Double-Loaded Doxorubicin/Resveratrol Polymeric Micelles Providing Low Toxicity on Cardiac Cells and Enhanced Cytotoxicity on Lymphoma Cells

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Apr 28

PMID 37111772

Authors

Lyubomira Radeva

Yordan Yordanov

Ivanka Spassova

Daniela Kovacheva

Virginia Tzankova

Krassimira Yoncheva

Affiliations

Soon will be listed here.

Abstract

The anthracycline antibiotic doxorubicin is a well-known antitumour agent, however its cardiotoxicity is a significant obstacle to therapy. The aim of the present study was to improve the safety of doxorubicin through its simultaneous encapsulation with a cardioprotective agent (resveratrol) in Pluronic micelles. The formation and double-loading of the micelles was performed via the film hydration method. Infrared spectroscopy proved the successful incorporation of both drugs. X-ray diffraction analyses revealed that resveratrol was loaded in the core, whereas doxorubicin was included in the shell. The double-loaded micelles were characterised by a small diameter (26 nm) and narrow size distribution, which is beneficial for enhanced permeability and retention effects. The in vitro dissolution tests showed that the release of doxorubicin depended on the pH of the medium and was faster than that of resveratrol. In vitro studies on cardioblasts showed the opportunity to reduce the cytotoxicity of doxorubicin through the presence of resveratrol in double-loaded micelles. Higher cardioprotection was observed when the cells were treated with the double-loaded micelles compared with referent solutions with equal concentrations of both drugs. In parallel, treatments of L5178 lymphoma cells with the double-loaded micelles revealed that the cytotoxic effect of doxorubicin was enhanced. Thus, the study demonstrated that the simultaneous delivery of doxorubicin and resveratrol via the micellar system enabled the cytotoxicity of doxorubicin in lymphoma cells and lowered its cardiotoxicity in cardiac cells.

Citing Articles

Nanomicellar Prodrug Delivery of Glucose-Paclitaxel: A Strategy to Mitigate Paclitaxel Toxicity.

Yan D, Ma X, Hu Y, Zhang G, Hu B, Xiang B Int J Nanomedicine. 2025; 20:2087-2101.

PMID: 39990288 PMC: 11844307. DOI: 10.2147/IJN.S500999.

Resveratrol-A Promising Therapeutic Agent with Problematic Properties.

Radeva L, Yoncheva K Pharmaceutics. 2025; 17(1).

PMID: 39861780 PMC: 11768323. DOI: 10.3390/pharmaceutics17010134.

The Potential Application of Resveratrol and Its Derivatives in Central Nervous System Tumors.

Nowacka A, Sniegocka M, Smuczynski W, Liss S, Ziolkowska E, Bozilow D Int J Mol Sci. 2025; 25(24.

PMID: 39769099 PMC: 11728356. DOI: 10.3390/ijms252413338.

Resveratrol-Loaded Pluronic Micelles Ameliorate Scopolamine-Induced Cognitive Dysfunction Targeting Acetylcholinesterase Activity and Programmed Cell Death.

Lazarova M, Stefanova M, Tsvetanova E, Georgieva A, Tasheva K, Radeva L Int J Mol Sci. 2024; 25(23).

PMID: 39684486 PMC: 11641279. DOI: 10.3390/ijms252312777.

pH-Sensitive Fluorescent Probe in Nanogel Particles as Theragnostic Agent for Imaging and Elimination of Latent Bacterial Cells Residing Inside Macrophages.

Zlotnikov I, Ezhov A, Belogurova N, Kudryashova E Gels. 2024; 10(9).

PMID: 39330169 PMC: 11431188. DOI: 10.3390/gels10090567.

References

Lee D . Alternatives to P value: confidence interval and effect size. Korean J Anesthesiol. 2016; 69(6):555-562. PMC: 5133225. DOI: 10.4097/kjae.2016.69.6.555. View

Osman A, Al-Harthi S, Alarabi O, Elshal M, Ramadan W, Alaama M . Chemosensetizing and cardioprotective effects of resveratrol in doxorubicin- treated animals. Cancer Cell Int. 2013; 13:52. PMC: 3680308. DOI: 10.1186/1475-2867-13-52. View

Chen L, Li L, Zhang L, Xing S, Wang T, Wang Y . Designed fabrication of unique eccentric mesoporous silica nanocluster-based core-shell nanostructures for pH-responsive drug delivery. ACS Appl Mater Interfaces. 2013; 5(15):7282-90. DOI: 10.1021/am401627u. View

Baur J, Sinclair D . Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006; 5(6):493-506. DOI: 10.1038/nrd2060. View

Ma W, Guo Q, Li Y, Wang X, Wang J, Tu P . Co-assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti-tumor efficacy. Eur J Pharm Biopharm. 2016; 112:209-223. DOI: 10.1016/j.ejpb.2016.11.033. View

Fares A, ElMeshad A, Kassem M . Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation, optimization using central composite design and in vivo bioavailability study. Drug Deliv. 2017; 25(1):132-142. PMC: 6058706. DOI: 10.1080/10717544.2017.1419512. View

Zhou W, Ouyang J, Hu N, Li G, Wang H . Protective Effect of Two Alkaloids from Linn. against Doxorubicin-Induced Toxicity in H9c2 Cardiomyoblasts. Molecules. 2021; 26(7). PMC: 8037594. DOI: 10.3390/molecules26071946. View

Akash M, Rehman K . Recent progress in biomedical applications of Pluronic (PF127): Pharmaceutical perspectives. J Control Release. 2015; 209:120-38. DOI: 10.1016/j.jconrel.2015.04.032. View

Monahan D, Flaherty E, Hameed A, Duffy G . Resveratrol significantly improves cell survival in comparison to dexrazoxane and carvedilol in a h9c2 model of doxorubicin induced cardiotoxicity. Biomed Pharmacother. 2021; 140:111702. DOI: 10.1016/j.biopha.2021.111702. View

10.

Repetto G, Peso A, Zurita J . Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc. 2008; 3(7):1125-31. DOI: 10.1038/nprot.2008.75. View

11.

Kataoka K, Harada A, Nagasaki Y . Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001; 47(1):113-31. DOI: 10.1016/s0169-409x(00)00124-1. View

12.

Ahmad N, Ahmad R, Alam M, Ahmad F . Enhancement of oral bioavailability of doxorubicin through surface modified biodegradable polymeric nanoparticles. Chem Cent J. 2018; 12(1):65. PMC: 5966352. DOI: 10.1186/s13065-018-0434-1. View

13.

Maeda H, Wu J, Sawa T, Matsumura Y, Hori K . Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000; 65(1-2):271-84. DOI: 10.1016/s0168-3659(99)00248-5. View

14.

Porto I, Nascimento T, Oliveira J, Freitas P, Haimeur A, Franca R . Use of polyphenols as a strategy to prevent bond degradation in the dentin-resin interface. Eur J Oral Sci. 2018; 126(2):146-158. DOI: 10.1111/eos.12403. View

15.

Zhang D, Xu Q, Wang N, Yang Y, Liu J, Yu G . A complex micellar system co-delivering curcumin with doxorubicin against cardiotoxicity and tumor growth. Int J Nanomedicine. 2018; 13:4549-4561. PMC: 6091483. DOI: 10.2147/IJN.S170067. View

16.

Fremont L . Biological effects of resveratrol. Life Sci. 2000; 66(8):663-73. DOI: 10.1016/s0024-3205(99)00410-5. View

17.

Wu J, Wang Z, Hsieh T, Bruder J, Zou J, Huang Y . Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine (Review). Int J Mol Med. 2001; 8(1):3-17. DOI: 10.3892/ijmm.8.1.3. View

18.

Pellosi D, Moret F, Fraix A, Marino N, Maiolino S, Gaio E . Pluronic P123/F127 mixed micelles delivering sorafenib and its combination with verteporfin in cancer cells. Int J Nanomedicine. 2016; 11:4479-4494. PMC: 5019320. DOI: 10.2147/IJN.S103344. View

19.

Wallemacq P, Capron A, Vanbinst R, Boeckmans E, Gillard J, Favier B . Permeability of 13 different gloves to 13 cytotoxic agents under controlled dynamic conditions. Am J Health Syst Pharm. 2006; 63(6):547-56. DOI: 10.2146/ajhp050197. View

20.

Montazeri Aliabadi H, Lavasanifar A . Polymeric micelles for drug delivery. Expert Opin Drug Deliv. 2005; 3(1):139-62. DOI: 10.1517/17425247.3.1.139. View