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 in vivo. However, poor lipid solubility has limited the encapsulation efficacy during formulation development. Moreover, although the active metabolite of CAT3, 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403), can penetrate the blood-brain barrier and approach the brain tissue with a 1000-fold higher anti-glioma activity than CAT3 in vitro, its bioavailability and Cmax were considerably low in plasma, limiting the anti-tumor efficacy. In this study, a novel oleic acid-CAT3 conjugate (OA-CAT3) was synthesized at the first time to increase the lipid solubility of CAT3. The OA-CAT3 loaded solid lipid nanoparticles (OA-CAT3-SLN) were constructed using an ultrasonic technique to enhance the bioavailability and Cmax of PF403 in plasma. Our results demonstrated that CAT3 was amorphous in the lipid core of OA-CAT3-SLN and the in vitro release was well controlled. Furthermore, the encapsulation efficacy and the zeta potential increased to 80.65 ± 6.79% and −26.7 ± 0.46 mV, respectively, compared to the normal CAT3 loaded SLN. As indicated by the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) quantitation, the monolayer cellular transepithelial transport rate of OA-CAT3-SLN improved by 2.42-fold relied on cholesterol compared to the CAT3 suspension. Hence, the in vitro cell viability of OA-CAT3-SLN in C6 glioma cells decreased to 29.77% ± 2.13% and 10.75% ± 3.12% at 48 and 72 h, respectively. Finally, compared to the CAT3 suspension, the in vivo pharmacokinetics in rats indicated that the plasma bioavailability and Cmax of PF403 as afforded by OA-CAT3-SLN increased by 1.7- and 5.5-fold, respectively. Overall, the results indicate that OA-CAT3-SLN could be an efficacious delivery system in the treatment of glioma.
Highlights
Glioblastoma multiforme (GBM) is an aggressive astrocytic cell neoplasm and is one of the leading causes of cancer-related deaths in both pediatric and adult populations, while having poor clinical outcomes [1]
The band at 2793 cm−1 of oleic acid-CAT3 conjugate (OA-CAT3) can be referred to NH+ asymmetric stretching
These bands disappeared from the spectra for oleic acid (OA)-CAT3, indicating the formation of the conjugate
Summary
Glioblastoma multiforme (GBM) is an aggressive astrocytic cell neoplasm and is one of the leading causes of cancer-related deaths in both pediatric and adult populations, while having poor clinical outcomes [1]. In 1999, the US Food and Drug Administration indicated oral temozolomide (TMZ), a DNA alkylating agent, as a first-line agent in the treatment of refractory anaplastic astrocytoma; in 2005, this indication was expanded to newly diagnosed glioblastoma patients [4,5]. Temozolomide has been associated with severe toxicity, with the ensuing drug resistance limiting the efficacy and clinical use [6,7]. CAT3 (Figure 1A) is a novel phenanthroindolizidine substance that selectively inhibits the hedgehog signaling pathway, demonstrating a significant inhibitory effect in GBM and TMZ-resistant GBM in orthotopic glioblastoma mice models following oral administration [8,9,10]. Central nervous system toxicity, one of the main obstacles in the development of phenanthroindolizidines, has not been associated with CAT3 [11]. PF403 (Figure 1B), reporting an in vitro anti-glioma activity aPphaprmroacxeiumticast2e0l2y0,11020, x0 times higher than CAT3 [8] in human cell lines, is the active metabolite of C3AofT233 sbyionathveasilizaebdilibtyy eismteprraosveseminevnitvoinanthdecaanctpiveenemtreattaebthoelibtel,ooPdF-4b0r3a,inbbyaOrrAier-CtoAdTe3m-SoLnNst.raTtoe aanchanietvi-egltihomesae egffoeaclst,[t1h2e–s1i4z]e. dAilstthroibuugthioCn,AzTe3tacpanotbenetaiabls,oDrbLe, dEEv,iasotlhide-gsatastterocihnatreasctitnearilztartaicotn, iotfisthaebdiroupgh,aarnmdaicneuvittircos crelalessaisfiecwateioren csoymstepmarecdlasbsetIwVedernugO,Ain-CsoAluTb3l-eSLinNwaantderC, wAiTth3-pSLoNor. bFiuor-tmheermmborraen,ethpeerCmaecaob-2ilicteyl,luanladr duepmtaoknes,tMraatidnignl-oDwarbbiyoacvaaniilnabeilkitidynaenyd cCemllasxtoraf nitssfaeccttievde wmietthabthoelitheu, PmFa4n03M, iDn Rvi1vgoe. nMeo(rMeoDvCerK, t-hMeDlipRi1d) smoolunboillaityyeor ftrCaAnTsf3eri,s aanlsdo tphoeoCr, 6fugrltihoemr ainccerlelacsyintogttohxeicchacatlilvenitgyeosfasOsAoc-iCaAteTd3w-SiLthNthweedreeveevloaplumateendt oinf avpitproro. pFirniaatlelyl,ipaindidnevliivveoryphvaerhmicalceos.kiHneetniccee,vtahleuaptoioonr boifoOavAa-iClaAbiTli3t-ySLanNdwthaes lcoowndauqcuteedouins aSnpdralgipuiedsDoaluwblielyiti(eSsDr)emraatsinuesdincgruthciealCoAbTst3acsulesspteontshioenc,liOniAca-Cl aApTp3l,icaantidonCAofTC3-ASTL3N. as controls
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