https://doi.org/10.62909/pcjmhs.2025.002 Pioneer College Journal for Medical and Health Sciences (PCJMHS)

Review

Nano-Formulating of Organic Shields for Hepatic Carcinoma

Therapy

Shahrazad Ahmed khalaf 1,

1 Department of Forensic sciences, College of Science, University of Diyala, Ba’quhba, Diyala, Iraq; Shahraza-

dah.kh@uodiyala.edu.iq

Abstract: Oxidative stress is a crucial element in the pathogenic mechanisms that initiate numerous

chronic liver illnesses and substantially aids in the progression of hepatocarcinogenesis. Natural

antioxidants mitigate oxidative stress by neutralizing free radicals and are essential in the manage-

ment of free-radical-induced hepatic disorders. Nonetheless, their effectiveness is often limited by

inadequate bioavailability and metabolic stability. Recent advancements have concentrated on cre-

ating nano-drug delivery methods that safeguard against degradation and augment therapeutic ef-

ficacy to overcome these constraints. Among the many significant advantages, they demonstrated

the capacity to enhance bioavailability and facilitate targeted distribution, thereby minimizing off-

target effects by precisely directing the antioxidant to the hepatic tumor location. Furthermore, these

nanosystems facilitated sustained release, extending the therapeutic impact over time. Several of

them shown synergistic effects when used in conjunction with other therapeutic drugs, resulting in

enhanced overall effectiveness. This study is to examine current scientific advancements in nano-

formulations using natural antioxidant compounds, emphasizing their potential as viable therapeu-

tic strategies for liver cancer therapy. This review's originality is rooted on its thorough examination

of recent advancements in nano-formulations of natural antioxidants for liver cancer therapy.

Keywords: hepatic carcinoma; nanoformulations; pharmaceutical application; natural substances;

hepatocellular carcinoma; oxidative stress; antioxidants

MSC:

1. Introduction

One of the most aggressive and constantly rising types of cancer worldwide, liver

cancer poses a serious danger to life [1]. It is the sixth most frequent kind of cancer, ac-

cording to recent data, and it affects more males (the fifth most common type) than

women (the ninth most common type) [2]. The liver parenchyma or other liver structures,

including the bile duct, blood vessels, and immune cells, are where primary liver cancer,

often referred to as primary hepatic cancer or primary hepatic malignancy, begins and

grows [3, 4]. On the other hand, the majority of liver cancers are secondary or metastatic,

which means they start in another body area (such the breast, colon, or lungs) and then

move to the liver. The most prevalent subtype of primary liver cancers is hepatocellular

carcinoma (HCC), which develops from hepatocytes and accounts for 80–90% of cases [5].

Intrahepatic cholangiocarcinoma (~6%), angiosarcoma and hemangiosarcoma (0.1–2.0%),

two uncommon and extremely aggressive forms of cancer that start from the endothelial

layer of blood vessels and spread quickly, and hepatoblastoma (~1%), a type of cancer

that develops in immature liver cells and mainly affects children under the age of 15 [6].

Citation: To be added by editorial

staff during production.

Academic Editor: Dr. Omoniyi Mi-

chael Popoola

Received: 4/1/2025

Revised: 2/2/2025

Accepted: 16/3/2025

Published: 20/3/2025

Submitted for possible open access

publication under the terms and

conditions of the Creative Commons

Attribution (CC BY) license

(https://creativecommons.org/license

s/by/4.0/).

PCJMHS 2025, Vol.1 9 of 13

Cirrhosis brought on by long-term viral infections (like hepatitis B and hepatitis C)

or excessive alcohol use, metabolic disorders (like nonalcoholic steatohepatitis, nonalco-

holic fatty liver diseases, obesity, and diabetes), and inherited liver diseases are risk fac-

tors that raise the incidence of primary liver cancer [7]. (such Wilson's disease and hemo-

chromatosis), aflatoxins, iron buildup [8], and certain biliary system conditions (like fasci-

oliasis, a zoonotic infectious illness brought on by parasitic worms belonging to the Fasci-

ola genus) [9].

The use of natural antioxidants has grown more and more significant in terms of both

the prevention and therapeutic treatment of liver cancer, given the mounting evidence

linking OS to the development of the disease and the liver's vital function as the body's

main organ of detoxification and homeostasis regulator [10]. With its wealth of (poly)phe-

nolic compounds, whose health benefits have been recognized since antiquity and whose

usage as medicinal herbs is a component of traditional medicine in many nations, the

plant kingdom provides the best resources in this area. Unfortunately, owing to their low

oral bioavailability, which is mostly caused by their quick first-pass metabolism and poor

solubility in water, the widespread use of these compounds as medications has not been

particularly effective up to this point. Furthermore, it is necessary to take into account

these compounds' inherent chemical instability, since they readily oxidize in light and air

[11].

A rapidly developing yet under-researched area, the employment of nanotechnology

and natural antioxidants in the treatment of liver cancer is the subject of this review. Fur-

thermore, this assessment couldn't have come at a more critical time, what with the grow-

ing worldwide prevalence of liver cancer and the pressing want for better focused, less

harmful treatments. Its originality comes from the fact that it analyzes in depth the nano-

formulations developed over the last ten years with the express purpose of increasing the

therapeutic efficacy of natural antioxidants; doing so sheds light on how these break-

throughs are starting to circumvent the shortcomings of conventional liver cancer thera-

pies.

2. Materials and Methods

2.2 Oxidation in Nano Formula: Polyphenols

Extensive research is now being conducted in the realm of oncology regarding plant-

derived polyphenols, which are well acknowledged as key OS effectors by the scientific

community. Phenolic acids, stilbenes, flavonoids, coumarins, and lignans are the main

categories into which these phytochemicals are grouped according to their chemical struc-

ture [12]. Of these, the stilbene-type aflatoxin resveratrol (RES) has garnered the most at-

tention due to its extensive plant-based distribution (e.g., grapes, berries, legumes, pea-

nuts, and different types of grasses) and, more significantly, its wide range of pharmaco-

logical activities, which encompass antioxidant, anti-inflammatory, anticarcinogenic, an-

tiplatelet, cardioprotective, immunomodulatory, hyperlipidemic, neuroprotective, and

vasorelaxant effects [13]. The trans-isomer of naturally occurring RES (3,5,4′-trihy-

droxystilbene; Figure 1) is more plentiful, stable, and therapeutically active than the cis-

isomer. Resveratrol has pharmacokinetic and physicochemical instability, much as any

polyphenol. Notwithstanding its high intestinal mucosal absorption rate (~75%), RES un-

dergoes substantial metabolism in the intestines and liver, leading to the formation of in-

ert 3-O-glucuronide and 3-O-sulfate molecules. Also, very little free RES is floating about

in the bloodstream because it binds to plasma proteins and LDLs.

PCJMHS 2025, Vol.1 10 of 13

Figure 1: (A) Respirable elastin scaffold (RES) chemical structure; (B) FA-HSA con-

jugate synthesis; (C) FA-HSA-RES-NPs shown as a result of RES encapsulation inside

FA-HSA by means of a high-pressure fluid nano-homogeneous emulsification tech-

nique; and (D) suggested mechanism of functional tumor targeting.

Using a similar high-pressure homogenization emulsification approach, the same sci-

entists had previously created a composite nano-formulation. that encapsulated RES in a

glycyrrhizic acid (GA)-HSA conjugate. Since GA accumulates on the surface of hepato-

cytes' cells and exerts its hepatoprotective and detoxifying activities toward GA receptors,

GA was used as a targeted ligand instead of FA in this instance. Recent studies or reviews

of the literature have focused on various nanoscale drug delivery devices that incorporate

GA for the treatment of HCC. In a manner similar to what was previously said, the tar-

geted ligand's free-COOH groups were used to conjugate with HSA in an alkaline envi-

ronment. The resultant GA-HSA conjugates were then loaded with RES. The GAHSA-

RES-NPs had an EE of 83.6% and DL of 11.5%, and they were around 108 nm in size,

making them virtually spherical. The nanosystem gently and steadily emitted RES. The

effect on the ability to block the growth of HepG2 cells was marginally better (1.5-fold)

when contrasted with the prior nano-formulation, namely, GA-HSA-RES-NPs → IC50 =

62.5 μg/mL vs. RES → IC50 = 95.5 μg/mL. This nano-formulation was validated by in vivo

body distribution experiments using a near-infrared fluorescence imaging approach in

mice with H22 tumors, as well as by in vitro cell uptake tests [14].

Curcumin, a secondary metabolite found in the tuberous root (rhizome) of different

species of turmeric, especially Curcuma longa L. [15], is a bright yellow-orange dia-

rylethene-structured compound that has been the subject of extensive research due to its

pharmacological importance and positive health effects. Another plant-derived polyphe-

nolic derivative, RES, has received the greatest amount of attention. In terms of pharma-

cological activity and pharmacokinetic restrictions, CUR and RES have a spectrum that is

quite similar.

Rather, by employing a high-pressure microfluidics approach, Zhao X. and col-

leagues aimed to create lipid NPs loaded with both CUR and Doxorubicin (Dox), a com-

monly used chemotherapeutic drug with limited efficacy in HCC management. This strat-

egy would take advantage of CUR's synergistic effects with Dox.

PCJMHS 2025, Vol.1 11 of 13

Figure 2 shows that rutin (RU) is a common natural form of Q. It is also known as

quercetin-3-O-rutinoside, rutoside, or sophorin, and it is simply Q with glucose and rham-

nose replaced for the hydroxy group at position C-3. Q, like other flavonoids, is best used

in nano-formulation preparations when it is in its glycoside form because it is more acces-

sible and more soluble in water than when it is in its aglycone form. Researchers devel-

oped PLGA-based NPs loaded with RU using the double emulsion-solvent evaporation

process. RU is a bioactive component.

In order to overcome these obstacles, Tang P. et al. [16] developed and manufactured

a nanodrug delivery system that incorporates HK onto a polymer backbone called chitin

(CH). This system is functionalized with a second bioactive component called epigallocat-

echin-3-gallate (EGCG; Figure 3). When it comes to the number of biopolymers found in

nature, CH is second only to cellulose. It finds its way into the exoskeleton of arthropods,

the cell walls of fungi, and the surface structures of a number of other invertebrates.

Chemically, it is a polysaccharide that contains N-acetyl-glucosamine units.

Figure 2. Chemical structure of rutin

Figure 3. Hierarchy of the gallate of epigallocat-

echin crystals.

3. Functional Nanoparticles Rapeseed Oil-Based Antioxidants

Antioxidant, anti-inflammatory, immunomodulatory, and anticancer actions are

only a few of the many pharmacological benefits enjoyed by terpenoids and other fasci-

nating classes of naturally occurring chemicals. The majority of terpenoids are produced

in chloroplasts by plants. They primarily function as a defense mechanism against heat

and oxidative stress, and they are made from the lipophilic 5-carbon unit isoprene via the

photosynthesis-dependent 2-C-methyl-D-erythritol-4-phosphate pathway. On the other

hand, terpenoids aren't only a component of secondary and primary metabolism; they

may also be produced by bacteria and yeasts. The isoprene unit, which has a C=C unsat-

uration, combines with ROS and quenches them, which is why these molecules work as

antioxidants. One way to categorize terpenoids is by the number of isoprene units they

contain. Monoterpenes have 2 units, sesquiterpenes have 3, diterpenes have 4, triterpenes

have 6, tetraterpenes have 8, and polyterpenes have more than 8. Due to their ability to

selectively kill liver cancer cells using a pleiotropic mode of action while sparing normal

cells, these phytochemicals have recently gained attention as a potentially useful class of

HCC chemopreventive and therapeutic agents [17].

Higher chemical stability and bioavailability compared to other poly(phenols) sug-

gest it may have a significant overall impact on shielding cells against damage caused by

OS [18], even if it is not as powerful as other natural antioxidants.

PCJMHS 2025, Vol.1 12 of 13

3. Obstacles and Ideas for the Future

All the big pharma firms are racing to be the first to market with nanomedicine and

natural substances. When it comes to administering bioactive compounds, nanomedi-

cine—the medical use of nanotechnology—holds tremendous promise, as it allows for the

customization of dosage, site, and formulation to achieve maximum efficacy with minimal

side effects. Various NP matrix properties, such as lipids in SLNPs, functionalizable or-

ganic polymers, or even real metals, allow for precise control over bioactive compound

solubility and release timing, as well as the development of stimuli-responsive delivery

platforms and the implementation of multiphase therapeutic treatments that involve the

gradual release of a single active ingredient or the simultaneous administration of multi-

ple active compounds with the ability to bind specific targets at different times and exert

synergistic effects. These characteristics are particularly important in cancer, where selec-

tivity of action is key, for both treatment and early detection by identifying tumor bi-

omarkers. The use of natural substances aligns well with the future of medicine, which is

focused on preventing and treating diseases through enhancing the body's defense sys-

tems and natural processes, as well as with the eco-sustainable methods of synthesizing

bioactive compounds and the green approach to resource management. There are still a

number of obstacles that need to be overcome before nano-formulations of natural anti-

oxidants can be used to their full therapeutic potential in the treatment of liver cancer.

The need for substantial clinical studies is one of the key obstacles. There is a huge

chasm between what works in the lab and what works in the clinic, even if preclinical

research has been encouraging. To determine the effectiveness, safety, and long-term con-

sequences of these nano-formulations in human patients with varying genetic variables,

liver functioning, and disease stages, clinical studies are essential. During production,

there is yet another major obstacle. Consistency, stability, and quality control from batch

to batch are especially challenging in the large-scale manufacture of nano-formulations.

Optimizing nano-formulation designs via continuous manufacturing processes allows for

reproducible control over nanoparticle size, shape, and surface properties, which in turn

improves targeted specificity and decreases the likelihood of side effects. Furthermore, it

would be fascinating to see research into the use of nano-formulated antioxidants in con-

junction with other therapeutic treatments to enhance the current standard of care for liver

cancer, such as immunotherapy, chemotherapy, and radiation. Antioxidant nano-formu-

lations show promise as a potential therapy for liver cancer, but more research is needed

to confirm this. To sum up, there are still obstacles, but there's no denying the promise of

nano-formulations of natural antioxidants in treating liver cancer. Improved outcomes for

patients with liver cancer may be possible with the help of more focused, tailored, and

effective treatments made possible by ongoing research and innovation.

Conflicts of Interest: Declare conflicts of interest or state “The authors declare no conflict of inter-

est.”

PCJMHS 2025, Vol.1 13 of 13

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