Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity

Abstract

BackgroundMesenteric lymph nodes (MLNs) are critical draining lymph nodes of the immune system that accommodate more than half of the body’s lymphocytes, suggesting their potential value as a cancer immunotherapy target. Therefore, efficient delivery of immunomodulators to the MLNs holds great potential for activating immune responses and enhancing the efficacy of antitumor immunotherapy. Self-microemulsifying drug delivery systems (SMEDDS) have attracted increasing attention to improving oral bioavailability by taking advantage of the intestinal lymphatic transport pathway. Relatively little focus has been given to the lymphatic transport advantage of SMEDDS for efficient immunomodulators delivery to the MLNs. In the present study, we aimed to change the intestinal lymphatic transport paradigm from increasing bioavailability to delivering high concentrations of immunomodulators to the MLNs.MethodsChlorogenic acid (CHA)-encapsulated SMEDDS (CHA-SME) were developed for targeted delivery of CHA to the MLNs. The intestinal lymphatic transport, immunoregulatory effects on immune cells, and overall antitumor immune efficacy of CHA-SME were investigated through in vitro and in vivo experiments.ResultsCHA-SME enhanced drug permeation through intestinal epithelial cells and promoted drug accumulation within the MLNs via the lymphatic transport pathway. Furthermore, CHA-SME inhibited tumor growth in subcutaneous and orthotopic glioma models by promoting dendritic cell maturation, priming the naive T cells into effector T cells, and inhibiting the immunosuppressive component. Notably, CHA-SME induced a long-term immune memory effect for immunotherapy.ConclusionsThese findings indicate that CHA-SME have great potential to enhance the immunotherapeutic efficacy of CHA by activating antitumor immune responses.

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration

“…A small number of SEDDS-based products have already been successfully introduced into the pharmaceutical market, with none of them loading drugs for the treatment of neurological disorders. Until now, several in vivo assays using oral SEDDS have been carried out for neuropharmaceuticals brain targeting [ 4 , 6 , 23 , 24 , 25 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 70 ], but only a few in vivo pre-clinical studies have been reported for IN administration of neurotherapeutics loaded in SEDDS. In fact, only six studies were found that investigated the IN administration of neurotherapeutics loaded in SEDDS: clonazepam [ 45 ], diazepam [ 44 ], and perampanel [ 28 ] for epilepsy treatment; Bdph for glioblastoma treatment [ 4 ]; huperzine A [ 30 ] for Alzheimer’s disease; and naringin [ 5 ] as a neuroprotective for Alzheimer’s and Parkinson’s disease.…”

“…In Table 2 , it can also be observed that the majority of the here-reviewed compounds belong to BCS class II or IV, similar to most chemical entities investigated to treat neurological disorders [ 6 , 7 ]. Only zolmitriptan [ 46 ], ginsenoside Rg1 [ 47 ], and chlorogenic acid [ 48 ] are reported to belong to BCS class III.…”

“…This demonstrates the advantages of using nasal SEDDS rather than a simple nasal solution, the oral route or the invasive IV route for brain delivery of drugs. By analyzing Table 2 , it is noted that, despite the pharmacokinetic evaluation, some authors also performed behavioral studies to compare the efficacy and safety of drugs loaded in SEDDS administered with those of simple solutions, suspensions or commercial preparations of the same drugs [ 4 , 25 , 29 , 31 , 32 , 33 , 46 , 48 , 49 , 50 ]. For the case of glioblastoma treatment, efficacy was directly assessed after oral administration of chlorogenic acid SMEDDS [ 48 ] or the new prodrug 13a-(S)-3-pivaloylocyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) [ 49 ].…”

“…By analyzing Table 2 , it is noted that, despite the pharmacokinetic evaluation, some authors also performed behavioral studies to compare the efficacy and safety of drugs loaded in SEDDS administered with those of simple solutions, suspensions or commercial preparations of the same drugs [ 4 , 25 , 29 , 31 , 32 , 33 , 46 , 48 , 49 , 50 ]. For the case of glioblastoma treatment, efficacy was directly assessed after oral administration of chlorogenic acid SMEDDS [ 48 ] or the new prodrug 13a-(S)-3-pivaloylocyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) [ 49 ]. For this, tumor growth in rodent glioma models was evaluated either by weighting the tumor after euthanasia [ 48 ] or through bioluminescence signals [ 49 ].…”

“…For the case of glioblastoma treatment, efficacy was directly assessed after oral administration of chlorogenic acid SMEDDS [ 48 ] or the new prodrug 13a-(S)-3-pivaloylocyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) [ 49 ]. For this, tumor growth in rodent glioma models was evaluated either by weighting the tumor after euthanasia [ 48 ] or through bioluminescence signals [ 49 ]. Both studies concluded that loading the drugs into SEDDS leads to a larger inhibition of tumor growth compared with the oral suspension.…”