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Oral Nano Drug Delivery Systems for the Treatment of Type 2 Diabetes Mellitus: An Available Administration Strategy for Antidiabetic Phytocompounds

Abstract In view of the worldwide serious health threat of type 2 diabetes mellitus (T2DM), natural sources of chemotherapies have been corroborated as the promising alternatives, with the excellent antidiabetic activities, bio-safety, and more cost-effective properties. However, their clinical application is somewhat limited, because of the poor solubility, instability in the gastrointestinal tract (GIT), low bioavailability, and so on. Nowadays, to develop nanoscaled systems has become a prominent strategy to improve the drug delivery of phytochemicals. In this review, we primarily summarized the intervention mechanisms of phytocompounds against T2DM and presented the recent advances in various nanosystems of antidiabetic phytocompounds. Selected nanosystems were grouped depending on their classification and structures, including polymeric NPs, lipid-based nanosystems, vesicular systems, inorganic nanocarriers, and so on. Based on this review, the state-of-the-art nanosystems for phytocompounds in T2DM treatment have been presented, suggesting the preponderance and potential of nanotechnologies.


Introduction
Diabetes mellitus, a chronic lifelong metabolic disorder, is a major global health issue that has reached alarming levels. 1 According to the latest data from the International Diabetes Federation, approximately 463 million adults worldwide are currently suffering from diabetes. Without sufficient action to control the pandemic, 578 million people will live with diabetes by 2030. By 2045, the number will jump to an astonishing 700 million. 2 T2DM is the most common type of diabetes. It has been estimated that nearly 95% of diabetic patients in the world have T2DM. 3,4 The major pathogenesis of T2DM is insufficient insulin secretion from β cells under the background of insulin resistance. After insulin being produced by the pancreas, it cannot be efficiently utilized by the cells, which is named "insulin resistance". 5 T2DM is characterized by high levels of blood glucose called hyperglycemia. Long-term hyperglycemia results in the glycation of proteins that in turn leads to secondary complications, 6 including retinopathy, cardiovascular disease, diabetic foot, neuropathy, and nephropathy. As a consequence, the quality of life decreases and the risk of disability or even mortality increases. 7,8 Frustratingly, there is no cure for T2DM. 9 At present, the therapeutic strategies for T2DM mainly include regular physical exercise, proper lowcarbohydrate diets, and adherence to long-term medication therapy, like the oral administration of chemical hypoglycemic drugs and the injection of insulin. 4 However, most diabetes medications promote weight gain, gastrointestinal disturbances, 10 diarrhea, renal failure, hypersensitivity, 11 and there is a proportionate risk of hypoglycemia using them to achieve tight glycemic control. 12,13 Drug resistance is another serious obstacle. For example, sulfonylureas lose their effectiveness after treatment for 6 years in approximately 44% of diabetics. 14 Therefore, it is momentous to discover new antidiabetic candidates with greater safety but fewer side effects.
Plants have always been an exemplary source of ethnic medicines or natural drugs. Phytocompounds are natural components isolated from plants, which have been paid increased attention with progressively in-depth research of modern medicine in the field of alternative medicine. 15 Nowadays, approximately 50% of the drugs approved by the Food and Drug Administration (FDA) are plantderived compounds or their derivatives. 16 For instance, metformin, a biguanidine-type antidiabetic drug, is developed from galegine which is isolated from Galega officinalis L. (Fabaceae) 17 and is currently used as the first-line oral medication for T2DM treatment. 18,19 Compared with conventional therapies, natural plant-derived agents are more affordable and accessible, with fewer side-effects, so pharmaceutical research is increasingly inclined to discover new antidiabetic drugs from plants. 20,21 About 1200 plants have been claimed to contain antidiabetic compounds, and more than 400 plants and their bioactive compounds have been scientifically evaluated for T2DM treatment. 21,22 Phytocompound-based therapies are able to be developed as new approaches to treat T2DM or as adjuvants to support the existing monotherapies.
Generally, oral administration is recognized as the easiest and most convenient way. It is preferred by the patients with chronic diseases who require repeated dosing, 23 like T2DM patients, since the oral administration of therapeutic drugs shows good patient compliance without any pain and risk of needlestick injuries. However, the shortcomings of orally delivered phytocompounds, such as poor solubility, instability in the GIT, extremely low bioavailability, short half-life, and so on, restrain the translation of biological activities from in vitro evaluations to in vivo applications, 24,25 so it is of paramount importance to design innovative oral delivery systems for diabetic patients. Nanomedicine has been proven to be able to effectively improve the oral delivery efficacy of compounds through circumventing various delivery restrictions. 26 It has been reported that the uptake of nanostructures is 15~250 times greater than that of microparticles. 27 Besides, nanostructures are always employed to sustain the release of encapsulated compounds in order to reduce dose and dosing frequency, thereby increasing patient compliance and minimizing side effects. 28 At present, a comprehensive review covering various oral nano delivery systems of phytocompounds for T2DM treatment in the preclinical stage is not available. In this review, we aimed to systematically summarize and critically analyze phytocompound-based oral nano delivery systems for T2DM treatment in recent years, and identify their therapeutic effects supported by experimental evidence in vitro or/and in vivo. On this basis, researchers could apply excellent delivery systems to undeveloped antidiabetic phytocompounds to explore more therapeutic possibilities in the future.
Under these conditions, phytocompounds can significantly reduce postprandial blood glucose levels by inhibiting αglucosidase and α-amylase. 36 Hyperglycemia may make the kidney reabsorb glucose above the normal level. 38 Sodium-glucose co-transporter 2 (SGLT2) is the principal co-transporter of glucose reabsorption in the proximal convoluted tubule of the kidney. Phlorizin, chlorogenic acid, quercetin, kaempferol, kurarinone, and sophoraflavanone, with SGLT2 inhibitory activity, can promote the excretion of glucose in urine and suppress the reabsorption of glucose in the kidney. The excretion of glucose leads to a decrease of glucose in plasma levels, thus ameliorating all glycemic parameters. Typically, some synthetic compounds derived from phlorizin, including dapagliflozin, canagliflozin, ertugliflozin, and empagliflozin, have been approved by the FDA for T2DM treatment. 39,40 Promotion of Glucose Uptake and Metabolism Flavonoids and polyphenolic compounds can potentiate glucose transporter isoform 4 (GLUT4) expression as well as glucose uptake. 41,42 GLUT4 is located at adipose tissue and skeletal muscle, which is mainly controlled by insulin secretion. Insulin stimulates the translocation of GLUT4 from an intracellular location to the cell surface, which can transport glucose into the inner and in turn decrease blood glucose levels. Pathologically, diabetic patients have lower expression of GLUT4. 43 The abnormality of GLUT4 expression causes a malfunction in the glucose uptake system and eventually results in insulin resistance in T2DM. Sayem etal 44 reviewed the action of phytocompounds on the modulation of GLUT4 translocation through insulin signaling pathways. For instance, berberine and vanillic acid improved the translocation of GLUT4 via adenosine 5'monophosphate-activated protein kinase (AMPK)dependent pathway whereas resveratrol via phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway.

Improvement of Insulin Action and Sensitivity
Glucagon-like peptide 1 (GLP1), an incretin hormone, can stimulate postprandial insulin secretion. Dipeptidyl peptidase 4 (DPP4) is a GLP1-degrading enzyme. 45,46 The evidence suggests that polyphenols such as chlorogenic acid, epicatechin, and syringic acid can stimulate the secretion of GLP1 from intestinal L-cells, increase the International Journal of Nanomedicine 2020:15 submit your manuscript | www.dovepress.com DovePress half-life of GLP1 by inhibiting DPP4, stimulate the secretion of insulin from β-cells, irritate the peripheral response to insulin, and ultimately result in improving the overall effects of the GLP1-insulin axis. 45 Phytocompounds can also regulate insulin sensitivity via the blockage of protein tyrosine phosphatase 1B (PTP1B) and the stimulation of peroxisome proliferator-activated receptor γ (PPARγ). PTP1B is an enzyme responsible for reversing the autophosphorylation of the insulin receptor. The inhibition of PTP1B results in a prolonged insulin signaling cascade, thereby increasing insulin sensitivity. 47 Researches have reported approximately 500 PTP1B inhibitors (248 phenolics, 159 terpenoids, 40 alkaloids, 24 fatty acids, and 17 steroids) isolated from 100 species of natural sources. These phytocompounds could be developed as antidiabetic drugs or at least as promising drug candidates in the near future. 48 PPARγ is the predominant molecular target of the thiazolidinedione class of insulin-sensitizing drugs like pioglitazone, troglitazone, and rosiglitazone. 49 Many in vivo studies have implied that some natural product activators of PPARγ like honokiol, amorphastilbol, amorfrutin 1, and amorfrutin B have similar effects on stimulating glucose uptake as full thiazolidinedione agonists, but with reduced side effects. 50,51

Antioxidant and Antiinflammatory Actions
The oxidation and inflammatory responses can establish a causal relationship in the occurrence of T2DM, which further leads to insulin resistance, or oxidation and inflammatory responses may be augmented by the hyperglycemic state, which results in T2DM-related complications. [52][53][54][55][56][57][58] Recently, Ahangarpour et al 58 and Gothai et al 57 reviewed the research progress of phytocompounds, including chlorogenic acid, ellagic acid, curcumin, resveratrol, apigenin, quercetin, naringenin, catechin, etc., ameliorating insulin resistance and diabetic complications by suppressing oxidation or/and inflammatory signaling pathways. Phytocompounds can not only treat diabetes but also reduce the risk of T2DMassociated complications, which is a very attractive feature.

The Necessity of Developing Antidiabetic Phytocompounds-Loaded Nano Drug Delivery Systems
Despite the promising pharmacological activities of various phytocompounds, there are still some difficulties in translating their beneficial effects via oral route in clinical practice. 59 A review of clinical trials showed that the dose of phytocompounds for diabetes treatment was a crucial variable affecting clinical response. 60 In most studies, higher doses of phytocompounds exhibited better curative activity which may be due to the low bioavailability. Improving oral bioavailability plays a key role in further clinical applications. The way to overcome the low bioavailability of phytocompounds through higher doses showed better efficacy but simultaneously caused toxicity in several organs. 60 This is because the apparent volume of distribution of phytocompounds is quite large, which results in a large accumulation of drugs in normal organs, thus increasing undesired side effects. 61 There is another problem with antidiabetic phytocompounds. Because of the low stability of phytocompounds in the process of absorption, they have a lower potential antidiabetic effect in vivo. 62 Great attempts have been made to develop delivery systems in order to overcome these critical shortcomings.
Conventional drug delivery systems like microspheres, 63,64 microemulsions, 65 amorphous solid dispersion, 66,67 β-Cyclodextrin, 68 pH-sensitive hydrogels 69 have been used to deliver antidiabetic phytocompounds for T2DM treatment. However, conventional drug delivery systems always have some restrictions, such as lack of curative effect because of ineffective or improper dose, diminished potency or altered effects because of drug metabolism, and lack of precise target specificity. More and more researches are focused on nano delivery systems. 70 In the past two decades, several nanotherapeutics have been approved by the FDA for the treatment of diabetes, high cholesterol, cancer, hepatitis, neurological diseases, autoimmune diseases, cardiovascular diseases, Parkinson's disease, and certain infectious diseases. 71 Oral nano delivery systems can not only protect antidiabetic phytocompounds from enzymatic and/or chemical degradation in GIT but also provide other benefits, such as avoidance of firstpass metabolism, improvement of pharmacokinetic and pharmacodynamic profile, fast onset of action, targeted drug delivery, sustained drug release, lower dose and dosing frequency, and fewer side effects. 2

Oral Nano Drug Delivery Systems of Antidiabetic Phytocompounds
This section will focus on different types of oral nano delivery systems of antidiabetic phytocompounds submit your manuscript | www.dovepress.com

Polymeric NPs
NPs are colloidal drug delivery systems that cover particles ranging from 10 nm to 1000 nm in diameter. They can be a reservoir system in which drugs are enclosed in a cavity surrounded by polymeric membranes called nanocapsules or as a matrix system in which drugs are dispersed throughout particles called nanospheres ( Figure 2). 2 Polymers have attracted much attention in therapeutic applications because of the design flexibility based on functionalization, polymer diversity, and macromolecular synthesis methods. 117 According to the different materials used to construct them, polymer-based delivery systems can be divided into synthetic polymer NPs and inartificial polymer NPs. 2

NPs Based Upon Inartificial Polymers
Inartificial polymers have the characteristics of low cost in processing and high abundance in nature. 118 Non-toxicity and biocompatibility are the primary advantages of inartificial polymers as compared to synthetic polymers. 119 Sodium alginate, chitosan, gum arabica, gum rosin, and dextran are the inartificially occurring polymers that have been developed for the delivery of antidiabetic phytocompounds.

Chitosan-Based NPs
Chitosan, a kind of polycationic polysaccharide, is produced by alkaline deacetylation of chitin 120 which is derived from the cell walls of fungi, the cuticle of insects, and the exoskeleton of crustaceans. 121,122 By far, chitosan is the most extensively used for the delivery of antidiabetic phytocompounds due to its easy surface modification, property to blend with multitudinous polymers, non-immunogenicity as well as non-toxicity, and significant compatibility with cells and tissues. 123 A bottom-up ionic gelation method was applied to prepare chitosan NPs encapsulating ferulic acid 72 or curcumin. 124 Chauhan et al 124 reported, in L6 rat skeletal muscle cells in vitro, curcumin chitosan NPs exhibited a superior effect on the translocation of GLUT4 to the cell surface as compared to free curcumin. In another study of Panwar et al, 72 ferulic acid chitosan NPs showed fourfold enhanced oral bioavailability in vivo compared with free ferulic acid and displayed better antidiabetic potential in streptozotocin (STZ)-induced diabetic rats than ferulic acid. This might be attributed to the unique ability of chitosan to temporarily open the tight junctions between epithelial cells. 125 Moreover, the high positive charge of chitosan makes it well suitable for oral drug delivery because it enhances the adhesion to negatively charged mucosal surfaces, thereby increasing the uptake of cells. 126 Besides, the −OH and −NH 2 active groups on the chitosan molecule are prone to chemical reactions. 127 Zhu et al investigated the grafting of catechin onto chitosan using hydrogen peroxide (H 2 O 2 ) and ascorbic acid (Vc) as redox initiator in acetic acid solution. 128 In vitro antidiabetic activity revealed that the inhibitory effect of α-glucosidase decreased in the order of catechin-g-chitosan > catechin > acarbose > chitosan, and the inhibitory effect of α-amylase decreased in the order of acarbose > catechin-g-chitosan > catechin > chitosan. Although chitosan possesses favorable biological properties, it is rarely used alone for oral drug administration because chitosan as a carrier is subject to leak out the entrapped drugs as it dissolves easily in acidic conditions. 125,129 Alginate/Chitosan-Based NPs Another inartificial polymer sought with chitosan is alginate. Alginate is a hydrophilic anionic copolymer broadly distributed in the cell walls of brown algae. The wide pharmaceutical applicability of alginate is owing to its unique ability to form gels in aqueous medium or at low pH under the presence of divalent cations like calcium ions. 130 Alginate and chitosan are able to form polyelectrolyte complexes through electrostatic interactions between oppositely charged groups. 125 The poor solubility of alginate network at low pH decreases the high solubility of chitosan at low pH, while chitosan which is less soluble at high pH stabilizes alginate which is more soluble at high pH. 118 The alginate/chitosan complex protects the encapsulated phytocompounds and effectively slows down the release than either chitosan or alginate alone. For instance, in vitro assays, the chitosan-alginate polyelectrolyte complex prolonged the average release time of curcumin by 40 min in simulated gastric fluid and concurrently reduced the loss of curcumin by 20%. Besides, the curcumin nanoformulation prepared by chitosanalginate complex had a 30% higher glucose-lowering effect in vivo than that prepared by chitosan only. 73 Maity et al 74 prepared a novel alginate coated chitosan core-shell nanocarrier system which was effectively used in the oral delivery of naringenin to STZ-induced diabetic rats. The innovation spot lied in its structural chemistry because the core-shell construction was designed to

Gum-Based NPs and Gum/Chitosan-Based NPs
Natural gums, like guar gum, gellan gum, karaya gum, gum acacia, locust bean gum, konjac gel, or xanthan gums have been extensively employed to develop friendly drug delivery systems. They have the capacity to form hydrogels when exposed to water and show high stability in a broad pH range. 131 Gum rosin is an inartificial anionic polymer derived from pine trees. 132 Rani et al 76 developed thymoquinone-loaded gum rosin nanocapsules using the nanoprecipitation method, also called the solvent displacement method. Thymoquinone nanoformulations contained only half the amount administrated as native thymoquinone but performed a better antihyperglycemic activity in type 2 diabetic rats. Rani et al 77 chose gum arabica and chitosan as basic polymers for the preparation of the glycyrrhizin-loaded NPs which were synthesized by the electrostatic interaction of negatively charged carboxylic groups (−COO) of gum arabica with positively charged amine group (−NH2) of chitosan. Glycyrrhizin-loaded NPs exerted striking antihyperglycemic and antihyperlipidemic effects in type 2 diabetic rats, which were comparable to the standard antidiabetic drug, metformin. In another study of Rani et al, 133 two kinds of nanoformulations discussed above were mixed to explore their combined effects.
Compared with the single nanoformulation, even at a decreased drug load, combined nanoformulations exhibited significant improvement on antidiabetic activity in vivo as proven by encouraging responses in all eight tested parameters.

Dextran-Based NPs
Dextran is a highly water-soluble polysaccharide with negatively charged. It predominantly contains linear α-1,6-linked glucopyranose units and some degree of 1.3-branching. 134 Dextran mainly comes from the sucrose-rich environment of Lactobacillus, Streptococcus, and Leuconostoc. 135 Because of the low affinity between hydrophilic polymeric matrix and lipophilic drugs, drug encapsulation is difficult. Kapoor et al 136 modified dextran by connecting hexadecyl chains with ether bonds to make it amphiphilic. This synthesized O-hexadecyl-dextran could self-assemble in aqueous media, enclosing berberine into the hydrophobic pockets, fabricating NPs. In vitro study on primary hepatocytes, berberine-loaded O-hexadecyl-dextran NPs, even at a 20-fold reduced concentration, were as efficient as berberine in preventing high International Journal of Nanomedicine 2020:15 submit your manuscript | www.dovepress.com DovePress glucose-induced oxidative stress, mitochondrial depolarization as well as downstream events of apoptotic cell death. Despite their highly biodegradable, the limitation of inartificial polymers is their batch-to-batch variability because they are usually extracted from different species, regions, and under various climatic conditions, which makes them less attractive than synthetic polymers that are more versatile and reproducible. 137

NPs Based Upon Synthetic Polymers
Unlike the inartificial polymers, synthetic polymers are available in a large variety compositions with desirable properties, the ease of control over the synthetic processes, and batch-to-batch reproducibility. 2,135,138 Synthetic polymer NPs usually consist of poly (vinyl alcohol) (PVA), poly (ε-caprolactone) (PCL), poly (lactic acid) (PLA), poly (lactic-co-glycolic acid) (PLGA), and poly (methyl methacrylate) (PMMA), which are approved by the FDA due to their biodegradability and biocompatibility. 1,139 Polyesters are applied in amphiphilic diblock copolymers where the versatility provided by changing the compositions and adjusting the block lengths can make changes in drug loading capacity, carrier size, and drug release. 140

PLGA-Based NPs
At first, PLGA acted as clinical suture materials because they could be thoroughly absorbed by the body. PLGA-based particles have been utilized as carriers for more than 15 small molecular drugs approved by the FDA. 137 PLGA polymers, with the capability to encapsulate a wide range of hydrophilic or hydrophobic drugs, are usually made by the ring-opening co-polymerization of glycolide and lactide. One of the most notable characteristics of PLGA polymers as drug delivery systems is the possibility of adjusting the physicochemical properties like lactide/glycolide ratio in order to obtain the desired release profile. 141 By following the solvent displacement technique, pelargonidin was encapsulated in PLGA to form nano pelargonidin which was found to protect alloxan-induced hyperglycemic L6 cells against mitochondrial dysfunction, oxidative stress, DNA damage, imbalance in glucose homeostasis in vitro and exhibited better protective effect than native pelargonidin with a ~10fold reduced dose or showed a ~10-fold greater protective effect with an equivalent dose. 141,142 Chitkara et al adopted the emulsion diffusion evaporation method to produce quercetin-loaded PLGA NPs for diabetes care with the aim to reduce dose and dosing frequency. In a pharmacokinetic study, the relative oral bioavailability of nano quercetin was increased by 523% as compared with quercetin suspension. The therapeutic effect on STZ-induced diabetic rats implied that the same dose of quercetin nanoformulation every 5 days was enough to produce a similar effect to the daily dose of quercetin suspension. 78 Using the same preparation method as quercetin, Kozuka et al 79 successfully fabricated γoryzanol-loaded PLGA NPs. Compared with regular γoryzanol, nano γ-oryzanol markedly ameliorated lipid and blood glucose metabolism in obese diabetic ob/ob mice with an unexpected amount (about 1000-fold lower dose). Even under the condition of treatment once every 2 weeks, such a prominent impact was also accomplishable. Marked efficacy differences between antidiabetic phytocompounds and their PLGA-based nanoformulations can be ascribed to the specialized uptake of NPs through payer's patches via M-Cells into lymphatic system and then directly into systemic circulation and thus avoiding first-pass metabolism. 143 Furthermore, the PLGA matrix provided a barrier for phytocompounds to prevent them from enzymatic degradation in the GIT. 144 PLA-Based NPs, PCL-Based NPs, and PVA-Based NPs PLA is often used with PGA to form PLGA. It is formed by the condensation polymerization of lactic acid, which is produced by the fermentation of sugars from carbohydrate sources like sugarcane, corn, or tapioca. 145 PLA is a hydrophobic polymer because of the presence of -CH 3 side groups. 146 The stevioside was encapsulated into Pluronic-F-68-PLA through the nanoprecipitation method. 147 The use of Pluronic F-68 surfactants in NPs synthesis can usually improve drug loading capacity, stability as well as cell-nanoparticle interaction. 148,149 In this research, Pluronic-F-68 copolymer increased the encapsulation and bioavailability of stevioside and provided a longer sustained-release activity. The half release and complete release were respectively observed at 25 ± 4 h and 200 ± 10 h in vitro. 147 Another compound, rebaudioside A, with one more extra glucose molecule in its chemical structure than stevioside, also possesses strong antidiabetic activity. To assess the effect of nano rebaudioside A and compare it with nano stevioside, the entirely same methodology as stevioside was applied to fabricate rebaudioside A PLA NPs. The antidiabetic effect of rebaudioside A NPs was claimed to be superior than that of stevioside NPs on account of achieved higher drug loading ability and similar in vitro release properties. 150 PCL is a hydrophobic, semi-crystalline polymer. 151 It is achiral and has the ability to resist chemical hydrolysis, submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020:15 which improves the structural stability of polymeric chains in the nanoencapsulation. 148 Kamaraj et al 152 made 14deoxy, 11, 12-didehydroandrographolide-loaded PCL NPs using the solvent evaporation technique. The results obtained from the study demonstrated that after nanoencapsulation, the glucose uptake effect in L6 myotubes in vitro was found to be improved because of its prolonged and sustained drug delivery. A biphasic pattern of drug release in vitro exerted an initial burst release at 24 h followed by a sustained release for up to 11 days.
PVA is a polymer with -OH hydrophilicity. It is produced by the radical polymerization of vinyl acetate and then followed with partial hydrolysis. Because of its unique properties like water solubility and multiple -OH groups for further chemical modification, it has been broadly used in drug delivery applications. 153 Mishra et al 80 completed the preparation of lutein PVA NPs by the precipitation method. The results showed that lutein PVA NPs at much lower doses caused a significant blood glucose-lowering effect along with prominent antihyperlipidemic and antioxidant effects compared with native lutein in non-insulindependent diabetic rats.

Poly (Ethylene Glycol) (PEG) Surface Modification
However, there are certain limitations of synthetic polymers such as opsonization by plasma proteins and subsequent recognition and clearance by mononuclear phagocyte system because of high surface hydrophobicity. 154 These drawbacks can be overcome by PEGylation approach. PEG is a hydrophilic, nontoxic, blood-compatible polymer that is the most widely used material for the surface modification of NPs. 155 PEG is applied to endow nanocarriers with a hydrophilic camouflage surface, which can provide several advantages in vivo applications, such as improving the hydrophilicity of synthetic polymer, minimizing immunogenicity and phagocytosis as related to rapid reticuloendothelial system, reducing intermolecular aggregation, and increasing aqueous solubility and stability in blood, eventually contributing to the prolonged circulation of NPs. 156 El-Naggar et al 81 successfully developed curcuminloaded PLA-PEG NPs using the emulsion-diffusion evaporation technique. In this amphiphilic system, PLA represented the hydrophobic segment of the copolymer and PEG, the hydrophilic one. 59 Hydrophobic curcumin was encapsulated into hydrophobic polymer's portion and stabilized by cationic surfactant (cetyltrimethylammonium bromide). The results validated the superiority of curcumin encapsulated into PLA-PEG NPs over both polymer NPs itself and free curcumin in elevating the level of plasma insulin, decreasing the level of plasma glucose, protecting the liver from inflammation, and ameliorating hepatic functioning in STZ-induced diabetic rats. 81 Used PLGA-PEG-COOH and PCL conjugate as carriers, novel polymeric NPs, which efficiently encapsulated fisetin, were fabricated by the nanoprecipitation technique. In the drug delivery system, PCL exhibited extraordinary capability to form blends with other polymers, which made it possible to design degradation kinetics and mechanical properties. 157 During the preparation of NPs, the PCL block could interact with PLGA to build a hydrophobic core, while the hydrophilic PEG-COOH chains could protrude from the particle surface to stabilize the core. 158 In vitro release assays demonstrated that NPs could preserve and protect the release of fisetin under gastric-simulated conditions, along with controlling release in the intestinal medium. What's more, fisetin nanoformulation obtained an approximately 20-fold higher α-glucosidase inhibitory effect than commercial acarbose. 157 Recent reports implied that PEG could cause an immunogenic response in mammals. However, the extent of this response elicited by the binding of anti-PEG antibodies is not clear. PEG remains the FDA approved polymer and is still the most extensively utilized polymeric coating of nanomedicines, either in industrial use or academic research. 159 Despite synthetic polymers-based NPs with numerous benefits, there are still a couple of concerns about potential toxicity. Polymer toxicity can be a result of residual monomer in the prepared polymer product and/or physical interactions with biological homeostatic mechanisms, that is, gill oxygen transport. 160 Besides, NPs also have certain other weaknesses including high manufacturing costs, unpredictable stability, and short shelf life. 2

Lipid-Based Nano Systems
Lipid-based nano delivery systems are comprised of biocompatible/biodegradable lipid ingredients generally recognized as safe (GRAS), which have attracted considerable research attention over the last 15 years after the discovery that the oral bioavailability of poorly watersoluble drugs could be improved when they are coadministered with a diet rich in fat. 162 Lipids are absorption enhancers because they can increase oral bioavailability of poorly water-soluble drugs in multitudinous ways like promoting dissolution as a micellar solution, acting as inhibitors of efflux transporters, and increasing International Journal of Nanomedicine 2020:15 submit your manuscript | www.dovepress.com DovePress the lymphatic uptake. [162][163][164] Besides, the structural and chemical richness of lipids provides multiple possibilities to form delivery systems with different characteristics and contain various active compounds. 165 Nanoemulsions (NEs) and Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) NEs NEs are colloidal dispersions consisting of an oily phase, surfactant, and a water phase. 166 It remains controversial in defined size values of NEs, with the upper limit fixed at 100 nm, 200 nm,or 500 nm. 167 Generally, as oil droplets' size decreases, the energy density required to break down oil droplets increases, which signifies that high energy input is necessary to form NEs. Mechanical devices are often used, like ultrasonification, microfluidizers, and high-pressure homogenizers. 168 NEs are drug delivery systems with the ability to entrap hydrophobic and hydrophilic molecules. 166 It markedly enhanced the absorption of antidiabetic phytocompounds entrapped in NEs, which can be realized by the small particle size and high surface-tovolume ratio of NEs, the surfactant-induced membrane fluidity then permeability improvement, the stimulation of various lipid sensing mechanisms in GIT, and the initiation of intestinal lymphatic transport pathway. [168][169][170] Bitter gourd seed oil was emulsified by the two-stage homogenization process for NEs preparation with a low surfactant to oil ratio (0.65). Bitter gourd seed oil NEs significantly ameliorated hyperglycemia and oxidative stressed state in alloxan-induced type 2 diabetic rats. Interestingly, compared with equivalent doses of bitter gourd seed oil conventional emulsion and 1% (w/v) bitter gourd seed oil NEs, 0.5% (w/v) bitter gourd seed oil NEs displayed maximum therapeutic efficiency possibly due to increased bioavailability. 82 Further studies on pharmacokinetics are needed to conduct. Xu et al 83 reported that NEs decreased the P-gp efflux of berberine by 2-fold and increased its permeability by 5.5-fold in vitro Caco-2 cells transport and in situ single-pass intestinal perfusion investigations. Compared with berberine control, NEs enhanced the oral bioavailability of berberine in vivo by 212.02% and reduced the blood glucose level of diabetic mice by 3-fold. Moreover, the therapeutic effect of berberine NEs on diabetes was better than that of metformin. Cyclodextrin-based nanosponges, an innovative delivery system, are made up of hyper-cross-linked cyclodextrins connected in a three-dimensional network. 171 They can surpass the limitations of native cyclodextrins. 172 Superior properties are ascribed to their nanoporous, sponge-like structure, beneficial for encapsulation of complex lipophilic and hydrophilic phytocompounds. 173 Nait Bachir et al synthesized two engineered NEs in order to enhance the bioactivity and stability of sage essential oil. 84 The first one was stabilized by native β-cyclodextrin employing physical method and the second one was stabilized by β-cyclodextrin nanosponges using naphthalene dicarboxylic acid as a cross-linking agent and employing polycondensation method. The experiment results revealed the stability of the latter was higher than that of the former. The antidiabetic activity in vivo of NEs stabilized by βcyclodextrin nanosponges performed better curative efficacy than that of NEs stabilized by natural β-cyclodextrin and free sage essential oil. 84 Hatanaka et al prepared three NEs of α-tocopherol at different loading amounts (10%, 30%, and 50%) via the mechanochemical method using a homomixer and microfluidizer. By comparison with the control mixture of oil and α-tocopherol, 10% α-tocopherol -loaded NEs exhibited a 2.6-fold increased bioavailability in vivo and a more significant antioxidative effect on several organs, especially the liver, in STZ-induced diabetic rats. However, when the content of α-tocopherol of NEs was 30% or higher, severe droplet aggregation occurred during long-time storage. 85 The main restriction that reduces the wide application of NEs is stability. 174 NEs are thermodynamically unstable and kinetically stable systems. 175 In other words, if NEs are given sufficient time, phase separation eventually occurs. Ostwald ripening is the main destabilization mechanism of NEs. 176 It was reported that during storage and applications, the stability of NEs could be maintained against environmental factors including pH and temperature by controlling size, surfactant, and oil concentrations. 177

SNEDDS
In contrast to NEs, SNEDDS do not incorporate any water, so they are much more chemically as well as physically stable, and therefore can be easily stored for a longer time. 178 Besides, free energy required to produce SNEDDS is very low, and the formulation is thermodynamically spontaneous. 179 SNEDDS (pre-emulsion concentrates) are anhydrous isotropic mixtures of oil, drug, surfactant, and/or co-surfactant. Such systems are diluted by aqueous phase (gastrointestinal fluids) in vivo, and then under gentle agitation provided by the digestive motility of the intestine and stomach, they can form fine oil-in-water NEs, providing a large interfacial surface area for submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020:15 improving drug absorption. So, one of the most crucial features of SNEDDS is the change that occurs when the system is diluted by body fluids after administration. 162,180,181 Hence, it is crucial to identify efficient self-emulsification regions and decide on the most suitable concentrations of surfactant, cosurfactant, and oil for the formulation of SNEDDS with good stability. Garg et al 87 prepared SNEDDS of polypeptide-k and curcumin for better antidiabetic efficacy in STZ-induced diabetic rats. A pseudo-ternary phase diagram was constructed through oil (labrafil M 1944 CS), surfactant (tween-80), cosurfactant (transcutol P) to select the efficient self-emulsification region. Box-Behnken design was utilized to optimize the liquid formulation based on the results of zeta potential, percentage drug loading, polydispersity index, and mean droplet size. Under the condition of variation in pH, dilution, and temperature, the absence of phase separation and drug precipitation suggested that the optimized formulation was stable. The rate of emulsification is a crucial index for the evaluation of the efficiency of emulsification. The self-emulsification time of optimal formula resveratrol SNEDDS (propylene glycol, tween 80, and olive oil in the ratio 533.3:266.7:200) was only 27 ± 0.8 s without precipitation in vitro. Ten milligram/kilogram resveratrol nanoformulation displayed significant hypolipidemic and hypoglycemic effects on STZ and glucose induced-diabetic rats, similar to the high dose (20 mg/kg) of free resveratrol. 88 In another study, the relative oral bioavailability in vivo of transcinnamic acid SNEDDS (10% PEG 400, 30% isopropyl myristate, and 60% Kolliphor EL) was approximately 246% as compared with trans-cinnamic acid suspension, indicating that SNEDDS have a remarkable capability to improve bioavailability. 89 These phenomena can be attributed to multi-concerted mechanisms like reduced intraenterocyte metabolism through cytochrome P450 enzymes, decreased P-gp efflux activity, and bypassed hepatic first-pass metabolism through lymphatic absorption. 182 SNEDDS of trans-cinnamic acid enhanced the antidiabetic efficacy of trans-cinnamic acid in alloxaninduced diabetic rats, which could be comparable to that of metformin. 89 SNEDDS are related with many merits, but they still have some defects. Characterization-and formulation-associated issues include the correlation of in vitro model with in vivo studies, the usage of a high amount of surfactant, the precipitation of drug in vivo, the oxidation potential of lipid components, the difficulty of low encapsulation, etc. 183 Nowadays, research is moving towards some novel applications of SNEDDS to make up for their shortcomings, such as self-double emulsions (w/o/ w), solid SNEDDS, controlled release SNEDDS, supersaturated SNEDDS, targeted SNEDDS. 175,184,185 For example, solid SNEDDS are more stable and amenable to compress into tablets as compared to their liquid counterparts. 186 Garg et al 86 solidified liquid SNEDDS of polypeptide-k using Aerosil 200 as hydrophobic carrier through the spray drying technique. The biochemical, hematological, and histopathological results of STZinduced diabetic rats revealed better antidiabetic potential of polypeptide-k loaded in SNEDDS than that of naive form.

Solid Lipid NPs (SLNs) and Nanostructured Lipid Carriers (NLCs)
Lipid-based NPs possess an inner solid lipid phase. According to their internal structure, lipid-based NPs are divided into solid lipid NPs (SLNs) and nanostructured lipid carriers (NLCs). 187 As the first generation of lipidbased NPs, SLNs are only composed of solid lipids, whereas NLCs, as the upgrade of SLNs, are composed of a mixture of liquid and solid lipids, but the solid lipid is in a relatively high amount to fabricate nanoparticles. This solid matrix realizes the controlled release of enclosed either lipophilic or hydrophilic molecules, protects them from degradation, and increases the long-time stability of the system. 188 Numerous methods have been reported for the preparation of lipid NPs like hot and cold highpressure homogenization, microemulsion-based technique, solvent emulsification/evaporation, solvent diffusion method, etc. 163 Probably the most vital reasons for lipid NPs as a suitable alternative to previous polymeric NPs, are low toxicity potential and the ease of large-scale production. 189 SLNs Because myricitrin is susceptible to high temperature, the cold homogenization method has been employed to prepare myricitrin SLNs. SLNs of myricitrin exhibited antioxidant, antidiabetic, and antiapoptotic activities in STZnicotinamide-induced diabetes in mice and hyperglycemic myotubes. 90 In another study, a solvent injection method was utilized to develop the resveratrol SLNs. Compared with pure resveratrol, oral administration of resveratrol SLNs to rats with T2DM showed better hypoglycemic effects and more significantly reduced the expression of SNARE proteins associated with insulin resistance in International Journal of Nanomedicine 2020:15 submit your manuscript | www.dovepress.com DovePress muscle and adipose tissue. 91 11.06 ± 6.24 µg/L, 9.228 ± 5.13 h, and 23.40 ± 13.92 h of pure berberine. The above results indicated that nanoformulations could promote absorption, possess a slow-release character, and reduce fluctuations in drug concentrations. Consequently, berberine SLNs exerted more powerful effectiveness than an equivalent dose of berberine in db/db mice, especially for the effect on improving insulin sensitivity and glucose tolerance. After further research, Xue et al 93 found that the drug concentration of berberine SLNs group in the liver was approximately 2-fold higher than that of berberine group. The maximum drug concentration in the liver was 20-fold higher than that in the blood after oral administration of berberine SLNs, suggesting a predominant accumulation of berberine SLNs in the liver. However, the capability of SLNs to transform crystalline phases-lowenergetic form results in an increased degree of order which decreases the imperfections in the crystal lattice followed by drug expulsion phenomena and low encapsulation efficiency (Figure 2). 71,190 For example, the encapsulation efficiency of the discussed SLNs of myricitrin, 90 resveratrol, 91 berberine 92,93 is 56.2%, 79.9%, 58%, respectively.

NLCs
NLCs are designed to triumph over SLNs shortcomings. NLCs are also maintained in solid state at room and body temperature. 165 However, instead of only a solid lipid, a liquid lipid or a mixture of liquid lipids are used to replace the part of a solid lipid, leading to a less ordered lipid matrix-imperfect crystal lattice (Figure 2) which contributes to increased loading efficiencies, enhanced stability along with the prevention of drug expulsion during storage, 190,191 as illustrated by the following studies.
Two lipid-based nanocarriers for oral delivery of silymarin were prepared through the method of emulsion/ evaporation/solidifying. 94,95 The first one was produced with lauroglycol 90 as liquid lipid, cetyl palmitate as solid lipid, and Brij S20 as surfactant, 94 the second one with capryol 90 as liquid lipid, stearic acid as solid lipid, and Brij S20 as surfactant. 95 Both encapsulation efficiency was more than 92% with excellent chemical and physical stability. In vitro release studies showed that NLCs may improve the passive permeation of silymarin via the Caco-2 cell layer. In vivo, both silymarin-loaded NLCs exhibited a more significant down-regulation of triglyceride and blood glucose levels compared with native silymarin. Besides, both nanoformulations performed a remarkable antihyperalgesic activity on STZ-induced neuropathy. However, the second nanoformulation showed more pronounced and longer lasting therapeutic effects. 94,95 Similarly, in another study, baicalin NLCs were formed by the hot melting high-pressure homogenization method using miglyol as liquid lipid and precirol as solid lipid. The results suggested that baicalin NLCs had a better capability to retain drugs and possessed relatively good physical stability. To be specific, during 1 month of storage at 4°C, aggregation and gelation were not found by visual observation and no significant change of zeta potential, particle size, and polydispersity index was discovered by data analysis, indicating relative good physical stability of baicalin NLCs; the average encapsulation efficiency of freshly prepared baicalin NLCs was 85.29 ± 3.42%, indicating their better ability to retain drugs. Compared with pure baicalin, baicalin NLCs had better hypoglycemic and hypolipidemic effects in vivo. 96 In the past few years, at the academic level, the potential of NLCs as drug delivery systems has been broadly researched. However, to the best of our knowledge, no NLCs for therapeutical use have obtained the regulatory approval or even have reached the clinical study stage until now. 191

Vesicular Systems
Vesicles are colloidal systems with a size of less than a micrometer. 192 Vesicular delivery systems are composed of an aqueous core generally surrounded by one or more lipidic bilayers. 193 The hydrophilic agents are enclosed in the inner aqueous core, while lipophilic drugs in the lipid bilayer. 194 The agents encapsulated in lipid vesicles can easily cross the cell membrane, which alters the rate and extent of the absorption of agents and their disposition. 195 Vesicular delivery systems of antidiabetic phytocompounds that have been studied so far are discussed below.

Liposomes
Phospholipids are the major component of all biological membranes. 196 Liposomes are phospholipid bilayer vesicles. It has been over 50 years that liposomes explored in pharmaceutical research as drug delivery systems. 197 Due to submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020:15 the use of phospholipids, liposomes possess a biofilm similar structure and exhibit excellent biocompatibility. 198,199 More than 40 liposomes loaded with drugs are under different clinical research stages or have been successfully marketed. 199 Amjadi et al used the ultrasonic-mechanical method for the fabrication of betanin liposomes. In vitro release studies, betanin-loaded liposomes exhibited a relatively favorable sustained release profile in simulated intestinal and gastric fluids. Liposomal encapsulation improved the physicochemical stability of betanin during in vitro digestion and more effectively regulated hyperlipidemia, hyperglycemia, and oxidative stress than free betanin in STZ-induced rats. 97 Yucel et al prepared nanoliposomal formulations containing resveratrol using the dry film hydration method. It was concluded that nanoformulation significantly decreased high glucose levels along with increasing insulin levels in glucose and STZ-induced diabetic β-TC3 cells, and exerted prolonged antioxidant activity for 24 h as compared with resveratrol solution. 200 However, the therapeutical use of liposomes exists some restrictions, predominantly their high formulation cost and poor stability under harsh conditions, typically exposed to the GIT. Some studies have been reported on the use of cochleates as an alternative platform to liposomes in order to surpass these limitations. 201 Nanocochleates Nanocochleates are stable phospholipid precipitates derived from the physical interaction of divalent cation with anionic lipid vesicles, 202 generally phosphatidylserine and calcium. 203 Nanocochleates have cylindrical (cigarlike) microstructures made up of solid, lipid bilayer sheet which was rolled up in a spiral or in stacked sheets to minimize their interaction with water, consequently, nanocochleates with no or little internal aqueous space. 203,204 This unique structure provides protection for the encapsulated drugs from biodegradation, even if they are exposed to hazardous environmental conditions in the GIT. 205 Yucel et al 206 developed resveratrol-loaded nanocochleates by the trapping method and assessed their therapeutic efficiency in diabetic pancreatic β TC cell line in vitro. Compared with native resveratrol, the lower dose of nanocochleates loaded with resveratrol better improved the decreased insulin levels rendered with glucose and STZ, markedly reduced the increased glucose levels, and also exhibited prolonged antioxidant activity for 24 h. However, self-aggregation, which usually happens during production and storage, is currently the major obstacle hindering the development of efficient cochleate-based drug delivery systems. 207 Niosomes Niosomes are such hydrated vesicular systems mainly consisting of cholesterol along with nonionic surfactants. Niosomes can keep stable over a longer period of time in different conditions and require less cost of production, so break through major restrictions of liposomes. 208 Sharma et al 209 prepared lycopene-loaded niosomes by developing a novel method called adsorption-hydration technique. The release mechanism of lycopene was Fickian type and followed zero-order release kinetics in the first 10 h, after that the regression equation best matched Korsmeyer-Peppas model. Thus, the lycopene release from niosomes in vitro was sustained and prolonged profile, which was beneficial to reduce dosing frequency. Antidiabetic studies in vivo showed lycopene-loaded niosomes had an activity similar to a standard antidiabetic drug, glibenclamide. 98 Similarly, embelin-loaded niosomes, produced by the thinfilm hydration process, displayed a hypoglycemic effect in vivo which was comparable to another standard antidiabetic agent, repaglinide. Moreover, lipid peroxidation decreased and glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) increased significantly, which verified the antioxidant efficacy of the nanoformulation. 99 In another study of Singhal et al, 100 researchers used the thin-film hydration technique to prepare gymnemic acid-loaded niosomes which revealed antioxidant, antihyperglycemic, antihyperlipidemic, and antiglycation (AGEs) effects and eventually, exerted a protective action in STZ-nicotinamide-induced diabetic nephropathy in Wistar rats.

Phytosomes
Phytosomes, also known as phytophospholipid complexes, are prepared by interactions between active phytocompounds and the polar part of phospholipids. 210,211 The biggest difference between liposomes and phytosomes is that, in liposomes, the active phytocompound is distributed in lipid layers of the membrane or in the medium containing a cavity, 211 whereas, in phytosomes, it is an integral part of the membrane, which gives the greater stability and better bioavailability because of the chemical links between active phytocompounds and phospholipid molecules ( Figure 2). 213 DovePress rapid solvent evaporation method followed by selfassembly technique. In vivo studies, this nanoformulation could produce a 3-fold enhanced oral bioavailability of berberine. More importantly, the antidiabetic efficacy was improved remarkably in db/db mice by ameliorating hyperlipidemia and lowering fasting glucose levels. Besides, the types of phospholipid matrix applied in the preparation of phytosomes influenced their performance. For instance, compared with pure chrysin and chrysin prepared with soya phosphatidylcholine, chrysin prepared with egg phospholipid exhibited a greater glucose uptake promoting effect in C2C12 muscle cells through upregulating gene expression of PPARγ and GLUT4. 214

Micelles
Micelles have been extensively studied as nanocarriers for hydrophobic drugs with core/shell design. They commonly have a particle size within 5-50 nm range. 215 Micelles are made by the self-assembly of amphiphilic molecules in aqueous media above the critical micelle concentration (CMC). 216 The hydrophobic portion of amphiphilic molecules constitutes the core of the micelle, which serves as a reservoir and protects the agent, while the hydrophilic portion constitutes the micelles' shell, which confers steric stability and aqueous solubility to the micellar structure. 217,218 The transplantation of islet β-cells is an efficient therapy for type 1 and 2 diabetes. However, the isolated islets are under hypoxic conditions and then undergo the apoptotic process. Therefore, it is necessary to protect islets against hypoxia for enhancing the efficacy of islet transplantation. A peptide micelle-mediated curcumin delivery system was demonstrated to be effective for islet β-cells protection in the process of transplantation in vitro. This delivery system was developed by Han et al through an oil-in-water (O/W) emulsion/solvent evaporation method. In addition, the peptides consisted of a 3-arginine hydrophilic stretch and a 6-valine hydrophobic stretch. 219 Zhang et al used the dialysis method to fabricate an amentoflavone-loaded micelle system composed of amphiphilic copolymer (N-vinyl pyrrolidone and maleic acid guerbet alcohol monoester). Owing to the micelle formation, the oral bioavailability of amentoflavone was increased by nearly 3.2 times in vivo. The antidiabetic effect of amentoflavone nanoformulation is comparable to that of metformin in insulin-resistant diabetic KKAy mice. 102 Soluplus ® is one such commercially triblock copolymer composed of PCL-Polyvinyl acetate (PVAc)-PEG units with the capability to enhance the solubility and bioavailability of poorly water-soluble drugs. 220 Singh et al 103 prepared quercetin-loaded soluplus ® /poloxamer 407 micelles by the cosolvent evaporation method. In this system, poloxamer 407 was used as a surfactant in order to enhance the solubilization of quercetin and increase the stability of nanomicelles. In vivo pharmacokinetic studies, the relative oral bioavailability of quercetin nanoformulation was 1676% as compared to pure drug suspension. Moreover, quercetin nanoformulation showed significantly lower glucose levels, higher catalase and SOD levels in STZ-induced diabetic rats. Pluronics is another type of triblock copolymers with a central hydrophobic poly (propylene oxide) (PPO) chain and two hydrophilic poly (ethylene oxide) (PEO) on each side, arranged in PEO-PPO-PEO structure. 221 Pluronic micelles are capable to increase the stability and solubility of incorporated drugs and improve their pharmacokinetics and biodistribution. 222 El-Far et al developed silymarinloaded pluronic nanomicelles 104 and curcumin-loaded pluronic nanomicelles 105 using the nanoprecipitation technique. Nanoformulations were found to significantly improve the antihyperlipidemic, antioxidant, and antihyperglycemic properties in STZ-induced diabetic rats when compared with their native candidates. As we discussed, both synthetic and inartificial polymers have their own merits and defects. Combinations of these polymers could make the best use of the advantages and bypass the disadvantages. Using alginate, chitosan, maltodextrin, pluronic P123, pluronic F127, and tween 80, Akbar et al 106 developed curcumin-loaded mixed polymeric micelles by the thin-film hydration method. The achieved results showed that the antidiabetic activity of curcumin-loaded mixed polymeric micelles was comparable to that of metformin in bisphenol A-induced diabetics rats. Besides, curcumin-loaded mixed polymeric micelles administered topically on the surface of wound performed superior wound healing potential (fast wound closure) with the reduction of scar formation in vivo. However, the primary challenge faced by micelles is that micelles tend to disintegrate and cannot keep entrapped drugs stabilized when they are diluted below the CMC. This phenomenon typically occurs when the drug/micelle formulation is infused into body and will lead to severely decrease drugs' bioavailability and deteriorate therapeutic performance. 223

Inorganic Nanocarriers
Inorganic materials have been employed to explore nanocarriers with controlled morphology and size. 224 Recent breakthroughs on the surface functionalization and submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020:15 structural control of inorganic nanocarriers have brought more possibilities for drug delivery. 225

Metallic NPs
Metallic NPs such as selenium, 226,227 gold, 228 silver, 229,230 and zinc oxide NPs 107,231 appear very promising for the treatment of T2DM. 232 However, metallic NPs are synthesized by physical and chemical methods with many shortcomings, including high energy consumption, the use of toxic solvents, and the generation of hazardous byproducts. 233 The biosynthesis of metallic NPs through medicinal plants has obtained widespread attention as a proper alternative to hazardous chemical synthetic technique. 234 Antidiabetic phytocompounds act as reducing and stabilizing agents during the synthesis of metallic NPs. Currently, there have been many papers reporting the use of antidiabetic phytocompounds as stabilizing and reducing agents to synthesize metallic NPs, such as gymnemic acid gold NPs, 235 vicenin gold NPs, 236 escin gold NPs, 237 docosahexaenoic acid zinc oxide NPs, 107 and guavanoic acid gold NPs. 238 In these studies, all of them showed good antidiabetic effects in vitro or/and in vivo. Besides, phytocompounds with antidiabetic effects can enhance the diabetic efficacy of metal NPs. For instance, Catathelasma ventricosum polysaccharides SeNPs exhibited significantly higher antidiabetic effects than other selenium preparations like SeNPs, selenocysteine, sodium selenite. 108 On the base of berberine-loaded NLCs, Yin et al 109 used an in-situ reduction technique to fabricate berberine-loaded SeNLCs, as Se 4+ was reduced to Se which precipitated on the surface of NPs. In vivo studies reported berberine SeNLCs yielded the highest C max and AUC 0-t , up to 172.88 ng/mL and 1,107.80 ng·h/mL, when compared with berberine solution (C max =45.06 ng/mL, AUC 0-t =173.74 ng·h/mL) and berberine NLCs (C max =148.21 ng/mL, AUC 0-t =689.54 ng·h/mL). Accordingly, the hypoglycemic activity of berberine SeNLCs was also significantly superior to that of berberine solution and berberine NLCs. It turned out that Se coating, plus the synergy of selenium, was basically responsible for increased oral bioavailability and enhanced hypoglycemic activity in vivo.

Carbon Nanotubes
Carbon nanotubes are tiny tubes approximately 10,000 times thinner than a human hair. They consist of rolledup sheets of carbon hexagons. 239 Either by noncovalent interactions or covalent attachment, drugs can be loaded within the interior core or onto the surface of carbon nanotubes. 240 In comparison with spherical NPs, carbon nanotubes' needlelike shape gives them superior flow dynamics and enhanced capacity to penetrate cellular membranes. 241 Ilie et al 242 firstly prepared nanotubes with oxidation properties using 1:3 (v/v) concentrated nitric acid and sulfuric acid, which gave them stability and hydrophilicity in aqueous systems because of the formation of -OH and -COOH groups on the lateral sides of or at the end of the tubes. And then, Ilie et al 242 covalently conjugated nicotinamide onto the surfaces of oxidized multiwalled carbon nanotubes. In vitro study, 1.4E7 cells administrated with nicotinamide-functionalized multiwalled carbon nanotubes better regulated insulin secretion and increased insulin production as compared with nicotinamide or multiwalled carbon nanotubes.

Mesoporous Silica NPs (MSNs)
Based on unique intrinsic properties of MSNs such as large pore volume, high surface area, facile functionalization of surface, uniform and tunable pore size, and stable framework, they have been utilized extensively as drug carriers. 225,243 It is widely agreed in published literature that endocytosis is a common mechanism for the translocation of MSNs. 243 Huang et al 110 designed the surface functionalization of MSNs with amine groups to act as reservoirs for efficient immobilization of phytocompounds into pores for antidiabetic therapies. The results revealed that 16-Hydroxycleroda-3,13-Dine-16,15-Olid incorporated into MSNs caused a reduction of DPP4 activity in a dose-and time-dependent fashion in vitro and simultaneously possessed less adverse effects and reliable efficacy in down-regulation of hyperglycemia in diet-induced diabetic mice.
Although inorganic NPs can be metabolized by the kidney after their degradation into small-sized fragments, 244 most inorganic nanomaterials still have high bioaccumulation risks. 245 Moreover, the generated ions, especially heavy metals, may lead to toxicity or damage to the related organs during the excretion. 244 Therefore, it is essential to systematically study the toxicity of these nanomaterials to different organs in the process of metabolism. 246 Nanosuspensions Drug nanocrystals are nanosized drug particles often formed as nanosuspensions, namely submicron dispersions in liquid media where surfactants and/or polymers act as International Journal of Nanomedicine 2020:15 submit your manuscript | www.dovepress.com DovePress stabilizers. Although, without any carriers, nanosuspensions are an excellent delivery platform for poorly watersoluble drugs. 247 Reducing the drug size to nanoscale usually causes a significant increase in solubility and dissolution rate along with a distinct improvement in oral bioavailability. 248 Up to now, several studies have been reported that nanosuspensions enhanced the therapeutic effects of antidiabetic phytocompounds on diabetes, such as ursolic acid, 113 berberine, 114 curcumin, 111 gymnemic acids. 115 Chen et al 249 prepared Fructus Mori polysaccharides with spherical particles by the antisolvent precipitation method. According to the research results, the smaller the particle, the higher the bioavailability. We can deduce that the smaller size after spheroidization is able to be beneficial for the improved bioavailability. In comparison with the corresponding native polysaccharide, the spheroidization improved the hypoglycemic activity and antioxidant ability in vitro. Zhao et al 116 developed betulin nanocrystallization by the antisolvent precipitation technique. The results exhibited that nano betulin possessed the same chemical structure as raw betulin, but have smaller crystal size and lower crystallinity. The solubility and dissolution rate of nano betulin were, respectively, 1.54 and 3.12 times of raw drug. Compared with raw betulin, betulin nanosuspensions showed a 1.21-fold increased bioavailability in vivo and an excellent hypoglycemic effect in STZ-induced diabetic rats. However, instability is the most disadvantage of nanosuspensions and restricts their application to pharmaceutical industry. 250 Stabilizers are crucial to prevent the aggregation of high energy nanosuspensions. Nonetheless, a suitable stabilizer is often selected by a trial and error method. 251 Meanwhile, the potential raised toxicity concerns if the stabilizers are used in large quantities for a long term. 252

Conclusion
As antidiabetic agents, phytocompounds are potential candidates with abundant sources, significant curative effects, and low side-effects. Generally, there are four hypoglycemic mechanisms of phytocompounds, including reduction of carbohydrate decomposition and glucose absorption, promotion of glucose uptake and metabolism, improvement of insulin action and sensitivity, and antioxidant and antiinflammatory actions. However, conventional oral administration of antidiabetic phytocompounds has some inherent defects. Oral nano drug delivery systems for phytocompounds to treat T2DM not only maintain the advantages of oral administration but also overcome the shortcomings of conventional oral drug delivery.
In this review, we discussed phytocompounds-based oral nano delivery systems for T2DM treatment, including polymeric NPs, lipid-based nanosystems, vesicular systems, micelles, inorganic nanocarriers, and nanosuspensions. As observed in studies, oral nano drug delivery systems for T2DM treatment have the following advantages: 1) phytocompounds encapsulated into nano delivery systems can improve the stability of the former and protect them from enzymatic and/or chemical degradation in GIT. 2) nano delivery systems act at the molecular level to increase the cellular drug uptake or block drug efflux mechanisms like P-glycoprotein (P-gp) pump, which further improves the pharmacokinetic and pharmacodynamic profile of antidiabetic molecules. 2 3) oral drug bioavailability can be significantly limited by first-pass hepatic metabolism. Intestinal lymphatic drug transport is regarded as the best for improving oral drug delivery through bypassing first-pass metabolism. Nano delivery systems can be transferred into the lymph, arrive at lymphatic system through M cells, and increase the subsequent release of drugs in systemic circulation. 253 4) tailored engineering of nanocarriers fulfills controlling drug release, preventing opsonization, and targeting drug delivery. 2 Due to the above advantages, phytocompounds have clearly shown better antidiabetic efficacy in oral nano drug delivery systems with increased bioavailability, decreased toxicity, targeted specific site, and reduced dose and dosing frequency.
However, there are still some deficiencies in the existing research. On the one hand, it is worth noting that a control group administered with non-loaded carrier is not conducted in the vast majority of works so that the drug-independent effect of the carrier cannot be ignored. Rho et al 254 reported that empty self-assembled hyaluronic acid NPs without any drug could be used as a therapeutic agent for T2DM treatment. On the other hand, most of those materials used for the preparation of nano delivery systems are usually obtained from inorganic matter or synthetic polymers through a rather complex and tedious synthesis process, which may inevitably result in potential toxicity. Even if materials from natural sources are employed as nanocarriers, organic chemicals may be introduced into the process due to the requirement for the preparation. Security is a prime concern. However, the majority of published data come from cellular and animal models but not a clinical study. submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020 :15 Since toxicological research in animals has limitations, clinical trials are ultimately required. There are few clinical trials on potential antidiabetic nano phytocompounds, only curcumin nanomicelle, 255 curcumin nanocapsules. 256 Despite few severe adverse effects were reported during the treatment, long-term human toxicology research is still lacking. The FDA recently issued guidance to help promote the safe development of nanotechnology-based products for clinical use. 257 More clinical research is worth conducting.
Above all, oral nano drug delivery systems for T2DM treatment are an available administration strategy for antidiabetic phytocompounds. This review could provide researchers with promising antidiabetic phytocompounds and excellent oral delivery systems to explore more therapeutic possibilities. With the extensive development of the pharmacological activity research of antidiabetic phytocompounds and the continuous progress of material science and technology, more and more excellent oral nano phytocompounds will be employed in clinical pharmaceutical intervention for T2DM treatment.