPs, in combination with pSLip/DTX treatment, exhibited a promising outcome as drug delivery systems for inhibiting prostate cancer progression and aggressiveness. This study proposes an alternative approach for cancer treatment that could be applied as a future platform strategy for solid tumor treatment.