Advances in herbal polysaccharides-based nano-drug delivery systems for cancer immunotherapy.

The boom in cancer immunotherapy has provided many patients with a better chance of survival, but opportunities often come with challenges. Single immunotherapy is not good enough to eradicate tumours, and often fails to achieve the desired therapeutic effect because of the low targeting of immunotherapy drugs, and causes more side effects. As a solution to this problem, researchers have developed several nano Drug Delivery Systems (NDDS) to deliver immunotherapeutic agents to achieve good therapeutic outcomes. However, traditional drug delivery systems (DDS) have disadvantages such as poor bioavailability, high cytotoxicity, and difficulty in synthesis, etc. Herbal Polysaccharides (HPS), derived from natural Chinese herbs, inherently possess low toxicity. Furthermore, the biocompatibility, biodegradability, hydrophilicity, ease of modification, and immunomodulatory activities of HPS offer unique advantages in substituting traditional DDS. This review initially addresses the current developments and challenges in immunotherapy. Subsequently, it focuses on the immunomodulatory mechanisms of HPS and their design as nanomedicines for targeted drug delivery in tumour immunotherapy. Our findings reveal that HPS-based nanomedicines exhibit significant potential in enhancing the efficacy of cancer immunotherapy, providing crucial theoretical foundations and practical guidelines for future clinical applications.

Isolation, Purification, and Structural Characterization of Polysaccharides from Codonopsis pilosula and Their Anti-Tumor Bioactivity by Immunomodulation.

The activity of polysaccharides is usually related to molecular weight. The molecular weight of polysaccharides is critical to their immunological effect in cancer therapy. Herein, the Codonopsis polysaccharides of different molecular weights were isolated using ultrafiltration membranes of 60- and 100-wDa molecular weight cut-off to determine the relationship between molecular weight and antitumor activities. First, three water-soluble polysaccharides CPPS-I (<60 wDa), CPPS-II (60-100 wDa), and CPPS-III (>100 wDa) from Codonopsis were isolated and purified using a combination of macroporous adsorption resin chromatography and ultrafiltration. Their structural characteristics were determined through chemical derivatization, GPC, HPLC, FT-IR, and NMR techniques. In vitro experiments indicated that all Codonopsis polysaccharides exhibited significant antitumor activities, with the tumor inhibition rate in the following order: CPPS-II > CPPS-I > CPPS-III. The treatment of CPPS-II exhibited the highest inhibition rate at a high concentration among all groups, which was almost as efficient as that of the DOX·HCL (10 µg/mL) group at 125 µg/mL concentration. Notably, CPPS-II demonstrated the ability to enhance NO secretion and the antitumor ability of macrophages relative to the other two groups of polysaccharides. Finally, in vivo experiments revealed that CPPS-II increased the M1/M2 ratio in immune system regulation and that the tumor inhibition effect of CPPS-II + DOX was superior to that of DOX monotherapy, implying that CPPS-II + DOX played a synergistic role in regulating the immune system function and the direct tumor-killing ability of DOX. Therefore, CPPS-II is expected to be applied as an effective cancer treatment or adjuvant therapy.

Rhodiola rosea polysaccharides-based nanoparticles loaded with DOX boosts chemo-immunotherapy for triple-negative breast cancer by re-educating Tumor-associated macrophages.

Hydrophobic drug delivery vectors suffer significant challenges in cancer therapy, including efficient encapsulation and tumor targeting ability. In the present study, Rhodiola rosea polysaccharides (RHPs), which have the ability to modulate Tumor-associated macrophages and typical structural characteristics, were employed as an immunoactive vector for drug delivery. Folic acid (FA) and stearic acid (SA) were chemically modified to the backbone of RHPs to obtain the self-assembly and tumor-targeting behavior. Further, the hydrophobic drug, doxorubicin (DOX), was encapsulated in the RHPs derivatives (FA-RHPs-SA) with high efficiency. Additionally, the optimally formed DOX@FA-RHPs-SA had a uniform size distribution of approximately 196 nm and a pH-sensitive release capacity in different acidic conditions. In vitro experiments demonstrated that tumor cells could efficiently uptake DOX@FA-RHPs-SA. Furthermore, the modulatory function of the FA-RHPs-SA on RAW264.7 macrophages was also demonstrated in the transition from M0 to M1 phenotypes, and the M2 differentiated into the M1. Finally, the in vivo antitumor study revealed that the inhibitory effect of DOX@FA-RHPs-SA was superior to the DOX monotherapy treatment, and the new preparation functioned synergistically by inducing tumor cell apoptosis and modulating immune cell function. In conclusion, this study described an RHPs-based hydrophobic delivery vector and achieved an additional helpful antitumor effect by modulating Tumor-associated macrophages.

[Biopharmaceutical classification and transport mechanism of 4 alkaloids in Mongolian herbal medicine Sophorae Flavescentis Radix].

In this study, we studied the solubility and permeability of matrine, oxymatrine, sophoridine, and oxysophocarpine, four alkaloids in the Mongolian herbal medicine Sophorae Flavescentis Radix, and evaluated the absorption mechanism with the Caco-2 cell model, so as to provide a basis for the new drug development and efficacy evaluation of Sophorae Flavescentis Radix. The results showed that all the four alkaloids had high solubility and high permeability and can be well absorbed, belonging to the class-I drugs of Biopharmaceutical Classification System(BCS). The absorption(AP→BL) and excretion(BL→AP) of matrine and oxymatrine were not affected by the concentration while the absorption depended on P-gp protein. The absorption(AP→BL) and excretion(BL→AP) of sophoridine and oxysophocarpine were positively related to the concentration and time, and the absorption process was independent from P-gp protein. The results provide scientific reference and an experimental basis for the development of Mongolian medical prescriptions containing Sophorae Flavescentis Radix.

[Absorption enhancing effects and safety of PAMAM dendrimers on liquiritin].

PAMAM dendrimer is one of the most widely studied dendrimers in recent years, which has a large number of functional groups on the surface and cavities inside, specific three-dimensional structure and good biocompatibility, permeability and stability. It has been widely applied in drug and gene carrier fields and may become a new absorption enhancer. In order to study the absorption enhancing effects of PAMAM dendrimers, liquiritin was selected as the model drug, with the protection of spleen and liver, detoxification and other functions, but it had not been widely used in clinical application because of its difficult absorption, first pass effect, and low bioavailability. This topic was based on the two main determinants (solubility and permeability) of intestinal absorption in the body, researched the physicochemical properties of liquiritin, analyzed the transport volume of liquiritin with or without PAMAM dendrimers by using Caco-2 cell model, and analyzed the cytotoxicity of PAMAM dendrimers on Caco-2 cells by MTT experiments. These results showed that 0.1% of the G4 generation PAG can promote the absorption of liquiritin safely and effectively, and it was suitable for further development into a new type of pharmaceutical excipients.

[Biopharmaceutics classification and absorption mechanisms primary study on four kinds of flavonoids].

The solubility and permeability on four kinds of flavonoids (kaempferol, hesperidin, apigenin, genistein) were test according to the theory of biopharmaceutics classification system (BCS), and their absorption mechanism. The solubility was investigated by the method in determination of solubility of "Chinese Pharmacopoeia 2010". To detect appearance permeability of compounds mentioned above, the appropriate concentrations were selected by the MTT method in cell transfer experiments in Caco-2 cell model, which established by in vitro cell culture method. Therefore, these compounds were classified with BCS according to solubility and permeability. In addition, to explore absorption mechanisms, the experiments in three different concentrations of compounds in high, medium and low in bidirectional transformation methods in Caco-2 cell model contacted. The study indicated that all of kaempferol, hesperidin, apigenin, genistein have the characteristics in low solubility and high permeability, which belong to BCSⅡ, and the absorption mechanism of kaempferol was active transportation. Whereas, hesperidin, apigenin, genistein were passive transportation. In this study, it carried out initial explorations on establishment of determination for solubility and permeability in flavonoids, and provided theoretical reference for further research on BCS in traditional Chinese medicine.

Design, synthesis of 6-substituted-pyrido[3,2-d]pyridazine derivatives with anticonvulsant activity.

Aim to find new compounds with stronger anticonvulsant activity and lower neurotoxicity, a novel series of 6-substituted-pyrido[3,2-d]pyridazine derivatives was synthesized using furo[3,4-b]pyridine-5,7-dione as the starting material. We evaluated their anticonvulsant activity and neurotoxicity using by maximal electroshock (MES) and rotarod neurotoxicity (TOX) tests. The results showed that N-m-chlorophenyl-[1,2,4]triazolo- [4,3-b]-pyrido[3,2- d]pyridazin-6-amine (3) was the most potent anticonvulsant, with ED50 value of 13.6 mg/kg and protective index ( PI = TD50/ED50) values of 7.2 in the MES test. Compound N-m-chlorophenyltetriazolo[5,1-b]-pyrido[3,2-d]pyridazin-6-amine (19), exhibited significant anticonvulsant activity in maximal electroshock test with PI value of 13.4, which was safer than marketed drug carbamazepine.

Design, Synthesis of 6-Substituted-pyrido[3,2-d]pyridazine Derivatives with Anticonvulsant Activity.

The aim of the present paper was to find new compounds with stronger anticonvulsant activity and lower neurotoxicity, a novel series of 6-substituted-pyrido[3,2-d]pyridazine derivatives was synthesized using furo[3,4-b]pyridine-5,7-dione as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and their neurotoxicity was measured by the rotarod test. The results of these tests demonstrated that N-m-chlorophenyl-[1,2,4]triazolo- [4,3-b]-pyrido[3,2-d]pyridazin-6-amine (3) was the most potent anticonvulsant, with ED50 value of 13.6 mg/kg and protective index (PI = TD50 / ED50) values of 7.2 in the MES test. Compound N-m-chlorophenyltetriazolo[5,1-b]-pyrido[3,2-d]pyridazin-6-amine (19), exhibited a little weaker activity than compound 3 in controlling the seizure induced by MES test at the dose of 15.9 mg/kg, but it possessed lower neurotoxicity with PI value of 13.4, which was safer than marketed drug carbamazepine.

Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives.

The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n). The bioevaluation demonstrated that most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED(50) value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 4h displayed broad-spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system.