Nanoparticle Formulations of Poly (ADP-ribose) Polymerase Inhibitors for Cancer Therapy

Abstract

A number of poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for clinical use in BRCA mutated and other cancers. However, off-target toxicity of PARP inhibitors and the emergence of drug resistance following prolonged administration of these inhibitors indicate the need for improved methods of drug delivery to the tumors. Nanomedicines based upon nanoparticle formulations of conventional small molecule drugs and inhibitors offer many advantages, such as increased solubility and bioavailability of drugs, reduced toxicity and drug resistance, and improved tissue selectivity and therapeutic efficacy. This review highlights the current trends in formulations of PARP inhibitors developed by nanotechnology approaches and provides an insight into the applications and limitations of these PARP inhibitor nanomedicines for cancer therapies.

Toxicology of Nanoparticles in Drug Delivery

“…As a result, producing ferritin nanoparticles in large quantities is challenging. Furthermore, ferritin nanoparticles’ high drug loading capacity is limited by their tiny size [ 77 ].…”

Radiation nanosensitizers in cancer therapy—From preclinical discoveries to the outcomes of early clinical trials

“…For example, twice a week administration of NanoOlaparib, a PEGylated lipid based‐NP loaded with the FDA approved PARP (poly[ADP‐ribose] polymerase) inhibitor Olaparib, has demonstrated greater tumor reduction when given along with radiation (focused beam; single dose of 10 Gy) in a prostate tumor model (using murine Pten pc−/− ; Trp53 pc−/− FKO1 cells in a nude mouse model), compared to either radiation or NanoOlaparib controls. 78 Strategies leveraging NP‐based delivery of PARP (poly[ADP‐ribose] polymerase) inhibitors in conjunction with radiotherapy have been reviewed by Singh et al 79 In addition, approaches using NP‐based delivery of siRNA targeting DNA repair proteins have also been developed. 80 , 81 For example, Kievit et al successfully knocked down Ape1 (apurinic endonuclease 1) using iron oxide NPs functionalized with PEG/chitosan/PEI (polyethyleneimine) to deliver siRNA in a genetic glioblastoma mouse model.…”

“…For Trp53 pcÀ/À FKO1 cells in a nude mouse model), compared to either radiation or NanoOlaparib controls. 78 Strategies leveraging NP-based delivery of PARP (poly[ADP-ribose] polymerase) inhibitors in conjunction with radiotherapy have been reviewed by Singh et al 79 In addition, approaches using NP-based delivery of siRNA targeting DNA repair proteins have also been developed. 80,81 For example, Kievit et al successfully knocked down Ape1 (apurinic endonuclease 1) using iron oxide NPs functionalized with PEG/chitosan/PEI (polyethyleneimine) to deliver siRNA in a genetic glioblastoma mouse model.…”

Nanoparticle-Based Therapies for Turning Cold Tumors Hot: How to Treat an Immunosuppressive Tumor Microenvironment

“…Scientists hypothesized that targeted delivery of STING agonists such as cyclic dinucleotide (CDN) could potentially activate immune-suppressed tumors, turning them from cold to hot. For this purpose, agonists ( Wilson et al, 2016 ; Cheng et al, 2018 ; Liang et al, 2020 ; Park et al, 2020 ), polymers directly inducing STING activation ( Luo et al, 2017 ; Li et al, 2021 ) or chemotherapies inducing cytosolic DNA breaks ( Eldehna et al, 2020 ) have been loaded on NPs (e.g., nanocages, liposomes, polymers, and hydrogels) designed to specifically target DCs and macrophages, demonstrating efficacy in preclinical tumor models. The use of liposome and silica NPs improved STING agonist responses, promoting a better infiltration of lymphocytes and reprogramming TAMs toward an M1 phenotype in murine tumor models ( Cheng et al, 2018 ).…”