Amelioration of the therapeutic potential of gefitinib against breast cancer using nanostructured lipid carriers
Abstract
Aim: This study aimed to improve the delivery and therapeutic potential of gefitinib (GTB) against breast cancer by preparing GTB-loaded, nanostructured lipid carriers (GTB-NLCs). Materials & methods: Box–Behnken design was used for optimization and GTB was loaded into NLCs using ultrasonication. The GTB-NLCs were characterized using in vitro, ex vivo and in vivo studies. The anticancer efficacy of GTB-NLCs was evaluated using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity and flow cytometry on MCF-7 breast cancer cell lines. Results: Optimized GTB-NLCs were successfully characterized and demonstrated improved internalization and enhanced cytotoxicity compared with plain GTB. Gut permeation studies showed enhanced intestinal permeability, and pharmacokinetic analysis revealed 2.6-fold improvement in GTB oral bioavailability. Conclusion: GTB-NLCs effectively enhanced the therapeutic potential of GTB against breast cancer.
Plain language summary
Gefitinib is an important drug approved for the treatment of cancer. However, there are issues with gefitinib, including its low water solubility and toxicity. Being poorly water soluble, the absorption of gefitinib in blood is low and therefore high doses are required to achieve the therapeutic level. Also, gefitinib is nonselective for cancer as well as noncancer cells, leading to toxicity on other organs. This study aimed to incorporate gefitinib into a lipid-based carrier, which improved its properties such as solubility, stability and bioavailability. The prepared formulation was tested for its drug release, stability and efficacy on breast cancer cell lines as well as toxicity using various methods. It was observed that the prepared formulation not only improved bioavailability but also improved the targeting as more gefitinib entered the cancer cells when present in the formulation, decreasing the toxicity of gefitinib on other organs. In conclusion, the prepared formulation can be regarded as an effective approach to improving the therapeutic potential of gefitinib.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Breast cancer management in 2021: a primer for the obstetrics and gynecology. Best Pract. Res. Clin. Obstet. Gynaecol. 82, 30–45 (2022). • Describes the management of breast cancer.
- 2. Therapeutic landscape of advanced HER2-positive breast cancer in 2022. Med. Oncol. 39(12), 1–14 (2022).
- 3. . Current state of cell therapies for breast cancer. Cancer J. 28(4), 301–309 (2002).
- 4. . Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020). J. Hematol. Oncol. 13(1), 1–23 (2020).
- 5. Gefitinib: an updated review of its role in the cancer management, its nanotechnological interventions. Recent Pat. Anticancer Drug Discov. 18(4), 448–469 (2023).
- 6. Uniform carboxymethyl chitosan-enveloped pluronic F68/poly(lactic-co-glycolic acid) nano-vehicles for facilitated oral delivery of gefitinib, a poorly soluble antitumor compound. Colloids Surf. B. 177, 425–432 (2019).
- 7. Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity. Clin. Lung Cancer 14(5), 502–507 (2013). •• Describes the toxicity of gefitinib.
- 8. EGFR inhibitor gefitinib induces cardiotoxicity through the modulation of cardiac PTEN/Akt/FOXO3a pathway and reactive metabolites formation: in vivo and in vitro rat studies. Chem. Res. Toxicol. 33(7), 1719–1728 (2020).
- 9. . Dual inhibition of AKT and MEK pathways potentiates the anti-cancer effect of GTB in triple-negative breast cancer cells. Cancers 13(6), 1205 (2021).
- 10. Efficacy of adjuvant chemotherapy on overall survival in patients with lymph node-positive esophageal squamous cell carcinoma: is oral chemotherapy promising? Cancer Med. 12(4), 4077–4086 (2023).
- 11. A review of nanomaterials from synthetic and natural molecules for prospective breast cancer nanotherapy. Front. Pharmacol. 14, 117 (2023). •• Describes nanoparticles for breast cancer treatment.
- 12. . Nanoparticles-based drug delivery and gene therapy for breast cancer: recent advancements and future challenges. Semin. Cancer Biol. 69, 226–237 (2021).
- 13. Recent advances in lipid-based nanoformulations for breast cancer theranostics. Cancer Nanotheran. 2, 175–200 (2021).
- 14. . Gefitinib-loaded starch nanoparticles for battling lung cancer: optimization by full factorial design and in vitro cytotoxicity evaluation. Saudi Pharm. J. 31(1), 29–54 (2023).
- 15. . Development of novel S PC-3 gefitinib lipid nanoparticles for effective drug delivery in breast cancer. Tissue distribution studies and cell cytotoxicity analysis. J. Drug Deliv. Sci. Technol. 61, 102073 (2021).
- 16. . Development and characterization of gefitinib loaded polymeric nanoparticles by ionic gelation method. Pharm. Nanotechnol. 5(4), 301–309 (2017). • Describes gefitinib-loaded nanoformulations.
- 17. Novel liposomal gefitinib (L-GEF) formulations. Anticancer Res. 32(7), 2919–2923 (2012).
- 18. . Cyclosporine A lipid nanoparticles for oral administration: pharmacodynamics and safety evaluation. Eur. J. Pharm. Biopharm. 101, 112–118 (2016).
- 19. Review on the scale-up methods for the preparation of solid lipid nanoparticles. Pharmaceutics 14(9), 1886 (2022).
- 20. . Nanostructured lipid carrier system: a compendium of their formulation development approaches, optimization strategies by quality by design, and recent applications in drug delivery. Nanotechnol. Rev. 11(1), 1744–1777 (2022).
- 21. . Nanostructured lipid carriers for oral bioavailability enhancement of exemestane: formulation design, in vitro, ex vivo, and in vivo studies. J. Pharm. Sci. 108(10), 3382–3395 (2019).
- 22. . Second generation lipid nanoparticles (NLC) as an oral drug carrier for delivery of lercanidipine hydrochloride. Colloids Surf. B. 116, 81–87 (2014).
- 23. Optimization and validation of stability indicating RP-HPLC method for the quantification of gefitinib in bulk drug and nanoformulations: an application towards in vitro and ex vivo performance evaluation. Arab. J. Chem. 15(12), 104333 (2022).
- 24. Lipid-nanopotentiated combinatorial delivery of tamoxifen and sulforaphane: ex vivo, in vivo and toxicity studies. Nanomedicine 15(26), 2563–2583 (2020). •• Describes the preparation of lipid-based nanoformulations.
- 25. . Curcumin-loaded nanostructured lipid carriers for ocular drug delivery: design optimization and characterization. J. Drug Deliv. Sci. Technol. 47, 159–166 (2018).
- 26. Ribociclib nanostructured lipid carrier aimed for breast cancer: formulation optimization, attenuating in vitro specification, and in vivo scrutinization. Biomed. Res. Int. 2022, 24 (2022).
- 27. Design-of-experiments (DoE)-assisted fabrication of quercetin-loaded nanoemulgel and its evaluation against human skin cancer cell lines. Pharmaceutics 14(11), 2517 (2022). •• Describes the nanoparticles optimized by design of experiment.
- 28. . Formulation development, optimization by Box–Behnken design, and in vitro characterization of gefitinib phospholipid complex based nanoemulsion drug delivery system. J. Pharm. Innov. 14, 1–13 (2022).
- 29. Development and evaluation of puerarin-loaded controlled release nanostructured lipid carries by central composite design. Drug Dev. Ind. Pharm. 47(1), 113–125 (2021).
- 30. . Enhanced pharmacokinetic activity of zotepine via nanostructured lipid carrier system in Wistar rats for oral application. Pharm. Nanotechnol. 8(2), 148–160 (2020).
- 31. QbD-steered development of biotin-conjugated nanostructured lipid carriers for oral delivery of chrysin: role of surface modification for improving biopharmaceutical performance. Colloids Surf. B. 197, 111429 (2021).
- 32. . PEGylated liposomes as an emerging therapeutic platform for oral nanomedicine in cancer therapy: in vitro and in vivo assessment. J. Mol. Liq. 303, 112649 (2020).
- 33. Optimization of nanostructured lipid carriers of lurasidone hydrochloride using Box–Behnken design for brain targeting: in vitro and in vivo studies. J. Pharm. Sci. 108(9), 3082–3090 (2019).
- 34. Design and optimization of curcumin loaded nano lipid carrier system using Box–Behnken design. Biomed. Pharmacother. 141, 111919 (2021).
- 35. . Formulation and optimization of nanostructured lipid carriers to enhance oral bioavailability of telmisartan using Box–Behnken design. J. Drug Deliv. Sci. Technol. 44, 431–439 (2018). • Describes the use of solid and liquid lipid in the preparation of nanostructured, lipid-based carriers.
- 36. . Long chain fatty acids can form aggregates and affect the membrane integrity. Colloids Surf. B. 204, 111795 (2021).
- 37. . The universal usefulness of stearic acid as surface modifier: applications to the polymer formulations and composite processing. J. Ind. Eng. Chem. 96, 1–33 (2021).
- 38. . Solubility, similarity, and compatibility: a general-purpose theory for the formulator. Curr. Opin. Colloid Interface Sci. 48, 65–76 (2020).
- 39. Gefitinib loaded nanostructured lipid carriers: characterization, evaluation and anti-human colon cancer activity in vitro. Drug Deliv. 27(1), 622–631 (2020).
- 40. . Optimization of gefitinib-loaded nanostructured lipid carrier as a biomedical tool in the treatment of metastatic lung cancer. Molecules 28(1), 448 (2023).
- 41. Cyclosporine-loaded solid lipid nanoparticles (SLN®): drug–lipid physicochemical interactions and characterization of drug incorporation. Eur. J. Pharm. Biopharm. 68(3), 535–544 (2008).
- 42. Resveratrol loaded functionalized nanostructured lipid carriers for breast cancer targeting: systematic development, characterization and pharmacokinetic evaluation. Colloids Surf. B. 181, 756–766 (2019). • Discusses the mechanism of lipid-based formulations.
- 43. . Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat. Nanotechnol. 16(3), 266–276 (2021).
- 44. . A potential delivery system for bioactive food molecules. Innov. Food Sci. Emerg. Technol. 19, 29–43 (2013).
- 45. . Short term stability testing of efavirenz-loaded solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC) dispersions. Pharmaceutics 11(8), 397 (2019).
- 46. . Curcumin-loaded nanostructured lipid carriers (NLCs) for nasal administration: design, characterization, and in vivo study. Drug Deliv. 23(4), 1326–1334 (2016).
- 47. . Development and characterization of nanostructured lipid carriers of oral hypoglycemic agent: selection of surfactants. Int. J. Pharm. Sci. Rev. Res. 7(2), 125–130 (2011).
- 48. . Nanostructured lipid carriers (NLCs) as drug delivery platform: advances in formulation and delivery strategies. Saudi Pharm. J. 29(9), 999–1012 (2021).
- 49. . Lipid-based nano-formulation platform for eplerenone oral delivery as a potential treatment of chronic central serous chorioretinopathy: in-vitro optimization and ex-vivo assessment. Drug Deliv. 28(1), 642–654 (2021).
- 50. . Dermatokinetic assessment of luliconazole-loaded nanostructured lipid carriers (NLCs) for topical delivery: qbD-driven design, optimization, and in vitro and ex vivo evaluations. Drug Deliv. Transl. Res. 12(5), 1118–1135 (2022).
- 51. Preparation and characterization of fenofibrate-loaded nanostructured lipid carriers for oral bioavailability enhancement. AAPS Pharm. Sci. Tech. 15, 1509–1515 (2014).
- 52. . Nanostructured lipid carriers for oral delivery of baicalin: in vitro and in vivo evaluation. Colloids Surf. 466, 154–159 (2015).
- 53. . Montelukast-loaded nanostructured lipid carriers: part II pulmonary drug delivery and in vitro–in vivo aerosol performance. Eur. J. Pharm. Biopharm. 88(1), 169–177 (2014). •• Applications of nanostructured, lipid-based carriers and other lipid-based formulations.
- 54. . Development of novel lipid matrix for improved sustained release effect of a hydrophilic drug via response surface methodology. J. Drug Deliv. Sci. Technol. 67, 102993 (2022).
- 55. . Nanostructured lipid carriers and their potential applications for versatile drug delivery via oral administration. Open Nano 8, 100064 (2022).
- 56. Nanostructured lipid carriers as promising delivery systems for plant extracts: the case of silymarin. Appl. Sci. 8(7), 1163 (2018).
- 57. Preparation and evaluation of gefitinib containing nanoliposomal formulation for lung cancer therapy. BioNanoScience 12(1), 241–255 (2022).
- 58. Non-ionic surfactants for stabilization of polymeric nanoparticles for biomedical uses. Materials 14(12), 3197 (2021).
- 59. Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. J. Neurooncol. 67, 19–28 (2014).
- 60. . Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride: optimization and pharmacokinetics. Int. J. Pharm. 535(1–2), 316–324 (2018).
- 61. . Formulation strategies to improve the efficacy of intestinal permeation enhancers. Adv. Drug Deliv. Rev. 177, 113925 (2021). •• Formulation strategies of nanostructured, lipid-based carriers.
- 62. . Intestinal permeation enhancers: lessons learned from studies using an organ culture model. Biochim. Biophys. Acta Biomembr. 1863(1), 183474 (2021).
- 63. . Nanostructured lipid carriers for site-specific drug delivery. Biomed. Pharmacother. 103, 598–613 (2018).
- 64. . Engineered nanoscale lipid-based formulation as potential enhancer of gefitinib lymphatic delivery: cytotoxicity and apoptotic studies against the A549 cell line. AAPS PharmSciTech. 23(6), 183 (2022).
- 65. . PEGylated SLN as a promising approach for lymphatic delivery of gefitinib to lung cancer. Int. J. Nanomed. 28, 3287–3311 (2022).
- 66. Amelioration of bioavailability through formulating and optimizing azilsartan entrapped nanostructured lipid carriers and its pharmacokinetic assessment. J. Drug Deliv. Sci. Technol. 77, 103894 (2022).
- 67. Enhanced oral bioavailability of an antipsychotic drug through nanostructured lipid carriers. Int. J. Biol. Macromol. 110, 269–275 (2018).
- 68. . Nanostructured lipid carriers: promising delivery systems for encapsulation of food ingredients. J. Agric. Res. 2, 100084 (2020).
- 69. . Are nanostructured lipid carriers (NLCs) better than solid lipid nanoparticles (SLNs): development, characterizations and comparative evaluations of clotrimazole-loaded SLNs and NLCs? Eur. J. Pharm. Sci. 47(1), 139–151 (2012). •• Applications of nanostructured, lipid-based carriers.
- 70. . Nanostructured lipid carriers as oral delivery systems for poorly soluble drugs. J. Drug Deliv. Sci. Technol. 42, 144–154 (2017).
- 71. Current state-of-art and new trends on lipid nanoparticles (SLN and NLC) for oral drug delivery. J. Drug Deliv. 2012, 750891 (2012).