**1. Introduction**

Natural products persist as incredibly valuable sources of new bioactive molecules with pharmacotherapy utility because of the enormous structural complexity found in them. From a long period of time, plants have been used to treat a wide range of diseases such as cancer with natural sources, accounting for more than 60% of today's anti-cancer medications. Plants, animals, aquatic species, and microorganisms all contribute to drugs,

**Citation:** Mujtaba, M.A.; Alotaibi, N.M.; Alshehri, S.M.; Yusuf, M.; Anwer, M.K.; Rahman, M.A.; Parveen, A. Novel Therapeutic Approach in PEGylated Chitosan Nanoparticles of Apigenin for the Treatment of Cancer via Oral Nanomedicine. *Polymers* **2022**, *14*, 4344. https://doi.org/10.3390/ polym14204344

Academic Editor: Edina Rusen

Received: 11 September 2022 Accepted: 12 October 2022 Published: 15 October 2022

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which makes nature an appealing source of new therapeutic entities that could be used as anti-cancer agents [1].

Apigenin (APG), chemically known as 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benz opyran-4-one, is a flavone found in several vegetables and fruits, which include parsley, celery, onions, oranges, wheat sprouts, corn, rice, tea, and is abundant in chamomile [2]. It has multiple biological effects; in addition, it has potent chemoprotective and chemotherapeutic features for a variety of cancers, including lung, breast, skin, prostate, and colon cancer. The possible mechanism for the anticancer effects of APG could be its capability of inhibiting migration or invasion, endorsement of cell cycle arrest, suppression of proliferation, initiation of apoptosis, or interruption with tumor cellular signal pathways [3,4]. APG has low internal toxicity with no mutagenic properties compared to other plant flavonoids, making it an effective frontrunner for the production of successful cancer therapies [5]. APG is a Biopharmaceutics Classification System (BCS) Class II drug with an aqueous solubility of less than 2.16 g/mL [6]. Unfortunately, its poor water solubility results in poor bioavailability, which significantly limits its clinical use [7]. Therefore, investigating emerging innovations or formulations to improve APG solubility and bioavailability and to enhance antitumor efficacy is, thus, the main issue at present.

Nanoparticles (NPs) are expected to be the key focus in drug-delivery applications; however, NPs are associated with various conjugation properties due to their higher surface area, resulting in in the quickest systemic clearance. To overcome the problem of rapid systemic clearance, NP's surfaces were coated with a hydrophilic polymer-like chitosan (CS) and polyethylene glycol (PEG). CS is a USFDA-approved and popular polymer because of its low cost of production, biocompatibility, biodegradability, and positive charge. The positive charge of CS enhances interaction as well as penetration inside heterogeneous tumors [8]. CS improves drug penetration by opening epithelial tight junctions and facilitating both paracellular and transcellular drug transport [9]. PEG is also a non-toxic and non-immunogenic polymer that changes a molecule's hydrophobicity and enhances its aqueous solubility. PEGylation is a well-known method that enhances stability and decreases proteolysis and renal excretion, thereby minimizing dosing frequency and improving pharmacokinetics. Coating with PEG was intended to improve oral nanoparticle bioavailability because it is known to reduce immune system interactions and can eliminate these interactions, thus further increasing systemic half-life [10,11]. One more feature of PEG coating has been shown to reduce nanoparticle agglomeration and improves the therapeutic agent's safety and efficacy [12,13]. Therefore, the aim of the present study was to create, optimize, and characterize PEGylated chitosan nanoparticles of APG and to evaluate the optimized formulation for its anti-oxidant and anti-tumor potential.

### **2. Methods and Materials**
