A Novel Formulation of Cisplatin with γ-Polyglutamic Acid and Chitosan Reduces Its Adverse Renal Effects: An In Vitro and In Vivo Animal Study

Our plain-English summary of A Novel Formulation of Cisplatin with γ-Polyglutamic Acid and Chitosan Reduces Its Adverse Renal Effects: An In Vitro and In Vivo Animal Study, by M. Sasai, K. Sakura, T. Matsuda, et al (Polymers, 2021).

The study

• Authors: M. Sasai, K. Sakura, T. Matsuda, H. Uyama
• Journal: Polymers
• Published: 2021;13(11)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cisplatin (cis-diamminedichloroplatinum (II); CDDP) is a key chemotherapeutic agent but causes renal damage and other off-target effects. Here, we describe the pharmacological and biochemical characteristics of a novel formulation of CDDP complexed with γ-polyglutamic acid (γ-PGA) and chitosan (CS), γ-PGA/CDDP-CS, developed by complexing CDDP with γ-PGA, then adding CS (15 kDa; 10 mol%/γ-PGA). We analyzed tumor cytotoxicity in vitro, as well as blood kinetics, acute toxicity, and antitumor efficacy in vivo in BALB/cAJcl mice. γ-PGA/CDDP-CS showed pH-dependent release in vitro over 12 days (9.1% CDDP released at pH 7.4; 49.9% at pH 5.5). It showed in vitro cytotoxicity in a dose-dependent manner similar to that of uncomplexed CDDP. In a mesothelioma-bearing mouse model, a 15 mg/kg dose of CDDP inhibited tumor growth regardless of the type of formulation, complexed or uncomplexed; however, all mice in the uncomplexed CDDP group died within 13 days. γ-PGA/CDDP-CS was as effective as free CDDP in vivo but much less toxic.

In plain English

This was a laboratory and mouse study of a cancer drug. It did not study people or asbestos exposure; asbestos appears only as background on mesothelioma. The authors made a new form of the chemotherapy drug cisplatin by binding it to gamma-polyglutamic acid and adding chitosan, then compared it with ordinary (free) cisplatin. In the laboratory, the new form released 9.1% of its cisplatin over 12 days at pH 7.4 and 49.9% at pH 5.5. It killed AB23G2 mouse mesothelioma cells in a dose-dependent way. Reported IC50 values were 7.50, 9.26 and 12.5 µg/mL for the new form and 0.0063, 0.0018 and 0.0016 for free cisplatin on Days 3, 5 and 7. In groups of five mice, none given 15 mg/kg free cisplatin survived beyond Day 5, while all given 15 mg/kg of the new form survived to Day 5. Kidney tubule damage was seen after 4.5 mg/kg free cisplatin but not after 45 mg/kg of the new form. In mice with tumors under the skin, the high-dose new form temporarily held back tumor growth on Days 13 to 15. The authors concluded the formulation may be useful in clinical chemotherapy, although many developmental factors remain.

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) and mouse (in vivo) experimental study of a new cisplatin drug formulation
• Who was studied: AB23G2 murine (mouse) mesothelioma cells derived from the AB22 cell line, and female BALB/cAJcl mice aged 6 to 8 weeks from CLEA Japan, studied at Osaka University; groups of 5 mice for survival and tumor experiments and 4 per group for kidney toxicity
• Exposure: Drug treatment, not asbestos: free cisplatin (CDDP) versus cisplatin complexed with gamma-polyglutamic acid and chitosan (γ-PGA/CDDP-CS), at 7.5 or 15 mg/kg injected into the abdomen, versus saline control. Kidney toxicity was tested with 4.5 mg/kg free CDDP and 45 mg/kg γ-PGA/CDDP-CS.
• Main results:
  • In laboratory release tests, cumulative cisplatin released from γ-PGA/CDDP-CS over 12 days was 9.1% at pH 7.4 and 49.9% at pH 5.5
  • IC50 against mouse mesothelioma cells was 7.50, 9.26 and 12.5 µg/mL for γ-PGA/CDDP-CS and 0.0063, 0.0018 and 0.0016 for free CDDP on Days 3, 5 and 7 (free CDDP data not shown)
  • Cisplatin from γ-PGA/CDDP-CS was detectable in mouse blood for up to 168 h (0.62% of total CDDP injected)
  • In the 15 mg/kg free cisplatin group, mice began dying on day 3 and none survived beyond Day 5. In the 7.5 mg/kg free cisplatin group, survival on Day 5 was 20%. In the 15 mg/kg γ-PGA/CDDP-CS group, survival was 100% on Day 5.
  • Kidney tissue showed damage to the proximal renal tubule in mice given free cisplatin (4.5 mg/kg) but not in saline controls or mice given γ-PGA/CDDP-CS (45 mg/kg)
  • In tumor-bearing mice, all mice in the high-dose free cisplatin group and 80% in the low-dose free cisplatin group had died by Day 14 after tumor implantation. In the high-dose γ-PGA/CDDP-CS group, tumor nodule growth was transiently suppressed from Days 13 to 15. The text says the low-dose group was similar to controls.
• The authors' conclusion: The authors concluded that their results suggest γ-PGA/CDDP-CS may be useful in clinical chemotherapy, although many developmental factors remain
• Limitations the authors state:
  • The authors stated that many developmental factors remain
  • The authors stated that most particles were trapped by the reticuloendothelial system (such as the liver), and that particle charge or PEG modification would need adjusting for a more effective antitumor effect
  • Drug-release data were shown for one representative experiment

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Mesothelioma.

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