Nanotechnology and herbal products: Advances and perspectives in the treatment of diabetes and some of its complications

INTRODUCTION

Diabetes mellitus, or diabetes, is a chronic metabolic syndrome that has as its primary sign plasma glucose levels above those considered normal and is directly related to problems in the production or functioning of the hormone insulin (Centers for Disease Control and Prevention (CDC), 2020; National Institute of Diabetes and Digestive and Kidney Diseases, 2018; Nelson and Cox, 2008; Powers and D’Alessio, 2012). The lack of adequate control of the disease can trigger complications of various types at the cardiovascular, ocular, renal, neurological, and other levels, in addition to the possibility of exacerbating comorbidities that, in the worst case, could lead to the death of the patient (International Diabetes Federation (IDF), 2019). By 2021, it was estimated that around the world, 573 million adults between 20 and 79 years of age had diabetes, which corresponds to approximately 10% of the population in this age range and was the cause of death of 6.7 million people during that same year (International Diabetes Federation, 2021). Due to the high prevalence of the disease and the costs associated with its treatment, there is a gap in access to therapies, especially in developing countries and those with the greatest social inequality (International Diabetes Federation, 2021; International Diabetes Federation (IDF), 2019, 2011). For this reason, it is important to seek therapeutic alternatives that facilitate access for all people suffering from the onslaught of this disease.

One of the possible alternatives for the treatment of diabetes is the use of phytotherapeutics. It is possible to find evidence of the employ of various plant species with high potential as adjuvants in the management of the disease (Arulselvan et al., 2014; Choudhury et al., 2018; Furman et al., 2019; Governa et al., 2018; Saadeldeen et al., 2020; Xu et al., 2018). Application of plant species in therapeutics, the obtaining and application of herbal extracts represent an area of special importance due to the possibility of selectively separating the compounds responsible for the biological activity of the herbal material without going to their strict purification, which would imply higher costs; in this way, a product of easy access for patients and health systems would be obtained (Camel, 2014; Harbourne et al., 2013; Hussain et al., 2019; World Health Organization (WHO), 2013).

When working with an herbal extract as an active ingredient, one relevant challenge is nature as a multicomponent system and its variable composition, such as low bioavailability, physicochemical instability, low water solubility, and potential toxicity (Capasso et al., 2000; Falzon and Balabanova, 2017; Ramzan and Li, 2015). To overcome these challenges, nanotechnology becomes a promising alternative that looks forward to the optimization of the herbal extracts’ effect thanks to its nanometric size and versatility, which favors the vectorization of the system to the site of action (Hu et al., 2015; Xiao et al., 2017). Thus, it is possible to improve its effectiveness, consequently leading to a positive impact on safety, reducing toxicity, side effects, and adverse events (Gunasekaran et al., 2014; McClements, 2020; Mosaddik et al., 2018; Muller and Keck, 2004; Paroha et al., 2020; Xiao et al., 2017). In addition, this kind of system can be designed to be used in different routes of administration, facilitating and favoring the delivery of multicomponent systems (Musicanti and Gasco, 2016).

Nanotechnology-based systems contribute in large numbers to contemporary applications in nanomedicine. The available information is extensive, making it difficult to recognize the latest advances in this field, specifically related to herbal products. This topic is broad due to the different species with the potential to be employed in diabetes and applying such technologies. Thus, understanding the current state of the art regarding these topics, recognizing what has been studied and, therefore, what perspectives to contribute to these advances, becomes a challenge for all who work in this field of knowledge. The influence of nanotechnological applications in diabetes treatment has already been reviewed by other authors (Marella and Tollamadugu, 2018; Paul et al., 2021; Zolkepli et al., 2022); however, their analysis is focused on the description of existing systems and their potential as therapeutic agents.

This article seeks to contribute to the understanding of state of the art regarding the application of nanotechnology in systems for the delivery of substances of plant origin as extracts or specific compounds, with potential application in the treatment of diabetes and some of its complications, as well as the influence of some of the variables involved in its procurement and development, from a pharmaceutical technology point of view.

METHODOLOGY

A systematic search was performed in the referral databases Scopus, PubMed, and Web of Science and the databases Science Direct, Springer Link, SAGE, Scielo, Wiley, and Taylor & Francis, until July 2022, using a search equation that included the terms “nanotechnology”, “herbal extracts” and “diabetes”. For each term of interest, the equations in Table 1 were applied.

The search was limited to research articles in Spanish and English. From this first filter, 4,922 articles were obtained, which were pre-selected by title, eliminating those results that did not refer to nanotechnology-based systems and those related to nanosystems made from inorganic materials. Subsequently, the selected articles were reviewed in the abstract, classifying them by type of herbal ingredient, type of nanosystem, therapeutic application, materials used, and tests performed, among other characteristics, which led to a final selection. In this way, those articles related to the study of nanosystems with herbal extracts or their derivatives, with application in the treatment of diabetes and some of its complications, were taken as working articles, thus obtaining a total of 86 articles. Finally, an exhaustive review was made of the selected articles based on the inclusion criteria, from which it was possible to extract the key information for comparisons by constructing a database that facilitated the centralization of information for the corresponding analysis.

Table 1. General search equation employed to obtain information about the topic of interest from several databases. [Click here to view]

RESULTS AND DISCUSSION

Herbal extracts and compounds of natural origin with nanotechnological applications in the treatment of diabetes and some complications

Figure 1. Percentage of contribution to the total number of articles selected for final review by consulted database. [Click here to view]

Figure 2. Chronologic evolution of nanotechnology applied for herbal products with diabetes application based on the number of articles published per year since 2009. [Click here to view]

In this review, it was possible to observe that the plant parts most used to obtain extracts or compounds of therapeutic interest in this field correspond to leaves, followed by seeds and fruits, which come mainly from the plant families Zingiberaceae, Asphodelaceae, Myrtaceae, Lamiaceae, and Ranunculaceae (Fig. 3). The use of extracts occurs in only 36% of the cases studied, with purified compounds of natural origin representing most of the substances used in nanotechnology-based systems for the treatment of diabetes (84%); these data are illustrated in Table 2 (Bonifácio et al., 2014; Kesarwani and Gupta, 2013). Although this trend may be due to the technological disadvantages of working with a multicomponent system as opposed to a purified compound, working with extracts may represent an alternative of great interest due to the ease of obtaining the product required as an active ingredient, which may even have an impact on the accessibility of these substances and the reduction of production costs, doing work with herbal extracts a topic of interest for further research into nanotechnology applications.

Figure 3. Principal botanic families studied to extract natural products with applications in nanotechnology and diabetes. [Click here to view]

To obtain the extracts with this therapeutic interest, it is evident that, maceration and Soxhlet techniques predominate over other technologies in the studies analyzed. Both are characterized by being simple and affordable and do not use much equipment and materials for their execution. In these techniques, the constant contact with the extraction solvent and the plant material allows for various compounds to be obtained without affecting their stability. The advantage of maceration over Soxhlet is the extraction of thermolabile substances due to the possibility of controlling the temperature of the technique (Kuete, 2017).

The Zingiberaceae family offers the highest proportion of substances studied for the above-mentioned purposes, mainly because turmeric is obtained from species belonging to this family, which is the most researched substance of natural origin for diabetes applications. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a polyphenol responsible for its characteristic coloration, is predominant in this spice extracted from the turmeric rhizome, possibly due to the number of conjugated bonds at the structural level, which in turn gives it an advantage when analyzing encapsulation in nanotechnology-based systems. This compound has been attributed to anti-inflammatory, antimicrobial, antioxidant, anticancer, and useful properties in treating liver disease and even metabolic diseases such as diabetes. However, curcumin has a low bioavailability due to its low solubility in water, being classified as class II according to the biopharmaceutical classification system, which affects its potential to be used in the treatment of liver disease and even in metabolic diseases such as diabetes (Hu et al., 2015), affecting the potential of its therapeutic action (Hewlings and Kalman, 2017), and makes it a model of interest for studies to improve these characteristics.

As shown in Figure 3, compounds from the Asteraceae and Lamiaceae families have also been studied importantly, with silymarin and rosmarinic acid being substances from these families, respectively, of therapeutic interest in diabetes. Silymarin is a complex compound consisting of silybin A, B, isosilybin A, and other flavonolignans. It is recognized for its potential uses as a hepatoprotective, anticancer, immunomodulator, and as renal, pancreatic, and neurological protector (Karimi et al., 2011). Regarding its application in diabetes, its use has been associated with treating complications such as retinopathy, neuropathy, and nephropathy. This is associated with different mechanisms; on the one hand, it reverses metabolic damage and improves the activity of mitochondrial respiration and, in turn, reduces the hydrolysis of glucose-6-phosphate, i.e., there is inhibition of gluconeogenesis and glycogenolysis (Stolf et al., 2017). Rosmarinic acid is also known for its antiviral activity and hepatic, pancreatic, and neurological protection (Guan et al., 2022).

Table 2. Extracts and natural compounds included in nanosystems in diabetes treatment and their complications. [Click here to view]

Polymeric nanoparticles and SLN

Nanoparticles are colloidal solid particles mainly characterized by their size. According to their structure, they can generally be classified as nanospheres and nanocapsules (Desai and Madjar, 2008). These types of systems present technological advantages in the delivery of bioactive substances by improving their stability and serving as modified release systems (Patra et al., 2018). Another relevant advantage is the nanometric size, which ensures better penetration of biological barriers depending on the selected route of administration and affects the direction conferred to the system, improving the selectivity for therapeutic targets (Desai and Madjar, 2008).

Polymeric nanoparticles are characterized by using polymers as the forming material for delivery systems, with or without stabilizing agents, bearing in mind that they should always be biocompatible (Sharma, 2019).

Obtaining nanoparticles using polymers is based on the self-assembly of micelles formed by the polymers, from the presence of hydrophilic portions and lipophilic portions in their structure, as well as by the formation of a polymeric matrix, which can lead to the formation of nanocapsules or nanospheres (Fattal and Vaulthier, 2007; Kumari et al., 2010; Nasir et al., 2015; Thassu et al., 2007).

Lipid solid nanoparticles are systems characterized by the presence of biocompatible and biodegradable lipids in their structure, which are solid at room and body temperature (Musicanti and Gasco, 2016). Due to the nature of their structural components, these types of systems are widely used for the delivery of compounds of lipophilic nature, helping to overcome some of the limitations of natural extracts. Due to the characteristics of the materials used, it is considered that they have almost zero toxicity levels and present greater affinity with biological barriers; additionally, they are easy to produce on a large scale (Doktorovová et al., 2016). Among the main limitations of this type of system are the low loading capacity and possible instabilities during storage, which have been improved by using other types of agents during their formulation (Musicanti and Gasco, 2016).

Nanoparticles applied to herbal antidiabetic formulations are narrowly related to the enhancement of stability of the active substance and administration route. Conversely, the use of nanoparticles is suitable and safe for almost any route of administration due to their size (Chenthamara et al., 2019). Most of the analyzed systems are proposed for the oral route due to the administration benefits in chronic therapeutic. As Table 2 describes, many of the pharmacologic markers studied for diabetes treatment are phenolic compounds. Those substances are characterized by differential chemical and physical stability (Osorio-Tobón, 2020), requiring formulations that protect the active ingredient and ensure their delivery to the expected site. The inclusion of those substances in nanoparticles has shown an important enhancement of stability and vectorization of therapies, allowing the reduction of dose, avoiding possible secondary effects, and controlling delivery.

Influence of obtention variables in nanoparticles properties

Polymeric nanoparticles and SLN have common study characteristics due to their physical state and similar obtention processes. One example is that, for both types of nanoparticles, the most used preparation method corresponds to solvent emulsion-evaporation (Table 3) (Fattal and Vaulthier, 2007; Mora-Huertas et al., 2010). The preference for this method may be due to its versatility and the low influence of other types of factors in addition to those involved in the formation of emulsions, which decrease the possible interactions between the components of the extracts and the materials of the formulation. According to the data observed, it can be inferred that the particle sizes expected after loading with herbal substances for this method are generally greater than 100 nm.

Another outstanding method in elaborating this type of nanosystem corresponds to nanoprecipitation, related to solvent displacement. This consists of the physicochemical application of solvent/non-solvent precipitation, two terms related to structural component solubility (Iván Martínez-Muñoz and Elizabeth Mora-Huertas, 2022). The systems obtained by this technique mostly present particle sizes larger than 200 nm.

In these two types of systems, the particle size behavior would be expected to be consistent with that analyzed by Manne et al. (2020), who established that the amount of substance loaded during the obtention process and the particle size have a directly proportional relationship. Although there is not enough data to corroborate this information for the systems analyzed, Figure 4 relates the encapsulation efficiency with the particle size of each system, inferring that these parameters do not have a specific relationship and suggesting that, above all, the encapsulation efficiency may depend on factors other than particle sizes, such as the materials and the production method.

The size of the nanosystem is also related to the technique employed, as observed in Figure 5; however, the use of an extract or a pure compound of natural origin as loading substances in these nanosystems presents great influence, as observed in the case of SLNs (Table 3). The largest sizes (defined as greater than 200 nm) were evident in those systems that used a pure compound isolated from a vegetative source. This could be related to its loading capacity, favored in turn by the type of intermolecular interactions between the active substance and the structural materials of the nanoparticle, which would facilitate its inclusion regarding what would be a multicomponent system, such as extracts, in which each of the substances involved in the encapsulation must have some type of interaction, and may differ according to their nature, and which for this reason may hinder this process. Figure 6 shows the main materials used to develop nanosystems, in which chitosan predominates. This finding is consistent with the search for interactions with the material to be encapsulated since chitosan has characteristics that can be modified by external factors such as pH, degree of acetylation, temperature, and polymer crystallinity. Likewise, its chemical structure allows modifications to obtain polymers with different properties and behaviors, thus improving the affinity to encapsulate the material (Aranaz et al., 2021). Additionally, the nanosystems prepared with the assistance of ultrasound are the ones that presented smaller sizes compared to those obtained with other technologies, proposing this agitation technique as an optimal mechanism for the control of particle size and polydispersity.

Materials and their influence on diabetes treatment

As for polymeric nanoparticles, the most used natural polymers are cellulose, gelatin, pullulan, chitosan, alginates, and gliadin (Abasian et al., 2020; Chakravarthi et al., 2007; George et al., 2019). One of the main difficulties in working with these materials is achieving reproducibility due to variations in their chemical composition and the possibility of causing the immunogenic response, so synthetic polymer applications tend to become more attractive every day. The versatility of these synthetic polymers allows them to be designed according to the desired characteristics of the system, being able to control their dissolution behavior, permeability, degradation, and even conferring targeting characteristics according to the site of action to be achieved (Chakravarthi et al., 2007). Some examples of synthetic polymers used to obtain nanoparticles are polylactide (PLA), poly(lactide-co-glycolide) (PLGA), polyanhydrides, poly-ε-caprolactone, and polyphosphazene (Abasian et al., 2020; Asem and Malmström, 2018; Chakravarthi et al., 2007; Kumari et al., 2010; Torchilin, 2001). In addition, most of those materials do not interfere with diabetes treatment, considering their biodistribution and metabolization post-administration, and the reason why they are potential alternatives for use in formulations oriented to this pathology. PLA, polycaprolactone (PCL), and poly vinyl alcohol (PVA) are commonly hydrolyzed by some enzymes, and their degradation products enter the Krebs cycle to be transformed finally in CO₂ and water (Su et al., 2019). Despite the main metabolic products of chitosan, the most studied polymer for the topic of interest is carbohydrates such as glucosamines; they have been associated with a lower risk of incident diabetes (Ma et al., 2020).

Table 3. Herbal materials loaded nanosystems applied to diabetes and some complications PCL, PLA, PVA, PLGA. [Click here to view]

For SLN, it is evident that the materials used are not unique and that, on the contrary, the spectrum of these is quite broad. Among these, there are different fatty acids and their corresponding salts, such as stearates and palmitates, which meet the primary characteristic of being solid at room temperature. Likewise, the systems are usually not composed of a single material but by the union of several materials with lipidic characteristics, some of them liquid at room temperature, which could correspond to the formation of nanostructured lipid carriers (NLC), which confers better encapsulation and stability characteristics (Chauhan et al., 2020). However, diabetic dyslipidemia is highly prevalent in patients with diabetes (International Diabetes Federation, 2021), and the use of lipids as materials for formulations that are focused on the treatment of this metabolic disorder could interfere with adequate disease management due to the changes in levels of those indicators, also for alterations in lipid metabolism (Athyros et al., 2018).

Models for the evaluation of therapeutic activity to treat diabetes

The activity evaluation models correspond to both in vitro and in vivo assays. The most outstanding in vitro assays for the systems studied were focused on the study of the antioxidant capacity of the material of natural origin present in the corresponding nanosystem, highlighting the application of the α-α-diphenyl-β- picrylhydrazyl “DPPH”, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS) and oxygen radical antioxidant capacity (ORAC) assays. These types of studies allow us to demonstrate the effectiveness of the antidiabetic activity evaluated since there is a close relationship between oxidative processes and diabetes, such as metabolic syndrome. Oxidative stress triggers the loss of homeostasis between antioxidant systems and reactive oxygen species (ROS). This imbalance is not only one of the pathophysiological mechanisms of diabetes but is also responsible for the complications related to the disease. ROS are highly reactive compounds and can react with other macromolecules such as lipids, proteins, or DNA, leading to alterations at the cellular level. Studies also show that in type 2 diabetes mellitus, enzymes with antioxidant activity can be altered or reduced. An example of the impact of this imbalance is major depressive disorder (Burgos-Morón et al., 2019; Réus et al., 2019).

A general resume of different assays employed in the articles reviewed is available in Table 4. The most frequent method employed, in in vitro studies, is the (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide) (MTT) assay to evaluate cytotoxicity. Although this study is important for subsequent investigations due to exists a correlation between the application potential, toxicity, and the desired effect, of course, it is not exactly an assay to evaluate the antidiabetic activity. For this reason, it is necessary to employ other tests that allow complement information regarding diabetes as a model of disease, where the in vivo studies are the best alternative. For instance, studies by Sonaje et al. (2007). indicated that PGLA and PCL nanoparticles improved oral absorption and activity, using rats. Furthermore, studies that use animal models show the influence of the nanoencapsulation process over characteristics like pharmacokinetics or bioavailability. Chellampillai and Pawar (2011) found the enhancement on oral bioavailability of andrographolide when this is included in Eudragit^® EPO nanoparticles, which was associated with changes in almost all pharmacokinetics parameters evaluated. These results support that this is a promising approach to follow-up pharmacokinetics parameters in evaluating new herbal nanosystems for diabetes treatment.

Figure 4. Relationship between size particle and entrapment efficiency. Chitosan polymeric nanoparticle with Syzygium cumini extract, 2. Chitosan polymeric nanoparticle with Homalomena pineodora extract (PM-CNPs-1: 5% extract)72 3. SLN with Silybum marianum L. extract NLCs-SLM 0.29%-CP (cetyl palmitate), 4. SLN with Silybum marianum L. extract Fluorescent NLCs (FITC-NLCs-CP) 73 5. Polymeric nanoparticle with gentiopicroside formulation 5 (F5): 5% w/v PLGA, 0.4% W/V PVA, GPS: 60 mg, Organic/Aqueous phase volume ratio 1:574 6. PLA Polymeric nanoparticles with Tinospora cardifolia system obtained (1% w/v TG, 0.1% w/v Triton X-100, and 2% AlCl3 using magnetic stirrer for homogenization),75 7. SLNs with ethanolic extract of Ficus religiosa L. 76 PLGA polymeric nanoparticles with pelargonidin encapsulated77, 9. Eudragit RS100 polymeric nanoparticle with Phoenix dactylifera L. extract78, 10. SLN with berberine79, 11. Chitosan polymeric nanoparticle with Pterocarpus marsupium extract80, 12. Chitosan polymeric nanoparticle with Physalis alkekengi extract81. [Click here to view]

Figure 5. Size particle obtained according to obtention technique. [Click here to view]

Figure 6. Main materials employed in nanosystems production. [Click here to view]

Table 4. Biological assays employed in nanotechnology systems. [Click here to view]

On the other hand, in vivo studies were mostly developed in Wistar rats in which diabetes was induced by chemical methods using streptozotocin (STZ) (Furman, 2021) or intraperitoneal alloxan. The use of zebrafish as an animal model was also found (Hayati et al., 2018). In most studies that include in vivo assays, it was possible to observe that changes in doses and pharmaceutical forms are allowed. Another important parameter is the number of groups included in the studies, which on average is six, corresponding to positive and negative controls, and the evaluation of raw extract compared with nanoparticle formulations at different doses to evaluate the effectiveness (Djamil et al., 2020). The wide variety of substances used as positive controls found between studies led to the proposal to standardize this parameter to grant comparison among prospective antidiabetic research.

CONCLUSION

The nanotechnology approach to formulating herbal systems for diabetes treatment is a current topic of study, proven by the growing number of publications about it during the last few years. There is a considerable variety of herbal materials studied with some nanotechnological application oriented to the treatment of diabetes and some of its complications, being the Zingiberaceae, Asphodelaceae, Myrtaceae, Lamiaceae, and Ranunculaceae the most representative botanic families included in these researches, using extracts or purified compounds obtained from some of those species, especially with the content of polyphenols, but not limited to those metabolites, despite the information regarding their effectiveness and mechanism of action not being described thoroughly, proposing a potential area of study. The approach to nanotechnological systems seeks to improve the stability of the compounds to be encapsulated and provide special characteristics that facilitate the administration of the formulation and the modification of some of its properties, like biopharmaceutical and pharmacokinetic parameters. Among the most widely studied systems with these applications are polymeric nanoparticles, SLN, and nanofibers, which in turn, show a wide spectrum of materials and techniques used to produce them, which responds to the great variety of substances found in nature with some biological activity useful in diabetes treatment, but found that the selection of materials could be a critical parameter, especially if they are part of some of the disease markers (as the lipids are) or their biodegradation could affect diabetes treatment due to produced metabolites. Between those systems, it is important to observe that techniques like emulsification-evaporation and nanoprecipitation are the most used to obtain them, reaching encapsulation efficiencies of about 89%. Similarly, other types of systems have been studied that can be adjusted to the specific needs of the route of administration or the therapeutic target, demonstrating that it is possible to use other types of technologies in the formulation of products of plant origin and broadening the scope of this kind of technologies. It is evident that the formulation challenges are persistent, such as the inclusion of substances of different natures in the same nanosystem, the improvement of encapsulation efficiencies, and even guaranteeing a synchronized release of the substances, among others, and that the development of new materials and systems plays an important role in the conception of novel, safe and effective phytotherapeutics, which also overcome the difficulties of working with this type of substances. Furthermore, there is evident difficulty in comparing the effectiveness between different systems due to the absence of standardized methods that allow the identification of the differences in terms of activity, despite the fact that most studies show an enhancement in some related characteristics and propose nanotechnological systems as a promising alternative to formulating phytotherapeutics to diabetes treatment.

ACKNOWLEDGMENTS

The authors acknowledge the funding of the Ministry of Science, Technology, and Innovation of the Republic of Colombia (Minciencias), through contract 187–2019, Project: Comparative evaluation of Physalis peruviana fruit extracts with antidiabetic activity, alone and included in nanostructured systems, with potential application in the development of phytotherapeutic products.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest related to the publication of this article.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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