Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates

Wang, Hongliang; Lin, Li; Ye, Jun; Wang, Rubing; Wang, Renyun; Hu, Jiye; Wang, Yanan; Dong, Wei; Xia, Xuejun; Yang, Yanfang; Gao, Yue; Gao, Lili; Liu, Yuling

doi:10.3390/pharmaceutics12020126

Cited by 21 publications

(27 citation statements)

References 57 publications

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“…Finally, compared with OA-CAT3-SLN, CAT3-SMEDDS shows the following advantages. The controlled release of CAT3 from CAT3-SMEDDS in vitro is the slowest compared with the CAT3 suspension and OA-CAT3-SLN [ 9 ]. Thus, this controlled release will make the encapsulated CAT3 more stable not only in the gastrointestinal fluid but also in plasma.…”

Section: Discussionmentioning

confidence: 99%

“…However, CAT3 is a biopharmaceutics classification system IV drug, which is insoluble in water and has low bioavailability in vivo [ 8 , 9 ]. Moreover, it demonstrates serious gastrointestinal side effects after oral administration, including severe loose stool or diarrhea, which limits its clinical application.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, it has been reported that CAT3 is not stable in intestinal fluid and about 59% of CAT3 is metabolized into PF403 after incubation with artificial intestinal fluid for 15 min [ 8 ]. Previous research has shown that oleic acid–CAT3 conjugate-loaded solid lipid nanoparticles (OA-CAT3-SLN) can greatly increase its bioavailability [ 9 ]; however, more serious gastrointestinal side effects were observed in vivo. Therefore, simply relying on increasing bioavailability to promote therapeutic effects will not work.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2021

Molecules

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2021

Molecules

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“…• In vivo: PLGA-NP (Sousa et al, 2019;Ye et al, 2019;Caban-Toktas et al, 2020;Chung et al, 2020), RGD-NP (Ullah et al, 2020), oleic acid NP (Wang H. et al, 2020) • In vitro only: PLGA-NP (Luque-Michel et al, 2019;Ferreira et al, 2020;Roberts et al, 2020), ethyl arachidate (TPLN) (Alves et al, 2020), FONP (Daniel et al, 2019), pSiNPs…”

Section: Use Experimental Setting and Nanoparticle Typementioning

confidence: 99%

“…2019; Shi et al, 2019;Sousa et al, 2019;Ye et al, 2019;Zhang et al, 2019;Zhao et al, 2019;ZhuGe et al, 2019;Alves et al, 2020;Caban-Toktas et al, 2020;Chung et al, 2020;Ferreira et al, 2020;Kazmi et al, 2020;Liang et al, 2020;Martinez-Rovira et al, 2020;Meng et al, 2020;Roberts et al, 2020;Ullah et al, 2020;Wang H. et al, 2020;Wang X. et al, 2020;Xu et al, 2020;Zhu et al, 2020; see Table 3 for examples of ligand targeting in glioma research). Another active targeting method to increase functional specificity of NPs that are used as gene delivery systems is the transcriptional targeting, which can occur at a transcriptional or posttranscriptional level (Golombek et al, 2018).…”

Section: Radiotherapy Enhancermentioning

confidence: 99%

Nanoparticles for Stem Cell Therapy Bioengineering in Glioma

Ruiz‐Garcia

Alvarado-Estrada

Krishnan

et al. 2020

Front. Bioeng. Biotechnol.

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Gliomas are a dismal disease associated with poor survival and high morbidity. Current standard treatments have reached a therapeutic plateau even after combining maximal safe resection, radiation, and chemotherapy. In this setting, stem cells (SCs) have risen as a promising therapeutic armamentarium, given their intrinsic tumor homing as well as their natural or bioengineered antitumor properties. The interplay between stem cells and other therapeutic approaches such as nanoparticles holds the potential to synergize the advantages from the combined therapeutic strategies. Nanoparticles represent a broad spectrum of synthetic and natural biomaterials that have been proven effective in expanding diagnostic and therapeutic efforts, either used alone or in combination with immune, genetic, or cellular therapies. Stem cells have been bioengineered using these biomaterials to enhance their natural properties as well as to act as their vehicle when anticancer nanoparticles need to be delivered into the tumor microenvironment in a very precise manner. Here, we describe the recent developments of this new paradigm in the treatment of malignant gliomas.

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Lipid‐Based Nanocarriers for The Treatment of Glioblastoma

Iturrioz-Rodríguez

Bertorelli

Ciofani

2020

Advanced NanoBiomed Research

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Glioblastoma multiforme (GBM) is the most common and malignant neoplasia having origin in the brain. The current treatments involve surgery, radiotherapy, and chemotherapy, being complete surgical resection the best option for the patient survival chances. However, in those cases where a complete removal is not possible, radiation and chemotherapy are applied. Herein, the main challenges of chemotherapy, and how they can be overcome with the help of nanomedicine, are approached. Natural pathways to cross the blood–brain barrier (BBB) are detailed, and different in vivo studies where these pathways are mimicked functionalizing the nanomaterial surface are shown. Later, lipid-based nanocarriers, such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, are presented. To finish, recent studies that have used lipid-based nanosystems carrying not only therapeutic agents, yet also magnetic nanoparticles, are described. Although the advantages of using these types of nanosystems are explained, including their biocompatibility, the possibility of modifying their surface to enhance the cell targeting, and their intrinsic ability of BBB crossing, it is important to mention that research in this field is still at its early stage, and extensive preclinical and clinical investigations are mandatory in the close future.

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Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates

Cited by 21 publications

References 57 publications

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

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

Nanoparticles for Stem Cell Therapy Bioengineering in Glioma

Lipid‐Based Nanocarriers for The Treatment of Glioblastoma

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