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Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes.

ABSTRACT: The preparation of novel macromolecular prodrugs via the conjugation of two platinum(IV) complexes to suitably functionalized poly(organo)phosphazenes is presented. The inorganic/organic polymers provide carriers with controlled dimensions due to the use of living cationic polymerization and allow the preparation of conjugates with excellent aqueous solubility but long-term hydrolytic degradability. The macromolecular Pt(IV) prodrugs are designed to undergo intracellular reduction and simultaneous release from the macromolecular carrier to present the active Pt(II) drug derivatives. In vitro investigations show a significantly enhanced intracellular uptake of Pt for the macromolecular prodrugs when compared to small molecule Pt complexes, which is also reflected in an increase in cytotoxicity. Interestingly, drug-resistant sublines also show a significantly smaller resistance against the conjugates compared to clinically established platinum drugs, indicating that an alternative uptake route of the Pt(IV) conjugates might also be able to overcome acquired resistance against Pt(II) drugs. In vivo studies of a selected conjugate show improved tumor shrinkage compared to the respective Pt(IV) complex.

SUBMITTER: Henke H

PROVIDER: S-EPMC4976076 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes.

Henke Helena H Kryeziu Kushtrim K Banfić Jelena J Theiner Sarah S Körner Wilfried W Brüggemann Oliver O Berger Walter W Keppler Bernhard K BK Heffeter Petra P Teasdale Ian I

Macromolecular bioscience 20160512 8

The preparation of novel macromolecular prodrugs via the conjugation of two platinum(IV) complexes to suitably functionalized poly(organo)phosphazenes is presented. The inorganic/organic polymers provide carriers with controlled dimensions due to the use of living cationic polymerization and allow the preparation of conjugates with excellent aqueous solubility but long-term hydrolytic degradability. The macromolecular Pt(IV) prodrugs are designed to undergo intracellular reduction and simultaneo ...[more]

PMID: 27169668

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Project description:Over the last decades, gold nanoparticles (AuNPs) have proven to be remarkable tools for drug delivery and theranostic applications in cancer treatment. On the other hand, Pt(IV) prodrugs have been employed as an interesting alternative to the more common Pt(II) complexes, such as cisplatin, for cancer chemotherapy. Searching to design an image-guided nanocarrier to deliver selectively Pt(IV) prodrugs to tumors expressing the gastrin releasing peptide receptor (GRPR), we have synthesized small core AuNPs carrying a thiolated DOTA derivative, a GRPR-targeting bombesin analog (BBN[7-14]) and a Pt(IV) prodrug attached to the AuNPs without (AuNP-BBN-Pt1) or with a PEGylated linker (AuNP-BBN-Pt2 and AuNP-BBN-Pt3). In the GRPR+ prostate cancer PC3 cell line, the cytotoxic activity of the designed AuNP-BBN-Pt nanoparticles is strongly influenced by the presence of the PEGylated linker. Thus, AuNP-BBN-Pt1 displayed the lowest IC50 value (9.3 ± 2.3 µM of Pt), which is comparable to that exhibited by cisplatin in the same cell line. In contrast, AuNP-BBN-Pt1 showed an IC50 value of 97 ± 18 µM of Pt in the non-tumoral RWPE-1 prostate cells with a much higher selective index (SI) towards PC3 cells (SI = 10) when compared with cisplatin (SI = 1.3). The AuNPs were also successfully labeled with 67Ga and the resulting 67Ga-AuNP-BBN-Pt were used to assess their cellular uptake in PC3 cells, with AuNP-BBN-Pt1 also displaying the highest cellular internalization. Finally, intratumoral administration of 67Ga-AuNP-BBN-Pt1 in a PC3 tumor-bearing mice showed a prolonged retention of the nanoparticle compared to that of cisplatin, with optimal in vivo stability and 20% of the injected platinum remaining in the tumor after 72 h post-injection. Furthermore, microSPECT imaging studies confirmed the uptake and considerable retention of the 67Ga-labeled AuNPs in the tumors. Overall, these results show the potential of these targeted AuNPs loaded with Pt(IV) prodrugs for prostate cancer theranostics.

Project description:The possibility of spontaneous self-assembly of dicarboxylato Pt(IV) prodrugs and the consequences on their uptake in cancer cells have been evaluated in different aqueous solutions. Four Pt(IV) complexes, namely, (OC-6-33)-diacetatodiamminedichloridoplatinum(IV), Ace, (OC-6-33)-diamminedibutanoatodichloridoplatinum(IV), But, (OC-6-33)-diamminedichloridodihexanoatoplatinum(IV), Hex, and (OC-6-33)-diamminedichloridodioctanoatoplatinum(IV), Oct, have been dispersed in i) milliQ water, ii) phosphate buffered saline, and iii) complete cell culture media (RPMI 1640 or DMEM) containing fetal bovine serum (FBS). The samples have been analyzed by dynamic light scattering (DLS) to measure the size and distribution of the nanoparticles possibly present. The zeta potential offered an indication of the stability of the resulting aggregates. In the case of the most lipophilic compounds of the series, namely, Oct and to a lesser extent Hex, the formation of nanosized aggregates has been observed, in particular at the highest concentration tested (10 μM). The cell culture media had the effect to disaggregate these nanoparticles, mainly by virtue of their albumin content, able to interact with the organic chains via noncovalent (hydrophobic) interactions. For Oct, at the highest concentration employed for the uptake tests (10 μM), the combination between passive diffusion and endocytosis of the self-assembled nanoparticles makes the cellular uptake higher than in the presence of passive diffusion only. During the study of cellular uptake on A2780 ovarian cancer cells pretreated with cytochalasin D, a statistically significant inhibition of endocytosis was observed for Oct. In these experimental conditions, the relationship between uptake and lipophilicity becomes almost linear instead of exponential. Since Oct anticancer prodrug is active at nanomolar concentrations, where the aggregation in culture media is almost abolished, this phenomenon should not significantly impact its antiproliferative activity.

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Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes.

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Macromolecular Pt(IV) Prodrugs from Poly(organo)phosphazenes.

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