0723806f83b787235944c797320a5ba2 pmc_35053575.pdf fe5e77066e5f9e31bb905de044bf04842d09a744 pmc_35053575.pdf 932cdbef461b8e9873e2dc45bb2de654b210c2d7f5dad851d37c44bc67b5dbf5 pmc_35053575.pdf Title: Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment Subject: Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood–brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood–brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration. Keywords: glioblastoma; bioinspired; Pt(IV); prodrug; catechol; platinum drugs; intranasal Author: Xiaoman Mao, Shuang Wu, Pilar Calero-Pérez, Ana P. Candiota, Paula Alfonso, Jordi Bruna, Victor J. Yuste, Julia Lorenzo, Fernando Novio and Daniel Ruiz-Molina Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Jan 14 11:11:01 2022 CET ModDate: Mon Jan 17 02:12:30 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1983937 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 YSAOHE+VnURWPalladioL Type 1 Custom yes yes no 15 0 DSYJZA+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 JEUVZQ+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 MDWDBE+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 36 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 40 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 44 0 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yes 171 0 XIRVNA+EURB10 Type 1 Builtin yes yes no 182 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 197 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 201 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 205 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 219 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 223 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 227 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 231 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-03-16 02:27:29 CET RepresentationInformation: pmc_35053575.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-01-31 03:37:51 CET Size: 1983937 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 466 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Chemicals and Instrumentation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Synthesis of Complex 1 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: In Vitro Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Cell Viability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Estimation of ROS Formation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Cellular Internalization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: DNA-Bound Pt Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: In Vivo Studies Destination: 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edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: In Vitro Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Children: Item: Title: Cytotoxicity and Cell Internalization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Pt Bound to DNA Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Oxidative Stress Assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: In Vivo Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Children: Item: Title: Tolerability Assessment in Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Efficacy Evaluation In Vivo Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Info: Title: Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment Author: Xiaoman Mao, Shuang Wu, Pilar Calero-Pérez, Ana P. Candiota, Paula Alfonso, Jordi Bruna, Victor J. Yuste, Julia Lorenzo, Fernando Novio and Daniel Ruiz-Molina Subject: Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration. 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