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Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment.

ABSTRACT: 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.

SUBMITTER: Mao X

PROVIDER: S-EPMC8774041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles.

Project description:Cisplatin is used to treat a variety of tumors, but dose limiting toxicities or intrinsic and acquired resistance limit its application in many types of cancer including prostate. We report a unique strategy to deliver cisplatin to prostate cancer cells by constructing Pt(IV)-encapsulated prostate-specific membrane antigen (PSMA) targeted nanoparticles (NPs) of poly(D,L-lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-functionalized controlled release polymers. By using PLGA-b-PEG nanoparticles with PSMA targeting aptamers (Apt) on the surface as a vehicle for the platinum(IV) compound c,t,c-[Pt(NH(3))(2)(O(2)CCH(2)CH(2)CH(2)CH(2)CH(3))(2)Cl(2)] (1), a lethal dose of cisplatin was delivered specifically to prostate cancer cells. PSMA aptamer targeted delivery of Pt(IV) cargos to PSMA(+) LNCaP prostate cancer cells by endocytosis of the nanoparticle vehicles was demonstrated using fluorescence microscopy by colocalization of green fluorescent labeled cholesterol-encapsulated NPs and early endosome marker EEA-1. The choice of linear hexyl chains in 1 was the result of a systematic study to optimize encapsulation and controlled release from the polymer without compromising either feature. Release of cisplatin from the polymeric nanoparticles after reduction of 1 and formation of cisplatin 1,2-intrastrand d(GpG) cross-links on nuclear DNA was confirmed by using a monoclonal antibody for the adduct. A comparison between the cytotoxic activities of Pt(IV)-encapsulated PLGA-b-PEG NPs with the PSMA aptamer on the surface (Pt-NP-Apt), cisplatin, and the nontargeted Pt(IV)-encapsulated NPs (Pt-NP) against human prostate PSMA-overexpressing LNCaP and PSMA(-) PC3 cancer cells revealed significant differences. The effectiveness of PSMA targeted Pt-NP-Apt nanoparticles against the PSMA(+) LNCaP cells is approximately an order of magnitude greater than that of free cisplatin.

| S-EPMC2582270 | biostudies-other

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| S-EPMC9448443 | biostudies-literature

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| S-EPMC5471451 | biostudies-literature

Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device.

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| S-EPMC2536766 | biostudies-literature

Comprehensive Vibrational Spectroscopic Investigation of trans,trans,trans-[Pt(N3)2(OH)2(py)2], a Pt(IV) Diazido Anticancer Prodrug Candidate.

Project description:We report a detailed study of a promising photoactivatable metal-based anticancer prodrug candidate, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (C1; py = pyridine), using vibrational spectroscopic techniques. Attenuated total reflection Fourier transform infrared (ATR-FTIR), Raman, and synchrotron radiation far-IR (SR-FIR) spectroscopies were applied to obtain highly resolved ligand and Pt-ligand vibrations for C1 and its precursors (trans-[Pt(N3)2(py)2] (C2) and trans-[PtCl2(py)2] (C3)). Distinct IR- and Raman-active vibrational modes were assigned with the aid of density functional theory calculations, and trends in the frequency shifts as a function of changing Pt coordination environment were determined and detailed for the first time. The data provide the ligand and Pt-ligand (azide, hydroxide, pyridine) vibrational signatures for C1 in the mid- and far-IR region, which will provide a basis for the better understanding of the interaction of C1 with biomolecules.

| S-EPMC4916484 | biostudies-literature

Red light active Pt(iv)-BODIPY prodrug as a mitochondria and endoplasmic reticulum targeted chemo-PDT agent.

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| S-EPMC9749958 | biostudies-literature

Facile Synthesis of a Pt(IV) Prodrug of Cisplatin and Its Intrinsically <sup>195m</sup>Pt Labeled Analog: A Step Closer to Cancer Theranostic.

Project description:Background aims and objectivesCisplatin is extensively used in chemotherapy for treatment of a broad range of cancers. But its undesired side reactions with biomolecules that lead to severe side effects especially on kidney and nervous system, are limiting its clinical utility. To reduce its side effects, the kinetically inert Pt(IV) prodrug was recognized as an alternative approach from satisfactory results of preliminary experiments. But, its approval as anticancer drug for clinical use requires detailed investigations of its anticancer action and pharmacological pathways by employing its analogue which can be traced by a suitable technique. As a step closer towards translation of Pt(IV)-based prodrug from research to clinical level, a protocol for efficient synthesis of 195mPt-radiolabeled Pt(IV) prodrug was devised.Materials and methodsIn order to achieve the aim, we started synthesis from elemental platinum avoiding lengthy steps. The synthesis protocol was standardized on its cold analogue, as [PtCl2(NH3)2(OCOCH2CH2COOH)2] which has been characterized with nuclear magnetic resonance (1H, 13C{1H} and 195Pt{1H}) spectroscopy, microanalyses and cyclic voltammetry. Also, cytotoxicity of [PtCl2(OCOCH2CH2COOH)2(NH3)2] was evaluated against MCF-7 human breast cancer cell lines using cisplatin as test control.ResultsIntrinsically, 195mPt-labeled analogue of prodrug was obtained with high radionuclidic and radiochemical purity. It was confirmed by chromatography and γ-ray spectrometry.ConclusionThe 195mPt-radiolabeled prodrug was synthesized in a facile manner. It can be utilized in evaluating the mechanism of anticancer action and pharmacokinetics by enabling synergistic use of molecular imaging and targeted drug delivery.

| S-EPMC8320819 | biostudies-literature

A Pt(IV) Prodrug Combining Chlorambucil and Cisplatin: a Dual-Acting Weapon for Targeting DNA in Cancer Cells.

Project description:In this study, two DNA-targeting agents, cisplatin and chlorambucil, were combined in a Pt(IV) prodrug, 1, which was thoroughly characterized by means of spectroscopic and spectrometric techniques. Tested towards a panel of various human tumor cell lines, this compound showed superior in vitro antitumor potential than the reference drug cisplatin. In addition, an antitumor potential of 1 was found, which is comparable to that of oxaliplatin in 3D spheroid models of colon cancer cells. Mechanistic studies performed in colon cancer cells confirmed that the conjugation of chlorambucil to Pt(IV) cisplatin-based scaffold tunes the lipophilicity of the prodrug, consequently improving the ability of the compound to accumulate into cancer cells and to target DNA, ultimately leading to apoptotic cancer cell death.

| S-EPMC6321036 | biostudies-literature

A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma.

Project description:Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.

| S-EPMC9881056 | biostudies-literature

Improvements in the Synthesis and Understanding of the Iodo-bridged Intermediate en Route to the Pt(IV) Prodrug Satraplatin.

Project description:Mixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH3-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(μ-I)]2, where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(μ-I)]2, where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH2C6H11)(NH3)I2] upon treatment with NH3.

| S-EPMC4243179 | biostudies-literature

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