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Hepatocellular carcinoma (HCC), accounting for 85% of liver cancer cases, continues to be the third leading cause of cancer-related deaths worldwide. Although various forms of chemotherapy and immunotherapy have been investigated in clinics, patients continue to suffer from high toxicity and undesirable side effects. Medicinal plants contain novel critical bioactives that can target multimodal oncogenic pathways; however, their clinical translation is often challenged due to poor aqueous solubility, low cellular uptake, and poor bioavailability. Nanoparticle-based drug delivery presents great opportunities in HCC therapy by increasing selectivity and transferring sufficient doses of bioactives to tumor areas with minimal damage to adjacent healthy cells. In fact, many phytochemicals encapsulated in FDA-approved nanocarriers have demonstrated the ability to modulate the tumor microenvironment with different molecular mechanisms. Although polymer-based and lipid-based nanocarriers usually provide great benefit for bioactives, a custom design and optimization of nanocarrier is recommended for targeting HCC.
- hepatocellular carcinoma
- liver cancer
- tumor microenvironment
- phytochemicals
- plant bioactives
- nanomedicines
- cancer drug targeting
1. Introduction
Several molecules originating from medicinal and dietary plants have been reported to be effective against different types of cancer by prohibiting the activation of oncogenic pathways at cellular levels. Molecules such as quercetin, curcumin, resveratrol, epigallocatechin-3-gallate, and many others have been studied extensively due to their high potency, minimum toxicity, and ability to overcome drug resistance [23,24]. However, the effects have been mostly limited in vitro, especially due to the poor bioavailability and low biological half-lives of the plant bioactive compounds. The body treats these molecules as xenobiotics, and they are rapidly cleared by the reticuloendothelial system (RES). The required therapeutic levels are, therefore, difficult to achieve and result in high inter- and intrasubject variability, as well as a lack of dose proportionality. Furthermore, the compounds vary in their molecular structures, resulting in differences in their physical states, solubilities, partitioning, and chemical stability. Nanotechnology-based approaches or nanomedicines can provide avenues to circumvent plant bioactive-related limitations.
2. HCC and Current Limitations of Drug Delivery Design
The liver is the largest abdominal organ, the hepatocytes are a major cell population in the liver (~85%), providing primary sites for protein synthesis, metabolism, and detoxification [28]. Other important cell-types include hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells, all of which contribute to the maintenance of liver homeostasis. In case of chronic injury to the liver, these cells commence a crosstalk, leading to production of fibrous collagen and extracellular matrix (ECM) remodeling factors. Consequently, liver diseases, such as HCC, typically initiate from underlying inflammation and cause significant changes in the liver’s extra- and intracellular pathophysiology, thus perturbing drug delivery. Low blood influx through the portal vein in HCC patients causes low nanoparticle penetration into the liver after systemic administration [29]. While the sinusoidal fenestrates are decreased, the nanoparticles must penetrate the endothelial barrier, the extracellular matrix (ECM), and the tumor stromal barriers to reach the HCC cells [30]. Understanding the biological barrier of the tumor is critical for the judicious selection of plant bioactive compounds and designing a new generation of nanomedicines for HCC therapy. Recent advancements in molecular biology techniques, including microarrays and high-throughput screening, have greatly improved our knowledge about the tumor characteristics and molecular mechanisms of HCC [31,32].
Tumor heterogeneity is another major factor that causes dynamic reprogramming of the tumor microenvironment and variable expression of therapeutic target proteins throughout the disease progression, thus leading to the development of resistance in HCC [41]. Heterogeneity may occur between the tumor nodules of the same patient (intertumor heterogeneity) and that between the different locations of the same tumor node (intratumor heterogeneity) [42]. Although the advent of cutting-edge single-cell and multi-region sequencing technologies has made the genetic landscape characterization of HCC heterogeneity possible, higher intratumor heterogeneity always decreases the success rate of precision medicine and other targeted delivery systems [43,44]. There are several receptors and proteins present all over HCC tumors and on normal liver cells which can be exploited for HCC drug targeting.
While the concepts of active and passive targeting of nanoparticles to the liver have been discussed in many works [49,54,55,56], here we sincerely focus on the specific aspects of HCC tumors. Passive targeting is based on the accumulation of nanoparticles in the tumor to attain higher local drug concentrations than in the organs. The efficacy of passive targeting typically depends on many parameters such as the physicochemical properties of the carriers, the route of administration and the EPR phenomenon. As described in the preceding section, the HCC tumor microenvironment is heterogeneous and hence influences tumor penetration, retention, and extravasation of the nanoparticles. All these variables have been explored to facilitate tumor targeting.
3. Molecular Mechanisms of Plant Bioactives
It was observed earlier that plant bioactives can inhibit cancer cells through induction of cell differentiation, stimulation of the immune system, nitrosation and nitration suppression, steroidal hormone metabolism, and prevention of DNA binding. More recent reports have explained that these compounds exert their anticancer effects through a variety of cell signaling pathways at multiple levels, such as post-translation regulations, protein synthesis, and intracellular messaging [76]. Most of the bioactives exert their anticancer effects via multiple superimposed pathways, the study of their individual activities is not always simple. Identification of major molecular targets and anticancer mechanisms of plant bioactives would enhance the possibility of translational applications in HCC therapy.
4. Current Nanoparticle-Based Delivery Systems for Plant Bioactives in HCC Therapy
Many preclinical and clinical studies long ago established the anticancer effects of plant bioactives. Polyphenols, terpenoids, alkaloids, phenolic acids, and flavonoids have all exhibited therapeutic potential against HCC cells. Despite such encouraging activities through different pathways, there exist certain biopharmaceutical constraints in the clinical translation of these effects. The diverse functional groups, molecular weights, and polarities of compounds cause wide variations in solubilities and chemical stabilities. The physicochemical properties of plant bioactive are a critical concern in the preformulation processes of phytopharmaceutical formulation. The physical structure and particle size of the bioactives are also involved in their solubility characteristics.
Considerable efforts have been devoted to the design of nanoparticle-based delivery systems since they can overcome critical problems, such as chemical instability, poor solubility, low bioavailability, and drug-resistance, that are often associated with conventional phytomedicines. Furthermore, the nanoencapsulation process increases the shelf-life of bioactives with controlled release opportunities at the target site. Multifunctional nanoparticles with tunable surface chemistry can navigate through the defective vascular structure of tumors. They exhibit great potential to achieve accurate treatment through cell-specific targeting and transporting payloads to specific organelles [158]. With the increasing number of cancer cell receptors now being identified, complimentary peptides have been attached to the nanocarrier surface to attempt to specifically deliver active compounds to target cancer cells. This strategy was mostly based on receptor-ligand-mediated endocytosis aiming to reduce systemic toxicity and decrease drug resistance [159]. With the continuous progress in the field of cancer therapy, numerous approaches with nanomedicines proposed to fight HCC have been reported including the use of lipid-based and polymer-based as nanocarriers. However, only a handful have been approved for clinical trials.
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15061611
