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Research Article

Design of rapamycin and resveratrol coloaded liposomal formulation for breast cancer therapy

    Leidiana Rocha dos Reis

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Marcela Tavares Luiz

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Rafael M Sábio

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Gabriel Davi Marena

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Leonardo Delello Di Filippo

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Jonatas Lobato Duarte

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Ligia de Souza Fernandes

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Victor H Sousa Araújo

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    ,
    Viviane Aline Oliveira Silva

    Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela St, 1331, Barretos, SP, 14784-400, Brazil

    Department of Pathology & Legal Medicine, Medical School of the Federal University of Bahia, BA, 40026-010, Brazil

    Laboratory of Pathology & Molecular Biology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, BA, 40296-710, Brazil

    &
    Marlus Chorilli

    *Author for correspondence: Tel.: +55 163 301 6998;

    E-mail Address: marlus.chorilli@unesp.br

    School of Pharmaceutical Science, Sao Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    Published Online:https://doi.org/10.2217/nnm-2022-0227

    Aims: The development of rapamycin (RAP) and resveratrol (RSV) coloaded liposomes (RAP-RSV-LIP) for breast cancer therapy. Materials & methods: Liposomes were prepared using a high-pressure homogenization technique and evaluated according to their physicochemical characteristics, cellular uptake and cytotoxicity against tumoral and normal cells. Results & conclusion: The RAP-RSV-LIP showed negative surface charge, size around 100 nm, low polydispersity and high encapsulation efficiency for RAP and RSV (58.87 and 63.22%, respectively). RAP-RSV-LIP showed great stability over 60 days and a prolonged drug-release profile. In vitro studies indicated that RAP-RSV-LIP were internalized in an estrogen receptor-positive human breast cancer cell line (MCF-7, 34.2%) and improved cytotoxicity when compared with free drugs. Therefore RAP-RSV-LIP showed great antitumoral potential against breast cancer cells.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. International Agency for Research on Cancer. Estimated number of deaths from 2020 to 2040 (breast cancer): mortality, both sexes, age 0–85+ (2020). https://gco.iarc.fr/tomorrow/en/dataviz/tables?group_cancers=1&multiple_cancers=1&cancers=20&single_unit=100000&years=2040&types=1&mode=population&sort_by=value0&populations=903_904_905_908_909_935_900
    • 2. Pallerla S, Abdul AURM, Comeau J, Jois S. Cancer vaccines, treatment of the future: with emphasis on HER2-positive breast cancer. Int. J. Mol. Sci. 22(2), 779 (2021).
    • 3. WHO. Breast cancer now most common form of cancer: WHO taking action (2021). www.who.int/news/item/03-02-2021-breast-cancer-now-most-common-form-of-cancer-who-taking-action
    • 4. Pfeiffer RM, Webb-Vargas Y, Wheeler W, Gail MH. Proportion of US trends in breast cancer incidence attributable to long-term changes in risk factor distributions. Cancer Epidemiol. Biomarkers Prev. 27(10), 1214–1222 (2018).
    • 5. American Cancer Society. Breast cancer facts and figures 2019–20 (2019). www.cancer.org/research/cancer-facts-statistics/breast-cancer-facts-figures.html
    • 6. Juan A, Cimas FJ, Bravo I, Pandiella A, Ocaña A, Alonso-Moreno C. An overview of antibody conjugated polymeric nanoparticles for breast cancer therapy. Pharmaceutics 12(9), 802 (2020).
    • 7. Patel A, Unni N, Peng Y. The changing paradigm for the treatment of HER2-positive breast cancer. Cancers (Basel) 12(8), 2081 (2020).
    • 8. Thanopoulou E, Khader L, Caira M et al. Therapeutic strategies for the management of hormone receptor-positive, human epidermal growth factor receptor 2-positive (HR+/HER2+) breast cancer: a review of the current literature. Cancer 12, 3317 (2020). • HER2+ is a subtype of aggressive breast cancer, and metastatic HER2+ tumors are considered incurable. Novel approaches focus on delaying resistance to drugs such as CDK4/6 inhibitors. To advance in this sense, there is an imminent need for more clinical trials.
    • 9. Tesch ME, Gelmon KA. Targeting HER2 in breast cancer: latest developments on treatment sequencing and the introduction of biosimilars. Drugs 80(17), 1811–1830 (2020).
    • 10. Ozates NP, Soğutlu F, Lerminoglu F et al. Effects of rapamycin and AZD3463 combination on apoptosis, autophagy, and cell cycle for resistance control in breast cancer. Life Sci. 264, 118643 (2021).
    • 11. Dos Santos KC, Dos Reis LR, Rodero CF et al. Bioproperties, nanostructured system and analytical and bioanalytical methods for determination of rapamycin: a review. Crit. Rev. Anal. Chem. 52(5), 897–905 (2022).
    • 12. Alayev A, Berger SM, Kramer MY, Schwartz NS, Holz MK. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells. J. Cell. Biochem. 116(3), 450–457 (2015). •• Study which used rapamycin and resveratrol synergism to inhibit the mTORC1 signaling pathway, preventing upregulation of Akt activation and autophagy and eading to cell apoptosis. The combination was proven to be versatile, and effective against both estrogen receptor-positive or -negative breast cancer cells.
    • 13. Liang Z-J, Wan Y, Zhu D-D et al. Resveratrol mediates the apoptosis of triple negative breast cancer cells by reducing POLD1 expression. Front. Oncol. 11, 569295 (2021).
    • 14. Barani M, Bilal M, Sabir F, Rahdar A, Kyzas GZ. Nanotechnology in ovarian cancer: diagnosis and treatment. Life Sci. 266, 118914 (2021).
    • 15. Subhan MA, Yalamarty SSK, Filipczak N, Parveen F, Torchilin VP. Recent advances in tumor targeting via EPR effect for cancer treatment. J. Pers. Med. 11(6), 571 (2021).
    • 16. Luiz MT, Tofani LB, Araújo VHS et al. Gene therapy based on lipid nanoparticles as non-viral vectors for glioma treatment. Curr. Gene Ther. 21(5), 452–463 (2021).
    • 17. Luiz MT, Dutra JAP, de Cássia Ribeiro T et al. Folic acid-modified curcumin-loaded liposomes for breast cancer therapy. Colloids Surf. A Physicochem. Eng. Asp. 645, 128935 (2022).
    • 18. Aires Fernandes M, Eloy JO, Tavares Luiz M et al. Transferrin-functionalized liposomes for docetaxel delivery to prostate cancer cells. Colloids Surf. A Physicochem. Eng. Asp. 611, 125806 (2021).
    • 19. Eloy JO, Ruiz A, de Lima FT et al. EGFR-targeted immunoliposomes efficiently deliver docetaxel to prostate cancer cells. Colloids Surf. B Biointerfaces 194, 111185 (2020). • Explored the properties of paclitaxel associated with rapamycin for breast cancer therapy. Coencapsulation of the drugs in PEGylated liposomes promoted synergism and significantly increased their cytotoxicity against breast cancer cells and in vivo, compared with free drugs in solution.
    • 20. Brandl M, Bachmann D, Drechsler M, Bauer KH. Liposome preparation by a new high pressure homogenizer. Drug Dev. Ind. Pharm. 16(14), 2167–2191 (1990).
    • 21. Bhattacharjee S. DLS and zeta potential – what they are and what they are not? J. Control. Rel. 235, 337–351 (2016).
    • 22. Gonzalez Gomez A, Hosseinidoust Z. Liposomes for antibiotic encapsulation and delivery. ACS Infect. Dis. 6(5), 896–908 (2020).
    • 23. Eloy JO, Petrilli R, Topan JF et al. Co-loaded paclitaxel/rapamycin liposomes: development, characterization and in vitro and in vivo evaluation for breast cancer therapy. Colloids Surf. B Biointerfaces 141, 74–82 (2016).
    • 24. Jagwani S, Jalalpure S, Dhamecha D, Jadhav K, Bohara R. Pharmacokinetic and pharmacodynamic evaluation of resveratrol loaded cationic liposomes for targeting hepatocellular carcinoma. ACS Biomater. Sci. Eng. 6(9), 4969–4984 (2020).
    • 25. Alaarg A, Jordan NY, Verhoef JJ, Metselaar JM, Storm G, Kok RJ. Docosahexaenoic acid liposomes for targeting chronic inflammatory diseases and cancer: an in vitro assessment. Int. J. Nanomed. 11, 5027–5040 (2016).
    • 26. Bachir ZA, Huang YK, He MY et al. Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles. Int. J. Nanomed. 13, 5657–5671 (2018).
    • 27. Pereira S, Egbu R, Jannati G, Al-Jamal WT. Docetaxel-loaded liposomes: the effect of lipid composition and purification on drug encapsulation and in vitro toxicity. Int. J. Pharm. 514(1), 150–159 (2016).
    • 28. de Souza Von Zuben E, Eloy JO, Araujo VHS, Gremião MPD, Chorilli M. Insulin-loaded liposomes functionalized with cell-penetrating peptides: influence on drug release and permeation through porcine nasal mucosa. Colloids Surf. A Physicochem. Eng. Asp. 622, 126624 (2021).
    • 29. Shi L, Zhang J, Zhao M et al. Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery. Nanoscale 13(24), 10748–10764 (2021).
    • 30. Behera A, Padhi S. Passive and active targeting strategies for the delivery of the camptothecin anticancer drug: a review. Environ. Chem. Lett. 18(5), 1557–1567 (2020).
    • 31. Di J, Gao X, Du Y, Zhang H, Gao J, Zheng A. Size, shape, charge and ‘stealthy’ surface: carrier properties affect the drug circulation time in vivo. Asian J. Pharm. Sci. 16(4), 444–458 (2021).
    • 32. Chen YQ, Zhu WT, Lin CY, Yuan ZW, Li ZH, Yan PK. Delivery of rapamycin by liposomes synergistically enhances the chemotherapy effect of 5-fluorouracil on colorectal cancer. Int. J. Nanomed. 16, 269–281 (2021). •• Investigated the properties of 5-fluorouracil with rapamycin for cancer therapy. Liposomes containing rapamycin had higher cellular uptake and higher tumor accumulation. The in vivo model showed synergism between the two drugs: liposomes containing rapamycin not only had a cytotoxic effect on colorectal cancer cells but also increased the antitumor effect of 5-fluorouracil by acting on the Akt/mTOR and p53 pathways.
    • 33. Luiz MT, Viegas JSR, Abriata JP et al. Docetaxel-loaded folate-modified TPGS-transfersomes for glioblastoma multiforme treatment. Mater. Sci. Eng. C 124, 112033 (2021).
    • 34. Tefas LR, Sylvester B, Tomuta I et al. Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach. Drug Des. Devel. Ther. 11, 1605–1621 (2017).
    • 35. Zhang Q, Wang J, Zhang H et al. The anticancer efficacy of paclitaxel liposomes modified with low-toxicity hydrophobic cell-penetrating peptides in breast cancer: an: in vitro and in vivo evaluation. RSC Adv. 8(43), 24084–24093 (2018).
    • 36. Marcos Luciano Bruschi. (Ed.). Mathematical models of drug release. In: Strategies to Modify the Drug Release from Pharmaceutical Systems. Bruschi ML (Ed.). Woodhead Publishing, Cambridge, UK, 63–86 (2015).
    • 37. Mircioiu C, Voicu V, Anuta V et al. Mathematical modeling of release kinetics from supramolecular drug delivery systems. Pharmaceutics 11(3), 140 (2019).
    • 38. Fang Y, Xue J, Gao S et al. Cleavable PEGylation: a strategy for overcoming the ‘PEG dilemma’ in efficient drug delivery. Drug Deliv. 24(2), 22–32 (2017).
    • 39. Hama S, Itakura S, Nakai M et al. Overcoming the polyethylene glycol dilemma via pathological environment-sensitive change of the surface property of nanoparticles for cellular entry. J. Control. Rel. 206, 67–74 (2015).
    • 40. Okamoto Y, Taguchi K, Imoto S, Giam Chuang VT, Yamasaki K, Otagiri M. Cell uptake and anti-tumor effect of liposomes containing encapsulated paclitaxel-bound albumin against breast cancer cells in 2D and 3D cultured models. J. Drug Deliv. Sci. Technol. 55, 101381 (2020).
    • 41. Wang H, Huang F, Zhang Z et al. Feedback activation of SGK3 and AKT contributes to rapamycin resistance by reactivating mTORC1/4EBP1 axis via TSC2 in breast cancer. Int. J. Biol. Sci. 15(5), 929–941 (2019).
    • 42. Gu PF, Xu H, Sui BW et al. Polymeric micelles based on poly(ethylene glycol) block poly(racemic amino acids) hybrid polypeptides: conformation-facilitated drug-loading behavior and potential application as effective anticancer drug carriers. Int. J. Nanomed. 7, 109–122 (2012).
    • 43. Alves RC, Schulte ZM, Luiz MT et al. Breast cancer targeting of a drug delivery system through postsynthetic modification of curcumin@N3-bio-MOF-100 via click chemistry. Inorg. Chem. 60(16), 11739–11744 (2021).