Active Targeted Nanoparticles
Subjects: Oncology

PARP inhibitors were introduced as tools to protect from inflammatory diseases. Later, these selective inhibitors were evaluated as nanotherapeutic agents in clinical trials as targeted treatment strategies against solid tumors derived from ovarian, prostate, breast, colorectal, and uterine tissues. Although previous reports have established that PARP inhibitors effectively treat BRCA1-deficient cancers and increase patients’ progression-free survival (PFS), new studies have suggested that HR-deficient cells may also be vulnerable to PARP inhibition.

  • nanotechnology
  • nanomaterials
  • DNA repair
  • Poly(ADP-ribose) polymerases
  • PARP inhibitors
  • targeted treatment
  • drug resistance mechanism
  • toxicity

1. Introduction

Over the past few years, there have been tremendous efforts to develop novel new carriers for various cancer treatments [7,8,9,10,11,12,13,14,15,16]. The advent of nanotechnology and machine learning have helped to design novel alternative targeting strategies to circumvent MDR [17,18,19,20]. As an innovative field with immense potential, nanomedicine allowed biocompatible materials to be developed for various theranostic applications [1,21,22]. Having ushered in multiple established drug delivery platforms, nanostructures such as niosomes [23], liposomes [24], nanomicelles [25], polymeric micelles [26], and nanoparticles (NPs) [27,28,29,30] were broadly used in clinics to enhance the efficacy of anticancer agents for single and combinatorial treatments. Due to their specific design, structural variety, pH-sensitivity, excellent stability, biocompatibility, high drug loading, and simple elaboration, these nano-sized materials have attracted much attention as a new reversal MDR tool in cancer therapy [31,32].

Small-molecule inhibitors have revolutionized the treatment of cancer [33], and autoimmune [34], infectious [35], and metabolic [36,37] diseases. These selective inhibitors can effectively target a wide range of signaling pathways in cancerous cells, such as protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) [38], mitogen-activated protein kinase (MAPK) pathway [39], vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and their receptors (VEGFR and EGFR) [40,41], hedgehog signaling pathway [42], the activator of transcription-3 (Stat3) signaling pathway [43], phosphoinositide 3-kinase (PI3K)/Akt and the mammalian target of Rapamycin signaling network [44,45], Wnt/beta-catenin signaling [46], transforming growth factor β (TGFB) signaling [47], insulinlike growth factor I receptor signaling [48], and DNA repair pathways [49,50,51,52].

The targeting of DNA repair pathways is among the different strategies to combat MDR [53]. In this context, the Poly(ADP-ribose) polymerase (PARP) family members are known to engage in various biological and cellular processes, such as DNA repair, gene transcription, signaling cascades, regulation of the cell cycle, cell division, and intracellular antioxidant response [54,55]. PARP inhibitors account for one of the most remarkable novel strategies for targeted therapy against cancer cells [56]. These synthetic small-molecules act through synthetic lethality in cancer cells having mutations in DNA repair genes [57]. Some of the PARP inhibitors have already been approved to treat cancers with germline mutations in the BRCA1 and BRCA2 genes [58]. At the same time, druggable genomic changes are varied and include a minority of patients with a specific cancer type, limiting the examination of the efficacy of these inhibitors in clinical trials [2].

Drug resistance and unwanted side effects are two significant drawbacks to using PARP inhibitors for cancer therapy [50,56]. Therefore, new formulations containing these selective inhibitors were subsequently designed to overcome MDR. Through this review, we hope to cast light on the most innovative progress made in applying PARP inhibitors for therapeutic purposes.

2. PARP Inhibitors

There PARP family is comprised of 17 members out of which the primary nuclear PARPs are of Poly(ADP-ribose) polymerase-1 (PARP-1), Poly(ADP-ribose) polymerase-2 (PARP-2) , Poly(ADP-ribose) polymerase-3 (PARP-3), PARP-5a, PARP5b, and tankyrase 1 and 2 [54]. The small-molecules including olaparib (AZD-2281, TOPARP-A), veliparib (ABT-888), talazoparib (BMN-673), rucaparib (AG014699, PF-01367338, CO338), niraparib (MK4827), BMN 763, AZD2461 (NCT01247168), E7016 (NCT01127178), INO-1001 (NCT00272415), EP9722 (NCT00920595) are potent submicromolar competitive nicotinamide adenine dinucleotide (NAD+) inhibitors of PARP-1 and PARP-2 enzymes [59,60]. Inhibition of PARP enzymes blocks PARylation reaction, through which ADP-ribose residues transfer to target substrates via ADP-ribosyl transferase using NAD+ [61]. It has been established that PARP trapping is responsible for the anticancer potency of PARP inhibitors [62]. Among all the PARP inhibitors in clinical development, talazoparib is the most potent PARP inhibitor, whereas veliparib demonstrated the lowest PARP trapping potency [60]. With less inhibitory effect than against PARP-1 and PARP-2, olaparib and rucaparib can also inhibit PARP-3 in BRCA-mutated advanced cancers [61].

Endogenous and exogenous DNA damaging agents cause cellular stresses that result in DNA damage [63]. These damages pose a threat to the genome and are routinely repaired by different mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), ataxia-telangiectasia mutated/ataxia-telangiectasia, and Rad3-related (ATM/ATR)-mediated DNA damage response, nonhomologous end-joining repair (NHEJ) and more importantly, homologous recombination (HR) pathways [64,65]. On the other hand, PARP enzymes contribute to these mechanisms by acting as proteins that share enzymatic and scaffolding activities and have broad roles in overall DNA repair mechanisms [54].

PARP1 consists of three domains that are involved in auto-modification, PARylation (catalysis) and DNA-binding. In case of single-strand break (SSB) or double-strand break (DSB) in DNA, PARP1 recruits to the damaged site and forms branched poly (ADP-ribose) (PAR) chains. Other PARPs, including PARP2, PARP5a, and PARP5b, create long branching PAR chains of up to 200 units in length [66]. The formed chain would protect DNA from nuclease enzymes and facilitates the recruitment of DNA repair proteins involved in BER, HR, and NHEJ pathways [54,67]. Later, the poly (ADP-ribose) glycohydrolase (PARG) enzyme effectively hydrolyses poly ADP-ribose units [68]. PARP inhibitors entrap PARP enzymes and destabilize replication forks at the damaged site of DNA [69]. This results in inducing apoptotic cell death via replication-stress mitotic catastrophe, and therefore suppresses tumor growth via suppressing the DNA damage repair pathway [70,71]. In addition to PARP inhibitors, PARG inhibitors can exacerbate replication deficiencies and be considered promising therapeutic modalities against cancer types with genomic instability [69]. 

NPs serve as a unique platform of drug delivery and therefore they have been extensively investigated for their potential use in anticancer drug delivery. NPs can be fabricated in a variety of ways to increase the drug encapsulation capacity at the inner core, and they can be also equipped with multiple functions on the outer core to improve the drug activity in the target environment [72]. Besides, they have the potential to deliver poorly water-soluble drugs and provide a sustained releasing profile to prolong the blood circulation time. Thus, NPs offer far superior pharmacokinetics compared to small molecule drugs [73]. Many promising drugs fail to pass clinical trials due to their short half-life and high toxicity in vivo. Besides, orally administered drugs undergo extensive degradation in the liver resulting in decreased optimum concentration of the drugs before reaching the target site. However, if the drugs could be loaded in specially designed NPs for delivery, the drugs would circulate for longer times in the blood, enabling sustained interaction with the tumor and leading to increased tumor accumulation. NPs also serve as a sheath that would shield the body from off-target toxicities of drugs, alter the cellular uptake of the drugs and lessen the probability of the emergence of drug resistance. At present, many NPs are being studied in clinical trials for a wide variety of medical treatments, and a few of them have been clinically approved for chemotherapies [74]. For example, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and off-target toxicities [75]. On the other hand, due to complementary activity of PARP inhibitors, the use of them during radiotherapy (RT) has yielded promising results. Unfortunately, this approach is often hindered by toxicity and poor in vivo stability of the PARP inhibitors [76]. Additionally, the preclinical PARP inhibitors are limited by their rapid washout kinetics and consequently modest pharmacological performances [77]. In several cases, these could be improved by loading the PARP into nanoparticulates, improving blood half-life, in vivo uptake and overall pharmacodynamics [77,78]. For instance, olaparib has advanced the treatment of ovarian cancer by providing patients with an effective and molecularly targeted maintenance therapy. However, olaparib must undergo first-pass metabolism. A nanoparticle delivery system has the advantage of administering olaparib directly into the peritoneal cavity for local treatment [79].

3. Nanoformulations for Delivery of PARP Inhibitors to Cancer Cells

Radiotherapy has been investigated for many years for the treatment of cancer. Recently, PARP inhibitors have been used in combination with radiotherapy to enhance DNA damage in the tumor cells. Lipid formulation was developed using olaparib (NanoOlaparib) to measure their efficacy in the prostate cancer cell lines. The activity of the NanoOlaparib was investigated along with the focused beam of X-ray radiation in the Pten/Trp53-deficient mouse model. The therapy elevated the DNA damage in the radiation-resistant cells. After 13 weeks of therapy with NanoOlaparib and radiation, the mice’s survival was prolonged. Additionally, the NanoOlaparib accumulated in the cancer cells up to 19 folds. Altogether, NanoOlaparib was found to be the optimistic delivery vehicle for improving the radiosensitivity in prostate cancer [100]. Nanoformulation containing olaparib (NanoOlaparib) and the nanoformulation with olaparib along with platinum conjugation (NnaoOlaparibPt) were formulated and the activity was demonstrated against the ovarian cancer cell line. The nanoformulations improved the pharmacokinetic and bioavailability profile. The cytotoxicity as studied on the ovarian cancer cell line revealed that nanoformulations were able to suppress cell proliferation. NanoOlaparib improved the therapeutic activity by reducing tumor proliferation. An elevated response was shown by using NanoOlaparib and NanoOlaparibPt on the MDR cell line SKOV-3. Additionally, the use of olaparib and cisplatin in the nanoformulation was developed and found to significantly affect cancer cell death [98].

Plectin is a protein that is mislocalized on the surface of ovarian cancer cells. Hence, it can be considered as a therapeutic target for active drug delivery in cancer. A study demonstrated this idea by developing the plectin-targeted peptide anchored to the NPs and loaded with an AZ7379 PARP inhibitor. The plectin-targeted peptide conjugated liposomes significantly decreased cell proliferation in the mice bearing OVCAR8 (epithelial ovarian cancer). The findings affirmed the advantage of nanotechnology and active targeting in improving cancer therapeutics [105].

Nanomaterials comprised of polymers have high stability, biodegradation, and biocompatibility. The composition of the NPs can modulate the drug release and enhance the targeting of the cancer cells.

Another novel molecule, fluorescent PARP inhibitor (PARPi-FL), a fluorescently labeled sensor of olaparib was studied to target the cancer cells. Nanoformulation was developed, which encapsulated the PARPi-FL. The encapsulation not only improved the delivery of the agent to the cancer cells but also helped in the imaging [124]. The nanoemulsion was stabilized with lipids and cholesterol. The nanoemulsion improved permeation followed by subsequent uptake by the PARP1-expressing small cell lung cancer (SCLC). The PARPi-FL nanoemulsion was tested in the xenograft mouse models of SCLC and exhibited good circulation. This nanoemulsion presented good imaging and targeting possibilities [77].

4. Conclusions and Outlook

PARP inhibition has opened windows of opportunity to treat many diseases, specifically solid tumors. Yet, drug resistance and unwanted side effects are two significant drawbacks to using them for therapeutic purposes. These selective inhibitors have been widely explored by formulating nanomedicine to reduce off-site toxicity or drug resistance. The NPs loaded with PARP inhibitors have shown significant improvement in cancer therapeutics. In addition, PARP inhibitors can be explored as diagnostic therapy along with targeted delivery in cancers. There is still a gap between the laboratory findings and clinical translation of these developed nanoformulations. Further investigations on the tumor microenvironment and MDR mechanisms are needed to minimize or eliminate the limitations of using these inhibitors. An extensive effort needs to be put into exploring nanoformulations in terms of their safety, non-specific accumulation, tissue targeting, and efficacy.

This entry is adapted from 10.3390/ijms221910319

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