Effect of Oxaliplatin-Loaded Poly (d,l-Lactide-co-Glycolic Acid) (PLGA) Nanoparticles Combined with Retinoic Acid and Cholesterol on Apoptosis, Drug Resistance, and Metastasis Factors of Colorectal Cancer

Abstract

Apoptosis signaling pathways, drug resistance, and metastasis are important targets to develop new cancer treatments. We developed cholesterol-coated Poly(d,l-Lactide-co-Glycolic Acid) (PLGA) nanoparticles for effective encapsulation and delivery of retinoic acid and oxaliplatin to analyze their antitumor activity in colorectal cancer. The cell viability and proliferation of tumoral cells lines (CT-26 and SW-480) decreased when compared to control in vitro after treatment with the nanoparticles. In addition, apoptosis of CT-26 cells increased. Importantly, cytoprotection of nontumor cells was detected. Expression of pro-apoptotic proteins was upregulated, while anti-apoptotic proteins were downregulated either in vitro or in vivo. In addition, drug resistance and metastasis factors were downregulated in vivo. Human colorectal tumors that highly expressed BCL-2 and Ki-67 had a greater tendency towards death within 60 months. Our results show that loading oxaliplatin combined with retinoic acid and cholesterol in a nanoparticle formulation enables determination of optimal antitumor activity and subsequent treatment efficacy.

Functionalized Nanoparticles Targeting Tumor-Associated Macrophages as Cancer Therapy

“…Controlled drug delivery by NPs can prevent premature drug degradation, improve drug absorption and reduce side effects. Depending on the NPs’ physicochemical properties, such as size, shape, charge and surface chemistry, as well as their optical properties, NPs have been widely used in tumor diagnostics and monitoring [ 11 ], drug delivery [ 12 ], optical imaging [ 13 ], development of synthetic vaccines [ 14 ] and the manufacturing of miniature medical devices [ 15 ] ( Figure 1 ). In comparison to the bulk material, NPs possess new chemical and physical properties, can increase the biocompatibility and stability of conventional drugs and overcome problems of solubility.…”

Retinoic acid-loaded PLGA nanocarriers targeting cell cholesterol potentialize the antitumour effect of PD-L1 antibody by preventing epithelial-mesenchymal transition mediated by M2-TAM in colorectal cancer

“…This therapeutic combination was more effective than free OXA and NP loaded OXA (NP1). In our previous study, we were able to show that NP1 had optimal anti-tumour activity by reducing the drug resistance and increasing the apoptosis in the TME of CRC [57] . Together, these results show that RA-loaded, CHO-coated NPs3 alone or in combination with an anti-PD-L1 immune checkpoint blocker have a strong immunomodulatory effect by upregulating anti-tumour immune cells and, consequently, reducing EMT.…”

“…A suspension of 1 × 10 6 CT-26 cells was subcutaneously injected into the flank of male Balb/c mice to induce colorectal tumors [ 57 ]. The UFRN's Committee on the Ethics of Animal Experiments accepted the procedure (CEUA, Permit Number: 170.020/2019).…”

“…Prior administration of the anti-PD-L1 inhibitor was only given in the first treatment, with the others being administered only saline solution, NP3 (RA)-CHO or NP1 (OXA, RA)-CHO. In this line, some mice were treated with OXA, a standard chemotherapy to CRC, and with NP1 loaded with OXA+RA and coated with CHO [ 57 ]. They were used in this study as control groups to compare their effects to NP3, which contained RA but not OXA.…”

“…Results were expressed as a growth curve from the average tumour volume (mm³) calculated by the following equation according to Oliveira et al. [ 57 ]: volume = (width x length²) x 0.52.…”