Combination Therapy Using Phytochemicals and PARP Inhibitors in Hybrid Nanocarriers: An Optimistic Approach for the Management of Colon Cancer

Abstract

DNA damage repair is a hallmark of any cancer growth, eventually leading to drug resistance and death. The poly ADP-ribose polymerase (PARP) enzyme is vital in repairing damaged DNA in normal and cancer cells with mutated DNA damage response (DDR) genes. Inhibitors of the PARP enzyme aid in chemotherapy, as shown by drug combinations such as Olaparib and Irinotecan in breast cancer treatment. However, the effect of Olaparib in colon cancer has not been studied extensively. Synthetic drugs have a significant limitation in cancer treatment due to drug resistance, leading to colon cancer relapse. Bioavailability of Olaparib and other PARP inhibitors is limited due to their hydrophobicity, which poses a significant challenge. These limitations and challenges can be addressed by encapsulating Olaparib in nanoparticles that could possibly increase the bioavailability of the drug at the site of action. New age nanoparticles, such as hybrid nanoparticles, provide superior quality in terms of design and circulatory time of the drug in the plasma. The side effects of Olaparib as a chemotherapeutic pave the way for exploring phytochemicals that may have similar effects. The combined impact of Olaparib and phytochemicals such as genistein, resveratrol and others in nano-encapsulated form can be explored in the treatment of colon cancer.

Keywords: Olaparib; PARP inhibitor; combination therapy; lipid hybrid nanoparticles; phytochemicals.

Figure 1

The PARP enzyme can repair DNA breaks using poly ADP ribose. However, in the presence of a PARP inhibitor like Olaparib (red), the enzyme is competitively inhibited and hence unable to repair the DNA break, resulting in cell death and eventually reducing the tumour size.

Figure 2

Mice with ATM gene mutation can be treated with a combination of Irinotecan and PARPi therapy.

Figure 3

Different phytochemicals that can inhibit the intracellular caspase-3/6 activity in colon cancer, resulting in PARP enzyme cleavage, thus acting as PARP inhibitors. The result is inability of the treated cell to repair DNA damage, resulting in apoptosis.

Figure 4

Different types of hybrid polymer–lipid nanoparticles that can carry the payload of hydrophobic drug molecules such as synthetic/phytochemical PARPi and effectively deliver the drug. In the figure, the drug molecule is shown in red, entrapped either in the polymer or in lipid. The lipid layers are shown in yellow/green as a core outer layer or in the form of a lipid bilayer. The outermost layer in most of the LPHNP is coated in lipid PEG, that is shown by a symbol with a tail. A hollow core is shown in white. In the cellular membrane functionalised nanoparticle, the grey colour represents the RBC layer.