Improved Safety and Anti-Glioblastoma Efficacy of CAT3-Encapsulated SMEDDS through Metabolism Modification

Abstract

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood–brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats’ plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15–30 nm), positive charge (5–9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2–6-fold and 1.3–7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.

Mechanism Study on Nanoparticle Negative Surface Charge Modification by Ascorbyl Palmitate and Its Improvement of Tumor Targeting Ability

“…The morphological evaluation of PTX–LNPs was carried out by transmission electron microscopy (TEM, Hitachi H-7650, Tokyo, Japan) [ 8 ]. Two drops of the PTX–LNPs were deposited on a film-coated copper grid and negatively stained with 1% ( w / v ) phosphotungstic acid for 5 min before observation under an electron microscope [ 44 ].…”

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.…”

“…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.…”