Original Article

Lipid-Based Nanocarriers Provide Prolonged Anticancer Activity for Palbociclib: In Vitro and in Vivo Evaluations

Abstract

Breast cancer therapy has remained one of the major healthcare challenges. Based on the critical role of cyclin-dependent kinase 4/6 (CDK 4/6) in cell cycle progression, targeting this signaling appears promising for cancer therapy. Palbociclib, a selective CDKs 4/6 inhibitor, is the first-line treatment for estrogen receptor-positive breast cancer. However, poor absorption or side effects may negatively affect its efficiency. This prompted us to incorporate palbociclib into the nanostructured lipid carriers (NLCs) and evaluate the anticancer effect of the nanoformulation (Pa-NLCs) in in vitro and in vivo models of breast cancer. Pa-NLCs were developed by high-pressure homogenization followed by assessment of the physicochemical characteristics and bioactivities in MCF-7 breast cancer cells and female Wistar rats exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The prepared Pa-NLCs demonstrated suitable physicochemical characteristics, including the controlled release pattern, efficient cellular uptake, and cytotoxicity, while free palbociclib failed to show significant effects. Rats treated with Pa-NLCs exhibited significantly reduced tumor volumes, increased survival rates, and histopathological improvement. Free palbociclib was significantly less efficient than Pa-NLCs. Pa-NLCs, by improving the pharmacological profile of palbociclib and providing longer-lasting effects, can be considered as a promising nanoformulation against breast cancer.

1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7-30.
2. Lange CA, Yee D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr Relat Cancer 2011;18:C19-24.
3. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res 2016;18:17.
4. Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 2017;17:93-115.
5. Spring L, Bardia A, Modi S. Targeting the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway with selective CDK 4/6 inhibitors in hormone receptor-positive breast cancer: rationale, current status, and future directions. Discov Med 2016;21:65-74.
6. Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R, et al. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett 1995;90:43-50.
7. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015;14:130-46.
8. Altenburg JD, Farag SS. The potential role of PD0332991 (Palbociclib) in the treatment of multiple myeloma. Expert Opin Investig Drugs 2015;24:261-71.
9. Rivadeneira DB, Mayhew CN, Thangavel C, Sotillo E, Reed CA, Grana X, et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 2010;138:1920-30.
10. Logan JE, Mostofizadeh N, Desai AJ, VON Euw E, Conklin D, Konkankit V, et al. PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res 2013;33:2997-3004.
11. Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P, Khan G, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 2010;18:63-73.
12. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 2013;19:6173-82.
13. Young RJ, Waldeck K, Martin C, Foo JH, Cameron DP, Kirby L, et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res 2014;27:590-600.
14. Nadji M, Gomez-Fernandez C, Ganjei-Azar P, Morales AR. Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5,993 breast cancers. Am J Clin Pathol 2005;123:21-27.
15. Sutherland RL, Green MD, Hall RE, Reddel RR, Taylor IW. Tamoxifen induces accumulation of MCF 7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle. Eur J Cancer Clin Oncol 1983;19:615-21.
16. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009;11:R77.
17. Trape AP, Liu S, Cortes AC, Ueno NT, Gonzalez-Angulo AM. Effects of CDK4/ 6 Inhibition in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Cells with Acquired Resistance to Paclitaxel. J Cancer 2016;7:947-56.
18. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 2011;20:620-34.
19. Hassanzadeh P. Colorectal cancer and NF-κB signaling pathway. Gastroenterol Hepatol Bed Bench 2011;4:127-32.
20. Wang W, Nag SA, Zhang R. Targeting the NF-κB signaling pathways for breast cancer Prevention and therapy. Curr Med Chem 2015; 22:264-89.
21. Whiteway SL, Harris PS, Venkataraman S, Alimova I, Birks DK, Donson AM, et al. Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells. J Neurooncol. 2013;111:113-21.
22. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16:25-35.
23. Ehab M, Elbaz M. Profile of palbociclib in the treatment of metastatic breast cancer. Breast Cancer (Dove Med Press) 2016;8:83-91.
24. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al. Targeting the NF-κB signaling pathways for breast cancer Prevention and therapy. Curr Med Chem 2015;22:264-89
25. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-38.
26. Rocca A, Farolfi A, Bravaccini S, Schirone A, Amadori D. Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother. 2014;15:407-20.
27. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015;21:995-1001.
28. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016;375:1925-36.
29. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/ 6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568-76.
30. Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer 2011;104:1862-8.
31. Tamura K, Mukai H, Naito Y, Yonemori K, Kodaira M, Tanabe Y, et al. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016;107:755-63.
32. Hassanzadeh P, Atyabi F, Dinarvand R, Dehpour AR, Azhdarzadeh M, Dinarvand M. Application of nanostructured lipid carriers: the prolonged protective effects for sesamol in in vitro and in vivo models of ischemic stroke via activation of PI3K signalling pathway. Daru 2017;25:25.
33. Hassanzadeh P, Arbabi E, Rostami F, Atyabi F, Dinarvand R. Aerosol delivery of ferulic acid-loaded nanostructured lipid carriers: A promising treatment approach against the respiratory disorders. Physiol Pharmacol 2017;21:331-42.
34. Hassanzadeh P, Arbabi E, Atyabi F, Dinarvand R. Ferulic acid-loaded nanostructured lipid carriers: A promising nanoformulation against the ischemic neural injuries. Life Sci 2018;193:64-76.
35. Müller RH. Lipid nanoparticles: recent advances. Adv Drug Deliv Rev 2007;59:375-6.
36. Yang R, Zhang S, Kong D, Gao X, Zhao Y, Wang Z. Biodegradable polymer curcumin conjugate micelles enhance the loading and delivery of low potency curcumin. Pharm. Res 2012;29:3512-25.
37. Zhao J, Bai Y, Zhang C, Zhang X, Zhang YX, Chen J, et al., Cinepazide maleate protects PC12 cells against oxygen–glucose deprivation-induced injury. Neurol Sci 2014;35:875-81.
38. Russo J, Russo IH. Atlas and histologic classification of Tumors of rat mammary gland. J Mammary Gland Biol Neoplasia 2000;5:187-200.
39. Russo IH, Russo J. Mammary gland neoplasia in long-term rodent studies. Environ Health Prospect 1996;104:938-67.
40. Vijayaraghavan S, Karakas C, Doostan I, Chen X, Bui T, Yi M, et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun 2017;8:15916.
41. Ouyang Z, Wang S, Zeng M, Li Z, Zhang Q, Wang W, et al. Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target. Cell Commun Signal 2019;17:17.
42. Bollard J, Miguela V, Ruiz de Galarreta M, Venkatesh A, Bian CB, Roberto MP, et al. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut 2017;66:1286-96.
43. Sacaan AI, Thibault S, Hong M, Kondegowda NG, Nichols T, Li R, et al. CDK4/6 Inhibition on Glucose and Pancreatic Beta Cell Homeostasis in Young and Aged Rats. Mol Cancer Res 2017;15 1531-41.
44. Hassanzadeh P, Ahmadiani A. Inflammatory pain induces neuronal alterations in NO and JNK dependent manners. DARU 2007;15:183-7.
45. Ahmadiani A. Hassanzadeh P, Aleboyeh M. Development of tolerance to anti-inflammatory effect of morphine. Arch Iranian Med 2003;6:307-9.
46. Ferrari M. Cancer nanotechnology: Opportunities and challenges. Nat Rev Cancer 2005;5:161-71.
47. Hassanzadeh P, Fullwood I, Sothi S, Aldulaimi D. Cancer nanotechnology. Gastroenterol Hepatol Bed Bench Spring 2011;4:63-9.
48. Hassanzadeh P, Atyabi F, Dinarvand R. Nanoparticles reshape the biomedical industry. Biomed Rev 2018;29:17-26.
49. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 2017;17:20-37.
50. Morawski AM, Winter PM, Crowder KC, Caruthers SD, Fuhrhop RW, Scott MJ, et al. Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI. Magn Reson Med 2004;51:480-6.
51. Cui Y, Qingqiao W, Hongkun P, Lieber CM. Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species. Science 2011;293:1289-92.
52. Hassanzadeh P. New perspectives in biosensor technology. Gastroenterol Hepatol Bed Bench 2010;3:105-7.
53. Harishingani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, van de Kaa CH, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348:2491-9.
54. Park JW. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res 2002;4:95-9.
55. Kircher MF, Mahmood U, King RS, Weissleder R, Josephson L. A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. Cancer Res 2003;63:8122-5.
56. Li KC, Pandit SD, Guccione S, Bednarski MD. Molecular imaging applications in nanomedicine. Biomed Microdevices 2004;6:113-6.
57. Hirsch LR, Halas NJ, West JL. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc Natl Acad Sci USA 2003;100:13549-54.
58. Puri A, Loomis K, Smith B, Lee JH, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: From concepts to clinic. Crit Rev Ther Drug Carrier Syst 2009;26:523-80.
59. Sai Li, Zhigui Su, Minjie Sun, Yanyu Xiao, Feng Cao, Aiwen Huang, et al. An arginine derivative contained nanostructure lipid carriers with pH-sensitive membranolytic capability for lysosomolytic anticancer drug delivery. Int J Pharm 2012;436:248-57.
60. Shenoy VS, Vijay IK, Murthy RS. Tumour targeting: biological factors and formulation advances in injectable lipid nanoparticles. J Pharm Pharmacol 2005;57:411-21.
61. Bondì ML, Azzolina A, Craparo EF, Botto C, Amore E, Giammona G, et al. Entrapment of an EGFR inhibitor into nanostructured lipid carriers (NLC) improves its antitumor activity against human hepatocarcinoma cells. J Nanobiotechnol 2014;12:21.
62. Barrett JC. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Perspect 1993;100:9-20.
63. Manna S, Chakraborty T, Damodaran S, Samanta K, Rana B, Chatterjee M. Protective role of fish oil (Maxepa) on early events of rat mammary carcinogenesis by modulation of DNA-protein crosslinks, cell proliferation and p53 expression. Cancer Cell Int 2007;7:6.
Files
IssueVol 59, No 6 (2021) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/acta.v59i6.6891
Keywords
Palbociclib Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor Nanostructured lipid carriers Breast cancer Michigan cancer foundation-7 (MCF-7) cells Rat

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Hassanzadeh P, Arbabi E, Rostami F. Lipid-Based Nanocarriers Provide Prolonged Anticancer Activity for Palbociclib: In Vitro and in Vivo Evaluations. Acta Med Iran. 2021;59(6):333-345.