Polyanionic Biopolymers for the Delivery of Pt(II) Cationic Antiproliferative Complexes

Our plain-English summary of Polyanionic Biopolymers for the Delivery of Pt(II) Cationic Antiproliferative Complexes, by M. Ravera, E. Gabano, I. Zanellato, et al (Bioinorganic Chemistry and Applications, 2016).

The study

• Authors: M. Ravera, E. Gabano, I. Zanellato, E. Perin, A. Arrais, D. Osella
• Journal: Bioinorganic Chemistry and Applications
• Published: 2016;2016:2380540
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Phenanthriplatin, that is, (SP-4-3)-diamminechlorido(phenanthridine)platinum(II) nitrate, an effective antitumor cationic Pt(II) complex, was loaded on negatively charged dextran sulfate (DS) as a model vector for drug delivery via electrostatic interactions. The free complex and the corresponding conjugate with DS were tested on two standard human tumor cell lines, namely, ovarian A2780 and colon HCT 116, and on several malignant pleural mesothelioma cell lines (namely, epithelioid BR95, mixed/biphasic MG06, sarcomatoid MM98, and sarcomatoid cisplatin-resistant MM98R). The in vitro results suggest that the conjugate releases the active metabolite phenanthriplatin with a biphasic fashion. In these experimental conditions, the conjugate is slightly less active than free phenanthriplatin; but both exhibited antiproliferative potency higher than the reference metallodrug cisplatin and were able to overcome the acquired cisplatin chemoresistance in MM98R cells.

In plain English

This was a laboratory chemistry study, not a study of people or asbestos exposure. The authors attached three positively charged platinum anticancer compounds to dextran sulfate, a negatively charged polymer, as a possible drug carrier. Phenanthriplatin bound best: measured as the platinum-to-sulfate molar ratio, its loading reached up to 50%, versus at most 10% for the other two. Only its conjugate, called 3-DS, with a ratio of 33 ± 2%, was studied further. In salt solutions, 3-DS released part of the drug within 10 to 15 hours and almost all of it within two weeks. Free phenanthriplatin, 3-DS and the standard drug cisplatin were tested for 72 hours on ovarian and colon cancer cell lines and on four malignant pleural mesothelioma cell lines. Three of these came from pleural fluid of patients, and one was resistant to cisplatin. Both forms of phenanthriplatin slowed cell growth at lower concentrations than cisplatin in every cell line, including the resistant one. 3-DS was slightly less active than the free drug. The authors stated animal experiments would be needed to judge any tumor-targeting benefit.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) chemistry and cell-culture experiment
• Who was studied: Human tumor cell lines: ovarian carcinoma A2780, colon carcinoma HCT 116, three primary malignant pleural mesothelioma cell lines derived from pleural effusions of patients with histologically confirmed mesothelioma (BR95 epithelioid, MM98 sarcomatoid, MG06 mixed/biphasic), and the cisplatin-resistant line MM98R. No human subjects or animals.
• Exposure: No asbestos exposure was studied. Cells were treated continuously for 72 h with cisplatin, free phenanthriplatin (complex 3), or phenanthriplatin bound to dextran sulfate (3-DS).
• Main results:
  • Loading was measured as the platinum-to-sulfate (Pt/S) molar ratio. Complexes 1 and 2 bound at most 10%, even when added at a 1 to 1 molar ratio to the sulfate groups. Phenanthriplatin (complex 3) reached up to 50% Pt loaded.
  • The conjugate used for all further work (3-DS) had a final Pt/S molar ratio of 33 ± 2%, which corresponds to 0.76 mg of complex 3 per mg of native dextran sulfate.
  • The freshly dialyzed 3-DS solution contained particles about 120 nm in mean diameter. Dextran sulfate alone was about 250 nm.
  • In phosphate buffered saline, drug release from 3-DS levelled off after 10 to 15 h at about 50%, 40% and 30% release for the different buffer strengths. Release then continued slowly and was almost complete within two weeks.
  • Across the cell lines, both free phenanthriplatin and 3-DS were more active than cisplatin, and free phenanthriplatin was slightly more active than 3-DS. For example, IC50 in A2780 cells was 0.46 ± 0.11 µM for cisplatin, 0.12 ± 0.02 µM for free 3 and 0.20 ± 0.04 µM for 3-DS.
  • In cisplatin-resistant MM98R mesothelioma cells, IC50 was 19.4 ± 2.8 µM for cisplatin (resistance factor 6.1), 2.09 ± 0.06 µM for free 3 (resistance factor 2.4) and 3.46 ± 0.36 µM for 3-DS (resistance factor 1.9).
  • In A2780 cells after 4 h, the platinum accumulation ratio was 0.62 ± 0.12 for cisplatin, 4.81 ± 1.08 for free 3 and 3.03 ± 0.57 for 3-DS. 3-DS accumulated slightly less than free 3, but both accumulated more than cisplatin.
• The authors' conclusion: The authors concluded that free phenanthriplatin and 3-DS showed higher antiproliferative activity than cisplatin in all tumor cell lines and were able to bypass acquired cisplatin resistance in MM98R cells. They attributed the slightly lower activity of 3-DS to incomplete drug release during the tests and to lower cellular accumulation.
• Limitations the authors state:
  • Any tumor-targeting (EPR) benefit of the conjugate could only be judged through further in vivo experiments.
  • The authors noted reported concerns that dextran sulfate may cause anaphylactoid reactions and gastrointestinal complaints.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Cisplatin.

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