PREPARATION AND EVALUATION OF ENTRECTINIB PLGA NANOBUBBLES BY CENTRAL COMPOSITE DESIGN

P. NANDINI; D. V. R. N. BHIKSHAPATHI

doi:10.22159/ijap.2025v17i1.50891

Authors

P. NANDINI BirTikandrajit University, Canchipur, Imphal West-795003, Manipur, India
D. V. R. N. BHIKSHAPATHI BirTikandrajit University, Canchipur, Imphal West-795003, Manipur, India

DOI:

https://doi.org/10.22159/ijap.2025v17i1.50891

Keywords:

Entrectinib, Cancer, Solvent-diffusion-evaporation technique, Central composite design, Nanobubbles, Ultrasound-assisted medication, Cytotoxicity

Abstract

Objective: For targeted delivery of entrectinib, we created nanobubbles with a poly(lactic-co-glycolic acid) (PLGA) shell and a perfluoropentane core.

Methods: Entrectinib was encapsulated in PLGA nanobubbles by a modified W/O/W double emulsion, solvent-diffusion-evaporation technique. Central composite design was utilized to explore how four independent factors like sonication distance (X1), amplitude (X2), time (X3), and power (X4)-affected droplet size (Y1) and polydispersity Index (PDI) (Y2).

Results: The optimal sonication distance, time, amplitude, and power were 2.41 cm; 3.61 min, 44.42%, and 77.35 W. Drug-loaded nanobubbles showed a PDI of 0.196±0.005 and an average particle size of 73.53±3.08 nm, indicating a unimodal system with low PDI high zeta potential indicate formulation stability. The mean drug loading capacity was 29.27±1.54 mg/g. The remarkable drug encapsulation efficiency (82.12±2.98%) supports an inclusion complex. Transmission Electron Microscopy shows drug encapsulation does not change nanobubbles' spherical shape. Fourier-transform infrared spectroscopy and Differential scanning calorimetry revealed nanobubble-drug complex production. Nanobubbles emitted more entrectinib than the solution. Drug release via ultrasound was different. At 6 h, sonication released 46.08% of entrectinib and 26.42% without. Entrectinib released 99.34% after 24 h versus 58.93% without ultrasonography. The formulation's consistent size distribution remained stable after 180 days. Parenteral safety and non-toxicity were shown by these nanobubbles at 15 mg/ml. In vitro ultrasonic increases cell uptake. The viability of MCF-7 cells was assessed following exposure to entrectinib at 10 to 120 μM dosages. All entrectinib formulations showed little cytotoxicity, up to 98% cell survival at 10 μM doses.

Conclusion: PLGA nanobubbles can be used in ultrasound-responsive formulations to deliver targeted drugs to fight cancer and other diseases.

Downloads

Download data is not yet available.

References

Frampton JE. Entrectinib: a review in NTRK+ solid tumours and ROS1+ NSCLC. Drugs. 2021 Apr;81(6):697-708. doi: 10.1007/s40265-021-01503-3, PMID 33871816.

Pravallika KE, Prameela RA, Ratna KM. Bioanalytical method development and validation of entrectinib in rat plasma by liquid chromatography-tandem mass spectrometry. Asian J Pharm Clin Res. 2020 Nov;13(11):155-63. doi: 10.22159/ajpcr.2020.v13i11.39005.

Palanati M, Bhikshapathi DV. Determination of in vitro cytotoxicity of entrectinib and pemigatinib nanosponges tablets on a 498 mcf-7 and panc-1 cell line. Int J Pharm Pharm Sci. 2024 Feb;16(2):12-6. doi: 10.22159/ijpps.2024v16i2.49567.

Rolfo C, Ruiz R, Giovannetti E, Gil Bazo I, Russo A, Passiglia F. Entrectinib: a potent new TRK ROS1 and ALK inhibitor. Expert Opin Investig Drugs. 2015 Nov;24(11):1493-500. doi: 10.1517/13543784.2015.1096344, PMID 26457764.

Meneses Lorente G, Bentley D, Guerini E, Kowalski K, Chow Maneval E, YU L. Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors. Invest New Drugs. 2021 Jun;39(3):803-11. doi: 10.1007/s10637-020-01047-5, PMID 33462752.

DE Braud FG, Niger M, Damian S, Bardazza B, Martinetti A, Pelosi G. Alka-372-001: First in human phase I study of entrectinib an oral pan TRK ROS1 and ALK inhibitor in patients with advanced solid tumors with relevant molecular alterations. J Clin Oncol. 2015;33 Suppl 15:2517. doi: 10.1200/jco.2015.33.15_suppl.2517.

Al Salama ZT, Keam SJ. Entrectinib: first global approval. Drugs. 2019 Sep;79(13):1477-83. doi: 10.1007/s40265-019-01177-y, PMID 31372957.

Parrott N, Stillhart C, Lindenberg M, Wagner B, Kowalski K, Guerini E. Physiologically based absorption modelling to explore the impact of food and gastric pH changes on the pharmacokinetics of entrectinib. AAPS J. 2020 May;22(4):78. doi: 10.1208/s12248-020-00463-y, PMID 32458089.

Liu D, Offin M, Harnicar S, LI BT, Drilon A. Entrectinib: an orally available selective tyrosine kinase inhibitor for the treatment of NTRK ROS1 and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul;14:1247-52. doi: 10.2147/TCRM.S147381, PMID 30050303.

Wang Q, Fang P, Zheng L, YE L. Quantification and pharmacokinetic study of entrectinib in rat plasma using ultra-performance liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2019 Apr;33(4):e4467. doi: 10.1002/bmc.4467, PMID 30549079.

Doebele RC, Drilon A, Paz Ares L, Siena S, Shaw AT, Farago AF. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-82. doi: 10.1016/S1470-2045(19)30691-6, PMID 31838007.

Wen H, Jung H, LI X. Drug delivery approaches in addressing clinical pharmacology related issues: opportunities and challenges. AAPS J. 2015 Nov;17(6):1327-40. doi: 10.1208/s12248-015-9814-9, PMID 26276218.

Kumari L, Choudhari Y, Patel P, Gupta GD, Singh D, Rosenholm JM. Advancement in solubilization approaches: a step towards bioavailability enhancement of poorly soluble drugs. Life (Basel). 2023 Apr;13(5):1099. doi: 10.3390/life13051099, PMID 37240744.

YU YQ, Yang X, WU XF, Fan YB. Enhancing permeation of drug molecules across the skin via delivery in nanocarriers: novel strategies for effective transdermal applications. Front Bioeng Biotechnol. 2021 Mar;9:646554. doi: 10.3389/fbioe.2021.646554, PMID 33855015.

Patra JK, Das G, Fraceto LF, Campos EV, Rodriguez Torres MD, Acosta Torres LS. Nano-based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018 Jan;16(1):71. doi: 10.1186/s12951-018-0392-8, PMID 30231877.

SS, SA, Krishnamoorthy K, Rajappan M. Nanosponges: a novel class of drug delivery system review. J Pharm Pharm Sci. 2012 Jan;15(1):103-11. doi: 10.18433/j3k308, PMID 22365092.

Foroughi Nia B, Barar J, Memar MY, Aghanejad A, Davaran S. Progresses in polymeric nanoparticles for delivery of tyrosine kinase inhibitors. Life Sci. 2021 Aug;278:119642. doi: 10.1016/j.lfs.2021.119642, PMID 34033837.

Jin J, Yang L, Chen F, GU N. Drug delivery system based on nanobubbles. Interdisciplinary Materials. 2022 Apr;1(4):471-94. doi: 10.1002/idm2.12050.

Pasupathy R, Pandian P, Selvamuthukumar S. Nanobubbles: a novel targeted drug delivery system. Braz J Pharm Sci. 2022 Dec;58. doi: 10.1590/s2175-97902022e19604.

Ponnaganti M, Ancha KB, Palanati M. Formulation and optimization of ceritinib loaded nanobubbles by box behnken design. Int J Appl Pharm. 2022 Apr;14(4):219-26.

Jin J, Yang L, Chen F, GU N. Drug delivery system based on nanobubbles. Interdisciplinary Materials. 2022 Apr;1(4):471-94. doi: 10.1002/idm2.12050.

Gao J, Liu J, Meng Z, LI Y, Hong Y, Wang L. Ultrasound assisted C3F8 filled PLGA nanobubbles for enhanced FGF21 delivery and improved prophylactic treatment of diabetic cardiomyopathy. Acta Biomater. 2021 Aug;130:395-408. doi: 10.1016/j.actbio.2021.06.015.

Jayita D, Anima D, Lalhlenmawia H. Formulation and in vitro evaluation of poly(d, l-lactide-co-glycolide) (PLGA) nanoparticles of ellagic acid and its effect on human breast cancer mcf-7 cell line. Int J Curr Pharm Res. 2021 May;13(5):56-62.

SU C, Ren X, Nie F, LI T, LV W, LI H. Current advances in ultrasound combined nanobubbles for cancer targeted therapy: a review of the current status and future perspectives. RSC Adv. 2021 Apr;11(21):12915-28. doi: 10.1039/d0ra08727k, PMID 35423829.

Hema AN, Gaayathri G, Gundeti S. Development of orodispersible tablets of loratadine containing an amorphous solid dispersion of the drug in soluplus® using design of experiments. Int J Pharm Pharm Sci. 2023 Aug;15(8):19-27.

Rampado R, Peer D. Design of experiments in the optimization of nanoparticle-based drug delivery systems. J Control Release. 2023 Jun;358:398-419. doi: 10.1016/j.jconrel.2023.05.001, PMID 37164240.

Iqbal M, Zafar N, Fessi H, Elaissari A. Double emulsion solvent evaporation techniques used for drug encapsulation. Int J Pharm. 2015 Feb;496(2):173-90. doi: 10.1016/j.ijpharm.2015.10.057, PMID 26522982.

Candioti LV, DE Zan MM, Camara MS, Goicoechea HC. Experimental design and multiple response optimization using the desirability function in analytical methods development. Talanta. 2014 Jun;124:123-38. doi: 10.1016/j.talanta.2014.01.034, PMID 24767454.

Kumar V, Bhalla A, Rathore AS. Design of experiments applications in bioprocessing: concepts and approach. Biotechnol Prog. 2014 Jan;30(1):86-99. doi: 10.1002/btpr.1821, PMID 24123959.

Paterakis NG, Gibescu M, Bakirtzis AG, Catalao JP. A multi-objective optimization approach to risk-constrained energy and reserve procurement using demand response. IEEE Trans Power Syst. 2017 Apr;33(4):3940-54. doi: 10.1109/TPWRS.2017.2785266.

Zhang X, Zheng Y, Wang Z, Huang S, Chen Y, Jiang W. Methotrexate loaded PLGA nanobubbles for ultrasound imaging and synergistic targeted therapy of residual tumor during HIFU ablation. Biomaterials. 2014 Jun;35(19):5148-61. doi: 10.1016/j.biomaterials.2014.02.036, PMID 24680663.

Yedgar S, Barshtein G, Gural A. Hemolytic activity of nanoparticles as a marker of their hemocompatibility. Micromachines. 2022 Dec;13(12):2091. doi: 10.3390/mi13122091, PMID 36557391.

Wang S, Liu X, Chen S, Liu Z, Zhang X, Liang XJ. Regulation of Ca2+ signaling for drug-resistant breast cancer therapy with mesoporous silica nanocapsule encapsulated doxorubicin/sirna cocktail. ACS Nano. 2019;13(1):274-83. doi: 10.1021/acsnano.8b05639, PMID 30566319.

Zhang X, Zheng Y, Wang Z, Huang S, Chen Y, Jiang W. Methotrexate loaded PLGA nanobubbles for ultrasound imaging and synergistic targeted therapy of residual tumor during HIFU ablation. Biomaterials. 2014 Jun;35(19):5148-61. doi: 10.1016/j.biomaterials.2014.02.036, PMID 24680663.

XU JS, Huang J, Qin R, Hinkle GH, Povoski SP, Martin EW. Synthesizing and binding dual mode poly (lactic-co-glycolic acid) (PLGA) nanobubbles for cancer targeting and imaging. Biomaterials. 2010 Jul;31(7):1716-22. doi: 10.1016/j.biomaterials.2009.11.052, PMID 20006382.

Yan Y, Chen Y, Liu Z, Cai F, Niu W, Song L. Brain delivery of curcumin through low-intensity ultrasound-induced blood-brain barrier opening via lipid-PLGA nanobubbles. Int J Nanomedicine. 2021 Nov;16:7433-47. doi: 10.2147/IJN.S327737, PMID 34764649.

Brzezinska R, Wirkowska Wojdyla M, Piasecka I, Gorska A. Application of response surface methodology to optimize the extraction process of bioactive compounds obtained from coffee silverskin. Appl Sci. 2023 Apr;13(9):5388. doi: 10.3390/app13095388.

Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018 May;10(2):57. doi: 10.3390/pharmaceutics10020057, PMID 29783687.