Study On Weichang’an Pill Regulating Intestinal Flora And Anti-colon Cancer Nano-drug Delivery System Of Active Traditional Chinese Medicine Ingredients Included Magnolol

As a traditional Chinese patent medicine,Weichang ’an Pill(WCA)is composed of ten Chinese herbs,including Aucklandiae Radix,Aquilariae agallocha,Fructus Aurantii,Magnoliae officinalis,Santalum album L.,Ligusticum chuanxiong hort,Moschus berezovskii Flerov,Rheum officina,Semen crotonis pulveratum and Ziziphus jujuba Mill.Clinically,it is often used for various functional diseases of gastrointestinal tract,especially for antibiotic associated diarrhea(AAD)and irritable bowel syndrome(IBS).Although there are many researches on its clinical effects,there are relatively few researches on its correlation with intestinal flora.Magnolia officinalis(HP)is the king medicine of WCA.It has the functions of regulating Qi and reducing dampness and is often used in the treatment of gastrointestinal diseases.Previous studies of our group also found that HP and its main active components,HK and MAG have anti-diarrhea,anti-enteritis and other regulatory functions of intestinal diseases,especially good anti-colorectal cancer activity.However,its molecular target and anticancer mechanism are not well studied.Therefore,in this study,Ampicillin was first used to establish AAD mouse model and acetic acid enema plus binding stress was used to establish IBS-D rat model to study the relationship between WCA and intestinal flora.Furthermore,the anticancer activities of HK and MAG were studied by modern pharmacological techniques.Meanwhile,in order to improve the pharmacological activity and targeting of HK,nanotechnology was introduced to conduct in vitro and in vivo experimental evaluation of HK-NPs against colorectal cancer.Meanwhile,in order to improve the pharmacological activity and targeting of HK,small molecule self-assembly technology was adopted to self-assemble HK into nanoparticles(SA)through hydrogen bonding.Compared with free HK,100% SA showed good physiological stability.Moreover,due to the EPR effect,SA had excellent tumor targeting ability,especially showing significant selectivity for the p53 pathway,and the nano-agent form greatly enhanced the HK-induced immune antitumor effect.Meanwhile,combined with several first-line anticancer drugs,SA also showed a good synergistic anticancer effect on colorectal cancer.To sum up,the self-assembled drug delivery system provides a safe and "molecular economic" strategy for the rational design of clinical treatment for this drug,which is about to enter clinical phase III,and will promote targeted anti-cancer therapy for HK.Single drug therapy usually cannot completely inhibit tumor growth,and combination therapy strategy is widely used in clinical practice.Therefore,in this study,SA was further coated with polydopamine(PDA)and folic acid(FA)was used to modify the PDA surface to form a new carrier free pure nano drug(PNDs)preparation.The results showed that the combined nanosystem could inhibit the growth of colorectal cancer cell lines through chemical-photodynamic dual therapy.Therefore,the SA@PDA-FA NPs system is a promising candidate as a nanoplatform for multimodal therapy for tumor ablation.In addition,our long-term study found that pentacyclic triterpenoid(PTs)also has good antitumor activity.However,the active ingredients of this kind of traditional Chinese medicine(TCM)have defects such as insoluble in water,short half-life in vivo and dose-limiting toxicity.Therefore,in combination with the characteristics of PTs,the efficacy and possible anticancer mechanism of three PTs(glycyrrhetinic acid,ursolic acid and oleanolic acid)were studied in depth in this study with the help of new nano-medical technology(Carbon dots).Most notably,PTs-CD can effectively target mitochondria rather than being captured by lysosomes after cell internalization,indicating their great potential as new mitochondrial trackers.At the same time,PTs-CD obtained induced selective killing effects of apoptosis,autophagy and ferroptosis by targeting tumor mitochondria,respectively,without the need for complex tumor-specific biomarker binding,making them suitable for effective cancer therapy.In summary,this study firstly confirmed the regulatory activity of WCA on intestinal flora and elucidated the pharmacodynamic mechanism of WCA in regulating intestinal diseases.Simultaneously,the study on the anti-colorectal cancer activity of the main active ingredients MAG and HK of Magnolia officinalis not only provides a technical method for the discovery of pharmacodynamic substance basis and mechanism of action of target-based anti-tumor Traditional Chinese medicine,but also plays a leading role in the development and research of similar qi traditional Chinese medicine.Finally,PTs-CDs designed and prepared in this study can be used to intuitively discover the interaction between the active ingredients of Traditional Chinese medicine and cancer cells,providing a new idea for the development of the active ingredients of traditional Chinese medicine into the development of new anti-tumor drugs in the future.