Self-Assembled Aggregated Structures of Natural Products for Oral Drug Delivery.

The self-assembling aggregated structures of natural products have gained significant interest due to their simple synthesis, lack of carrier-related toxicity, and excellent biological efficacy. However, the mechanisms of their assembly and their ability to traverse the gastrointestinal (GI) barrier remain unclear. This review summarizes various intermolecular non-covalent interactions and aggregated structures, drawing on research indexed in Web of Science from 2010 to 2024. Cheminformatics analysis of the self-assembly behaviors of natural small molecules and their supramolecular aggregates reveals assembly-favorable conditions, aiding drug formulation. Additionally, the review explores the self-assembly properties of macromolecules like polysaccharides, proteins, and exosomes, highlighting their role in drug delivery. Strategies to overcome gastrointestinal barriers and enhance drug bioavailability are also discussed. This work underscores the potential of natural products in oral drug delivery and offers insights for designing more effective drug delivery systems.

Advances in oral absorption of polysaccharides: Mechanism, affecting factors, and improvement strategies.

Polysaccharides have been widely used as biomaterials and drugs after oral administration due to their suitable physicochemical properties, good bioactivities and low toxicities. However, studies on their pharmacokinetics and absorption mechanism after oral administration are significantly restricted by the lack of polysaccharide detection methods. With the advancement of polysaccharide detection technologies such as immunoassays, fluorescent and isotopic labelling, the oral pharmacokinetics of polysaccharides have gradually been revealed. Here, paracellular pathway, transcellular pathways and M cell-mediated transport were analysed as mechanisms for oral absorption. The potential factors affecting the oral absorption of polysaccharides, including their charge, molecular weight, spatial structure and dose, as well as the species and physiological state of organisms, were analysed. Based on the absorption mechanism and influencing factors, we look forward to further investigating possible strategies for improving the oral absorption of polysaccharides.

A critical review of Astragalus polysaccharides: From therapeutic mechanisms to pharmaceutics.

As the important active ingredients of Astragali Radix (AR), Astragalus polysaccharides (APs) have therapeutic potential for multiple diseases including nervous system diseases, cardiovascular diseases, diabetes mellitus, and cancer. A large number of cell experiments combined with animal experiments have shed light on the therapeutic mechanisms and therapeutic effects of APs on a variety of diseases. However, the clinical application of APs is not widespread, except for the use of injected APs in the clinical adjuvant therapy of cancer. Due to the excessive molecular weight, bulky, low solubility and negatively charged characteristics, APs have low bioavailability which limits their clinical application. With the deepening of researches on the pharmaceutics of APs, the nanocrystals and moderate structural modification enormously boost the bioavailability, which may expand the application of APs. This review summarizes the studies in pharmacodynamic properties and pharmaceutics of APs, with the purpose of providing experimental researches and clinical application data for expanding the clinical development through expounding the therapeutic mechanisms and pharmaceutical researches of APs.

Low Molecular Weight Fucoidan Can Inhibit the Fibrosis of Diabetic Kidneys by Regulating the Kidney Lipid Metabolism.

In this study, a diabetic kidney disease model was established by placing the test rats on a high-sugar/high-fat diet combined with streptozotocin induction. Histopathological examination (H&E, Masson, and PASM stain) showed pathological changes in the diabetic rat kidneys, in addition to fibrotic symptoms and collagen deposition. Immunohistochemistry and western blot analyses indicated that the diabetic condition significantly increased the expressions of fibrotic markers including collagen, α-SMA, and fibronectin. The levels of cholesterol, triglyceride, and low-density lipoprotein were also increased in diabetic kidney disease (DKD) rat blood, while the level of high-density lipoprotein was decreased. The results of Oil red O staining experiments indicated that the kidneys of diabetic rats exhibited appreciable fat deposition, with high contents of triglyceride and cholesterol. To inhibit fibrosis and reduce fat deposition, low molecular weight fucoidan (LMWF) may be used. Based on PCR and western blot analyses, LMWF can regulate the expression levels of important lipid metabolism regulators, thereby impeding the development of kidney fibrosis. Through the vitro model, it also be indicated that LMWF could inhibit fibrosis process through regulating lipid metabolism which induced by palmitic acid.

Safety Assessment of Saccharide Esters as Used in Cosmetics.

This is a safety assessment of 40 saccharide ester ingredients as used in cosmetics. The saccharide esters are reported to function in cosmetics as emollients, skin-conditioning agents, fragrance ingredients, and emulsion stabilizers. The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the relevant data for these ingredients. The Panel concluded that the saccharide esters are safe in cosmetics in the present practices of use and concentrations described in this safety assessment.

Oral absorption characteristics and mechanisms of a pectin-type polysaccharide from Smilax china L. across the intestinal epithelium.

The elucidation of the oral absorption of natural polysaccharides contributes to their further research and utilization. Herein, to explore the absorption of a pectin-type polysaccharide from Smilax china L. (SCLP), SCLP was respectively fluorescently labeled with fluorescein-5-thioicarbazide (FSCLP) and Cyanine7 amine (Cy7-SCLP) for in vitro and in vivo tracking. The near-infrared imaging demonstrated that Cy7-SCLP was absorbable in the small intestine and distributed in the liver and kidney after oral administration. Subsequently, in vitro intestinal epithelial tissue experiments showed that the jejunum was the dominant site of FSCLP transport. Further transport studies in the Caco-2 cell monolayer illustrated that FSCLP was delivered across the monolayer via transcellular transport by caveolae-mediated endocytosis and macropinocytosis together with paracellular transport by reversibly affecting tight junctions. In summary, this work presents the oral absorption characteristics and mechanisms of SCLP through the intestinal epithelium, which will facilitate the further development of SCLP and pectin polysaccharides.

Study on the pharmacokinetics of mulberry fruit polysaccharides through fluorescence labeling.

A sensitive and efficient fluorescence labeling method was developed and validated for the microanalysis and detection of polysaccharides. Fluorescein isothiocyanate (FITC) was successfully labeled on mulberry fruit polysaccharides (MFP) through a reductive amination reaction with the assistant of tyramine. The fluorescent labeled polysaccharides (FMFP) was identified by fluorescence, UV-visible, flourier transform infrared (FT-IR) and 1H NMR spectrum. Results demonstrated that the labeling efficiency of FMFP was 0.32%, and the FMFP was stable in simulated digestion fluid without cytotoxicity. The pharmacokinetics and biodistribution after administration were analyzed in rats, which indicated that the FMFP obtained could be absorbed in a short time (tmax 0.50 h) but eliminated slowly (t1/2 8.77 ± 1.38 h). At 24 h after administration, the polysaccharide could be tested mainly in intestine, stomach, liver and kidney. The FITC labeling method lays a foundation for investigating the absorption and metabolism of MFP, and provides references for the microanalysis research of bioactive polysaccharides.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

Nanoparticles composed of the tea polysaccharide-complexed cationic vitamin B12-conjugated glycogen derivative.

Tea polysaccharides exhibit multiple important bioactivities, but very few of them can be absorbed through the small intestine. To enhance the absorption efficacy of tea polysaccharides, a cationic vitamin B12-conjugated glycogen derivative bearing the diethylenetriamine residues (VB12-DETA-Gly) was synthesized and characterized using FTIR, 1H NMR, and UV-vis spectroscopy. An acidic tea polysaccharide (TPSA) was isolated from green tea. The TPSA/VB12-DETA-Gly complexed nanoparticles were prepared, which showed positive zeta potentials and were irregular spherical nanoparticles in the sizes of 50-100 nm. To enable the fluorescence and UV-vis absorption properties of TPSA, a Congo red residue-conjugated TPSA derivative (CR-TPSA) was synthesized. The interactions and complexation mechanism between the CR-TPSA and the VB12-DETA-Gly derivatives were investigated using fluorescence spectroscopy, resonance light scattering spectroscopy, and UV-vis spectroscopy. The results indicated that the electrostatic interaction could play a major role during the CR-TPSA and VB12-DETA-Gly-II complexation processes. The TPSA/VB12-DETA-Gly nanoparticles were nontoxic and exhibited targeted endocytosis for the Caco-2 cells, and showed high permeation through intestinal enterocytes using the Caco-2 cell model. Therefore, they exhibit potential for enhancing the absorption efficacy of tea polysaccharides through the small intestinal mucosa.

The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19.

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.

Fucoidan: a promising agent for brain injury and neurodegenerative disease intervention.

Brain injury and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are urgent medical problems, which severely threaten the life quality of patients and their carers. However, there are currently no effective therapies. Fucoidan is a natural compound found in brown algae and some animals, which has multiple biological and pharmacological activities, such as antioxidant, anti-tumor, anti-coagulant, anti-thrombotic, immunoregulatory, anti-viral, and anti-inflammatory effects. A growing number of studies have shown that fucoidan also exerts a neuroprotective function. Particularly, recent findings have indicated that fucoidan could slow down the neurodegenerative processes and show protective effects against brain injury, which might be of therapeutic value for intervening in brain injury and neurodegenerative diseases. In this review, we have discussed the pharmacokinetics of fucoidan as well as the molecular mechanisms by which fucoidan exerts its neuroprotective effect on some neurological disorders. Along with this, we have also summarized the potential benefits of fucoidan in combination with other drugs in the treatment of neurodegenerative diseases and brain injury. Although the extraction process of fucoidan has been improved well, more efforts should be devoted to the translational research and clinical trials of fucoidan in the near future.

Preparation and characterization of folic acid conjugated sulfated polysaccharides on NK cell activation and cellular uptake in HeLa cells.

In this study, the sulfated polysaccharide (SP) of Codium fragile was conjugated to folic acid (SP-FA). FT-IR and 1H NMR techniques revealed the occurrence of esterification reaction between the hydroxyl group of SP and the γ-carboxyl group of FA that confirming the SP-FA conjugation. SP and SP-FA did not show any direct toxicity on NK cells and HeLa cells. However, the treatment of SP and SP-FA enhance the NK cells cytotoxicity against HeLa cells by the upregulation of IFN-γ, TNF-α, perforin, and Granzyme-B. Moreover, NK cells activation was stimulated through NF-кB and MAPK pathways. The binding capacity studies exposed the targeting ability of HeLa cells by folate receptor (FR) which was assessed by a confocal quantitative image cytometer analysis. These results indicate that SP-FA could be used as selective drug delivery systems for targeting FR-overexpressed cancer cells with less toxicity.

Formation of a novel coating material containing lutein and zeaxanthin via a Maillard reaction between bovine serum albumin and fucoidan.

The effective delivery of bioactive compounds has recently been receiving attention. In this study, a conjugate with BSA and fucoidan synthesized via the Maillard reaction was confirmed through electrophoresis, the o-phthalaldehyde assay, and through changes in absorbance. Two moles of fucoidan were glycated with one mole of BSA at 60 °C and 79% relative humidity for 4 days. The droplet coated with B-F conjugate remained stable during storage at 4 and 25 °C and slightly increased only at 55 °C however, the droplet coated with intact BSA and B/F mixture significantly increased. L/Z were degraded about 82, 79, and 36% for 4, 25, and 55 °C, respectively, regardless of the type of emulsifier. Although the conjugates could not prevent the degradation of lutein and zeaxanthin during storage, they improved the stability of the emulsion and showed 4.20-fold and 1.32-fold higher bioaccessibility than intact BSA and B/F mixtures, respectively.

Bioinspired lipid-polysaccharide modified hybrid nanoparticles as a brain-targeted highly loaded carrier for a hydrophilic drug.

Lipid-polysaccharide modified biohybrid nanoparticles (NPs) are eminent drug carriers for brain targeting, owing to their ability to prolong the circulation time and penetrate the blood brain barrier (BBB). Biohybrid NPs particular interest arises from their potential to mimic biological components. Herein, we prepared bioinspired lipid polymeric NPs, either naked or surface modified by a synthesized biocompatible dextran-cholic acid (DxC). The nanoprecipitation method was tailored to allow the assembly of the multicomponent NPs in a single step. Modulating the solvent/antisolvent system provided lipid polymer hybrid NPs in the size of 111.6 ± 11.4 nm size. The NPs encapsulated up to 92 ± 1.2% of a hydrophilic anti-Alzheimer drug, rivastigmine (Riv). The brain uptake, biodistribution and pharmacokinetics studies, proved the efficient fast penetration of the bioinspired surface modified NPs to the brain of healthy albino rats. The modified nanocarrier caused a 5.4 fold increase in brain targeting efficiency compared to the drug solution. Furthermore, the presence of DxC increased Riv's brain residence time up to 40 h. The achieved results suggest that the fabricated biohybrid delivery system was able to circumvent the BBB and is expected to minimize Riv systemic side effects.

Advances in tracking of polysaccharides in vivo: Labeling strategies, potential factors and applications based on pharmacokinetic characteristics.

Due to their good physicochemical properties, high biocompatibility and low toxicity, polysaccharides have been widely used as biomaterials in the fields of medicine and biology. However, in vivo investigations of their pharmacokinetics are significantly restricted by the difficulty in detection of polysaccharides. To date, polysaccharide labeling has become one of the most promising approaches for tracking polysaccharides in vivo. Here, we review fluorescent and radioisotopic labeling methods for polysaccharides and their applications in tracking polysaccharides in vivo, and compare the advantages and disadvantages of different labeling methods. The potential factors affecting the pharmacokinetics of polysaccharides in vivo were summarized, including the monosaccharide composition, charge, molecular weight and dosage of polysaccharides, as well as the physiological state of the organism. This review also prospects the applications of polysaccharides in medicine based on the reported pharmacokinetic characteristics in vivo.

Dietary Isomalto/Malto-Polysaccharides Increase Fecal Bulk and Microbial Fermentation in Mice.

SCOPE: The prevalence of metabolic-syndrome-related disease has strongly increased. Nutritional intervention strategies appear attractive, particularly with novel prebiotics. Isomalto/malto-polysaccharides (IMMPs) represent promising novel prebiotics that promote proliferation of beneficial bacteria in vitro. The present study investigates for the first time the in vivo effects of IMMP in mice. METHODS AND RESULTS: C57BL/6 wild-type mice received control or IMMP-containing (10%, w/w) diets for 3 weeks. IMMP leads to significantly more fecal bulk (+26%, p < 0.05), higher plasma non-esterified fatty acids (colorimetric assay, +10%, p < 0.05), and lower fecal dihydrocholesterol excretion (mass spectrometry, -50%, p < 0.05). Plasma and hepatic lipid levels (colorimetric assays following lipid extraction) are not influenced by dietary IMMP, as are other parameters of sterol metabolism, including bile acids (gas chromatography/mass spectrometry). IMMP is mainly fermented in the cecum and large intestine (high-performance anion exchange chromatography). Next-generation sequencing demonstrates higher relative abundance of Bacteroides and butyrate producers (Lachnospiraceae, Roseburia Odoribacter) in the IMMP group. CONCLUSION: The combined results demonstrate that IMMP administration to mice increases fecal bulk and induces potentially beneficial changes in the intestinal microbiota. Further studies are required in disease models to substantiate potential health benefits.

In vitro and in vivo evaluation of the influences of polysaccharides derived from Glycyrrhiza uralensis on three alkaloids and potential interaction mechanisms.

The purpose of this study was to investigate the influences of the polysaccharides derived from Glycyrrhiza uralensis Fisch. (GCPs) on aconitine (AC), hypaconitine (HA), and benzoylmesaconine (BMA) from Aconitum carmichaelii Debx. and to explore potential interaction mechanisms. Biopharmaceutical properties in vitro including stability, aqueous solubility and permeability were determined by UPLC. Pharmacokinetic parameters in vivo were determined using UPLC-MS/MS. Phase solubility analysis, UV-vis spectrophotometry and differential scanning calorimetry (DSC) were used to explore potential interaction mechanisms. The results showed that GCPs could increase the stabilities of three alkaloids and solubilities of AC and HA, significantly decrease permeabilities of three alkaloids. The pharmacokinetic studies demonstrated that, after combination with GCPs, AC exhibited a higher Cmax value, shorter t0.5, higher elimination rate and greater area under the concentration-time curve (AUC) value compared to free AC. GCPs also improved the Cmax, t0.5, AUC(0-tn) and AUC(0-∞) values of HA to play a therapeutic role, and improved the t0.5 and AUC(0-∞) values of BMA to prolong the pharmacological effect and increase bioavailability. In addition, the results for the apparent formation constants and DSC analysis showed that an inclusion complex could be formed between GCPs and AC, GCPs and HA, and GCPs and BMA.

Ultrasonic-assisted extraction and antioxidant activity of polysaccharides from Eucommia ulmoides leaf.

Eucommia ulmoides is valuable medicinal plant in China. In this study, ultrasonic technology was used to extract polysaccharides and orthogonal design was applied to choose the optimal extraction conditions. The optimal extraction conditions of E. ulmoides polysaccharides were made up of the ratio of water to raw 30, extraction time 80 min, extraction temperature 60°C and extraction power 200 W. Under these conditions, the extraction polysaccharides content reached 164.95 mg/g. In addition, the potential antioxidant activity of crude polysaccharides (Cp) and pure polysaccharides (Pp) was demonstrated by evaluating reducing power assay, DPPH radical-scavenging assay, OH radical-scavenging assay and ABTS radical-scavenging assay. The results showed that E. ulmoides polysaccharides had significantly impact on the scavenging of DPPH radicals, OH radicals and ABTS radicals, expecially in DPPH radicals with an IC50 values of 0.005 mg/mL and 0.011 mg/mL in Cp and Pp, respectively. However, they were less effective in reducing power assay with low IC50 values of 1.091 mg/mL and 1.041 mg/mL separately. These results indicated that polysaccharides from E. ulmoides leaf could be applied as potential antioxidant.

Polysaccharide Nanoparticles Bearing HDAC Inhibitor as Nontoxic Nanocarrier for Drug Delivery.

The histone deacetylase inhibitors (HDACi) are potent drugs in the treatment of inflammatory diseases and defined cancer types. However, major drawbacks of HDACi, such as valproic acid (VPA), are limited serum half-life, side effects and the short circulation time. Thus, the immobilization of VPA in a polysaccharide matrix is used to circumvent these problems and to design a suitable nanocarrier system. Therefore, VPA is covalently attached to cellulose and dextran via esterification with degree of substitution (DS) values of up to 2.20. The resulting hydrophobic polymers are shaped to spherical nanoparticles (NPs) with hydrodynamic diameter between 138 to 221 nm and polydispersity indices from 0.064 to 0.094 by nanoprecipitation and emulsification technique. Lipase treatment of the NPs leads to in vitro release of VPA and hence to an inhibition of HDAC2 activity in a HDAC2 assay. NPs are rapidly taken up by HeLa cells and mainly localize in the cytoplasm. The NPs are hemocompatible and nontoxic as revealed by the shell-less hen's egg model.

Novel nano-pomegranates based on astragalus polysaccharides for targeting ERα-positive breast cancer and multidrug resistance.

Chemotherapy is an important method for treating breast cancer. However, multidrug resistance is one of the major challenges in breast cancer chemotherapy. There is an urgent need to develop novel, effective antitumor strategies that will perfect existing therapeutic regimens. In this study, the double-targeted nanocarrier, Quercetin-3'3-dithiodipropionic acid-Astragalus polysaccharides-Folic acid (QDAF), was successfully synthesized and self-assembled into a neoteric nano-targeted delivery strategy, named nano-pomegranates, and which were utilized to effectively inhibit multidrug resistance in estrogen receptor α (ERα)-positive breast tumor. The outstanding abilities of nano-pomegranates to release the drug in a reducing environment was determined by in vitro release assay. The cellular studies in MCF-7 cells were examined that nano-pomegranates have remarkable efficiencies of enhancing cellular uptake, inhibition and necrosis and apoptosis. In vivo antitumor experiments showed that nano-pomegranates have better anti-tumor effects and lower systemic toxicity than free Cur. In conclusion, nano-pomegranates have great potential in anti-breast cancer treatment.