Development and Characterization of Ultrasound-assisted PLGA Nanobubbles for the Triggered Delivery of Pemigatinib by Design of Experiments


  • P Nandini BirTikandrajit University, Canchipur, Imphal West, Manipur, India
  • DVRN Bhikshapathi BirTikandrajit University, Canchipur, Imphal West, Manipur, India
  • M Viswaja TRR College of Pharmacy, Meerpet, Hyderabad, Telangana, India
  • P Mamatha TRR College of Pharmacy, Meerpet, Hyderabad, Telangana, India



Pemigatinib, metastatic cholangio carcinoma, nanobubbles, sonication distance, droplet size, polydispersity index, central composite design


This study used a central composite design (CCD) to evaluate how the independent attributes—sonication distance (X1), amplitude (X2), time (X3), & power (X4)—impacted two outcomes—droplet-size (Y1) & polydispersity index (PDI) (Y2). With the time-consuming & inefficient "changing one factor at a time" approach would have been an option for this multifactor optimization, but we opted against it since we wanted to be sure we had the best possible values. Here, a mathematical model of the combined influence of the processing elements led to the selection of a CCD, which is known to be significantly more dependable. Using a double emulsion technique, we created and fine-tuned a drug delivery system consisting of nanobubbles loaded with pemigatinib. Pemigatinib nanobubbles were studied for their shape, surface charge, and particle size to determine their physicochemical characteristics and found that they were spherical with the Zeta potential (ZP) and particle size of -25.3±2.98 & 38.53±2.14 respectively. Pemigatinib-loaded nanobubbles were also tested for their release behaviors and drug encapsulation effectiveness. Finally, we tried to study the anti-tumor activity and cellular absorption of poly (lactic-co-glycolic acid) nanobubbles-Pemigatinib in vitro.


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Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh DY, Dotan E, Catenacci DV, Cutsem EV, Ji T, Lihou CF, Zhen H, Feliz L, Vogel A. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncology. 2020;21(5):671-684. Available from:

Patel TH, Marcus L, Horiba MN, Donoghue M, Chatterjee S, Mishra- Kalyani PS, Schuck RN, Li Y, Zhang X, Fourie Zirkelbach J, Charlab R, Liu J, Yang Y, Lemery SJ, Pazdur R, Theoret MR, Fashoyin-Aje LA.FDA approval summary: Pemigatinib for previously treated, unresectable locally advanced, or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. Clinical Cancer Research. 202;29(5):838-842. Available from:

Vogel A, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh DY,Dotan E, Catenacci DV, Cutsem EV, Lihou CF, Zhen H, Feliz L, Abou- Alfa GK. FIGHT-202: A phase II study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Annals of Oncology. 2019;30:v876. Available from:

Rizzo A, Ricci AD, Brandi G. Pemigatinib: Hot topics behind the first approval of a targeted therapy in cholangiocarcinoma. Cancer Treatment and Research Communications.2021; 27:100337. Available from:

Reddy MR, Gubbiyappa KS. Formulation development, optimization, and characterization of Pemigatinib-loaded supersaturable self-nano emulsifying drug delivery systems. Future Journal of Pharmaceutical Sciences.2022;8(1):45. Available from: 10.1186/s43094-022-00434-4

Wu L, Zhang C, He C, Qian D, Lu L, Sun Y, Xu M, Zhuo J, Liu PC, Klabe R, Wynn R, Covington M, Gallagher K, Leffet L, Bowman K, Diamond S, Koblish H, Zhang Y, Soloviev M, Hollis G, Burn TC, Scherle P, Yeleswaram S, Huber R, Yao W. Discovery of pemigatinib: a potent and selective fibroblast growth factor receptor (FGFR) inhibitor. Journal of Medicinal Chemistry. 2021; 64(15):10666- 10679. Available from: 10.1021/acs.jmedchem.1c00713.

Al-Abboodi AS, Eid EE, Azam F, Al-Qubaisi MS. Inclusion complex of clausenidin with hydroxypropyl-ƒÀ-cyclodextrin: Improvedphysicochemical properties and anti-colon cancer activity. Saudi Pharmaceutical Journal. 2021;29(3):223-235. Available from:

Bhalani DV, Nutan B, Kumar A, Singh Chandel AK. Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines. 2022;10(9):2055. Available from: 10.3390/biomedicines10092055.

Satapathy S, Patro CS. Solid lipid nanoparticles for efficient oral delivery of tyrosine kinase inhibitors: a nano targeted cancer drug delivery. Advanced Pharmaceutical Bulletin. 2022; 12(2):298- 308. Available from: 10.34172/apb.2022.041.

Tian B, Hua S, Liu J. Cyclodextrin-based delivery systems for chemotherapeutic anticancer drugs: A review. Carbohydrate polymers. 2020; 232:115805. Available from: 10.1016/j.carbpol.2019.115805.

Fu Q, Lu HD, Xie YF, Liu JY, Han Y, Gong NB, Guo F. Salt formation of two BCS II drugs (indomethacin and naproxen) with (1R, 2R)-1, 2-diphenylethylenediamine: Crystal structures, solubility, and thermodynamics analysis. Journal of Molecular Structure. 2019;1185:281-289. Available from:

Sanches BM, Ferreira EI. Is prodrug design an approach to increase water solubility?. International Journal of Pharmaceutics. 2019;568:118498. Available from: 10.1016/j. ijpharm.2019.118498.

Winuprasith T, Koirala P, McClements DJ, Khomein P. Emulsion Technology in Nuclear Medicine: Targeted Radionuclide Therapies, Radiosensitizers, and Imaging Agents. International Journal of Nanomedicine. 2023;18:4449-4470. Available from:

Abdifetah O, Na-Bangchang K. Pharmacokinetic studies of nanoparticles as a delivery system for conventional drugs and herb-derived compounds for cancer therapy: a systematic review. International Journal of Nanomedicine. 2019;14:5659-5677. Available from:

Jin J, Yang L, Chen F, Gu N. Drug delivery system based on nanobubbles. Interdisciplinary Materials. 2022;1(4):471-494. Available from:

Pasupathy R, Pandian P, Selvamuthukumar S. Nanobubbles: A Novel Targeted Drug Delivery System. Brazilian Journal of Pharmaceutical Sciences.2022;58:e19608. Available from:

Kulkarni AD, Gulecha VS, Dolas RT, Zalte AG, Deore SR, Deore SS, Pande VV. Nanobubbles: Fundamentals and recent drug delivery applications. International Journal of Health Sciences. 2022;6(S8):1004.1025. Available from:

Jin J, Yang L, Chen F, Gu N. Drug delivery system based on nanobubbles. Interdisciplinary Materials. 2022;1(4):471-494. Available from:

Gao J, Liu J, Meng Z, Li Y, Hong Y, Wang L, He L, Hu B, Zheng Y, Li T, Cui D. Ultrasound-assisted C3F8-filled PLGA nanobubbles for enhanced FGF21 delivery and improved prophylactic treatment of diabetic cardiomyopathy. Acta Biomaterialia. 2021;130:395-408. Available from:

Rampado R, Peer D. Design of experiments in the optimization of nanoparticle-based drug delivery systems. Journal of Controlled Release. 2023;358:398-419. Available from:

Struzek AM, Scherlies R. Quality by Design as a Tool in the Optimisation of Nanoparticle Preparation-A Case Study of PLGA Nanoparticles. Pharmaceutics. 2023;15(2):617-622. Available from:

Iqbal M, Zafar N, Fessi H, Elaissari A. Double emulsion solvent evaporation techniques used for drug encapsulation. International Journal of Pharmaceutics. 2015;496(2):173-190. Available from:

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;124:123-138. Available from: talanta.2014.01.034.

Njoku CN, Otisi SK. Application of Central Composite Design with Design Expert v13 in Process Optimization. Intech Open. 2023. Available from: 10.5772/intechopen.109704.

Bhattacharya S. Central Composite Design for Response Surface Methodology and Its Application in Pharmacy. Response Surface Methodology in Engineering Science. Intech Open. 2021 Jan 28.

Paterakis NG, Gibescu M, Bakirtzis AG, Catalao JP. A Multi-Objective Optimization Approach to Risk-Constrained Energy and Reserve Procurement Using Demand Response. IEEE Transactions on Power Systems. 2018;33(4):3940-3954. Available from:

Zhang X, Zheng Y, Wang Z, Huang S, Chen Y, Jiang W, Zhang H, Ding M, Li Q, Xiao X, Luo X. Methotrexate-loaded PLGA nanobubbles for ultrasound imaging and synergistic targeted therapy of residual tumor during HIFU ablation. Biomaterials. 2014;35(19):5148-5161. Available from:

Yedgar S, Barshtein G, Gural A. Hemolytic Activity of Nanoparticles as a Marker of Their Hemocompatibility. Micromachines (Basel). 2022;13(12):2091. Available from:

Wang S, Liu X, Chen S, Liu Z, Zhang X, Liang XJ, Li L. Regulation of Ca2+ signaling for drug-resistant breast cancer therapy with mesoporous silica nanocapsule encapsulated doxorubicin/siRNA cocktail. ACS Nano. 2018;13(1):274-283. Available from:

Xu JS, Huang J, Qin R, et al. Synthesizing and binding dual-mode poly (lactic-co-glycolic acid) (PLGA) nanobubbles for cancer targeting and imaging. Biomaterials. 2010;31(7):1716-1722. Available from:

Brzezi.ska R, Wirkowska-Wojdy.a M, Piasecka I, Gorska A. Application of Response Surface Methodology to Optimize the Extraction Process of Bioactive Compounds Obtained from Coffee Silverskin. Applied Sciences.2023;13(9):5388. Available from:

Ahmed Z, Mehmood T, Ferheen I, Noori AW, Almansouri M, Waseem M. Optimization of exopolysaccharide produced by L. kefiranofaciens ZW3 using response surface Methodology. International Journal of Food Properties. 2023;26(1):2285-2293. Available from:

Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57. Available from:

Teixeira MI, Lopes CM, Goncalves H, Catita J, Silva AM, Rodrigues F, Amaral MH, Costa PC. Formulation, characterization, and cytotoxicity evaluation of lactoferrin functionalized lipid nanoparticles for riluzole delivery to the brain. Pharmaceutics. 2022;14(1):185. Available from:






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How to Cite

“Development and Characterization of Ultrasound-Assisted PLGA Nanobubbles for the Triggered Delivery of Pemigatinib by Design of Experiments”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 16, no. 3, May 2024, pp. 399-11,