Development and Optimization of Lipid-polymer Hybrid Nanoparticles Containing Melphalan Using Central Composite Design and Its Effect on Ovarian Cancer Cell Lines

Document Type : Research article

Authors

1 Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran.

2 Department of Pilot Nano-biotechnology, Pasteur Institute of Iran, Tehran, Iran.

3 Department of Chemical Engineering, South Tehran Branch, Islamic Azad University, Tehran, Iran.

Abstract

The development of controlled-release drug delivery systems has a great potential to improve the efficacy of anticancer drugs. This study aimed to develop and optimize the production of hybrid lipid-polymer nanoparticles (HLPNPs) for the targeted delivery of melphalan anticancer drugs. Response surface methodology (RSM) and central composite design (CCD) were used to evaluate and optimize the effects of three independent variables including lipid, polymer, and polyvinyl alcohol (PVA) ratios on the nanoparticles (NPs) size and drug entrapment efficiency (EE%). Hybrid NPs were prepared using the nanoprecipitation method. The results demonstrated that spherical NPs were synthesized, and the rate of EE% went up by increasing the polymer as well as decreasing the PVA concentrations. The nanoformulation released melphalan in a sustained and controlled manner (17.39% in a period time of 48 h). Also, cytotoxicity evaluations showed that HLPNPs caused an increase in the efficacy of melphalan against human ovarian A2780CP and SKOV3 cancer cells. Overall, the results of this study demonstrated that HLPNPs can be considered as a promising carrier for the delivery of hydrophobic anticancer drugs such as melphalan and the evaluation in-vivo.

Graphical Abstract

Development and Optimization of Lipid-polymer Hybrid Nanoparticles Containing Melphalan Using Central Composite Design and Its Effect on Ovarian Cancer Cell Lines

Keywords


  1. References

    1. Ghaferi M, Koohi Moftakhari Esfahani M, Raza A, Al Harthi S, Ebrahimi Shahmabadi H and Alavi SE. Mesoporous silica nanoparticles: synthesis methods and their therapeutic use-recent advances. J. Drug. Target. (2021) 29: 131-54.
    2. Caruso G, Caffo M, Alafaci C, Raudino G, Cafarella D, Lucerna S, Salpietro FM and Tomasello F. Could nanoparticle systems have a role in the treatment of cerebral gliomas? Nanomedicine. (2011) 7: 744-52.
    3. Kim BY, Rutka JT and Chan WC. Nanomedicine. N. Engl. J. Med. (2010) 363: 2434-43.
    4. Alavi SE, Cabot PJ and Moyle PM. Glucagon-like peptide-1 receptor agonists and strategies to improve their efficiency. Mol. Pharmaceutics (2019) 16: 2278-95.
    5. Misra R, Acharya S and Sahoo SK. Cancer nanotechnology: application of nanotechnology in cancer therapy. Drug Discov. Today (2010) 15: 842-50.
    6. Tahir N, Madni A, Balasubramanian V, Rehman M, Correia A, Kashif PM, Mäkilä E,  Salonen J and Santos HA. Development and optimization of methotrexate-loaded lipid-polymer hybrid nanoparticles for controlled drug delivery applications. Int. J. Pharm. (2017) 533: 156-68.
    7. Zhang L, Gu F, Chan J, Wang A, Langer R and Farokhzad O. Nanoparticles in medicine: therapeutic applications and developments. Clin. Pharmacol. Ther. (2008) 83: 761-9.
    8. Kim TY, Kim DW, Chung JY, Shin SG, Kim SC, Heo DS, Kim NK and Bang YJ. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin. Cancer. Res. (2004) 10: 3708-16.
    9. Tong R and Cheng J. Anticancer polymeric nanomedicines. J. Macromol. Sci. Polymer. Rev. (2007) 47: 345-81.
    10. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. (2005) 4: 145-60.
    11. Alavi SE, Cabot PJ, Yap GY and Moyle PM. Optimized Methods for the Production and Bioconjugation of Site-Specific, Alkyne-Modified Glucagon-like Peptide-1 (GLP-1) Analogs to Azide-Modified Delivery Platforms Using Copper-Catalyzed Alkyne–Azide Cycloaddition. Bioconjug. Chem. (2020) 31: 1820-34.
    12. Huo ZJ, Wang SJ, Wang ZQ, Zuo WS, Liu P, Pang B and Liu Km, . Novel nanosystem to enhance the antitumor activity of lapatinib in breast cancer treatment: therapeutic efficacy evaluation. Cancer Sci. (2015) 106: 1429-37.
    13. Zhang L, Chan JM, Gu FX, Rhee J-W, Wang AZ, Radovic-Moreno AF, Alexi F, Longer R and Farokhzad OC. Self-assembled lipid− polymer hybrid nanoparticles: a robust drug delivery platform. ACS. Nano. (2008) 2: 1696-702.
    14. Pajaie HS and Taghizadeh M. Optimization of nano-sized SAPO-34 synthesis in methanol-to-olefin reaction by response surface methodology. J. Ind. Eng .Chem. (2015 ) 24: 59-70.
    15. Miksa B. Recent progress in designing shell cross-linked polymer capsules for drug delivery. RSC Adv. (2015) 5: 87781-805.
    16. Wen A, Mei X, Feng C, Shen C, Wang B and Zhang X. Electrosprayed nanoparticles of poly (p-dioxanone-co-melphalan) macromolecular prodrugs for treatment of xenograft ovarian carcinoma. Mater. Sci. Eng. C. Mater. Biol. Appl. (2020) 111: 110759.
    17. Chan JM, Zhang L, Yuet KP, Liao G, Rhee J-W, Langer R and Farakhzad OC. PLGA–lecithin–PEG core–shell nanoparticles for controlled drug delivery. Biomaterials (2009) 30: 1627-34.
    18. Hao J, Wang F, Wang X, Zhang D, Bi Y, Gao Y, Zhao X and Zhang Q .Development and optimization of baicalin-loaded solid lipid nanoparticles prepared by coacervation method using central composite design. Eur. J. Pharm. Sci. (2012) 47: 497-505.
    19. Ghaferi M, Amari S, Mohrir BV, Raza A, Shahmabadi HE and Alavi SE. Preparation, characterization, and evaluation of cisplatin-loaded polybutylcyanoacrylate nanoparticles with improved in-vitro and in-vivo anticancer activities. Pharmaceuticals (Basel) (2020) 13: 44.
    20. Xu JQ, Xu HX, Newaz Z, Li R, Zhang Y, Liu H and Yin Y. Synthesis, Characterization and in vitro Drug Release of Melphalan Magnetic Microspheres. J. Nano Res. (2013) 22: 31-40.
    21. Panwar P, Pandey B, Lakhera P and Singh K. Preparation, characterization, and in vitro release study of albendazole-encapsulated nanosize liposomes. Int. J. Nanomedicine (2010) 5: 101-8.
    22. Bhusari SS, Borse G and Wakte P. Development and Validation of UV-Visible Spectrophotometric method for Simultaneous Estimation Of Etoposide And Picroside-II In Bulk And Pharmaceutical Formulation. J. Drug Deliv. Ther. (2019) 9: 257-62.
    23. Alavi SE, Koohi Moftakhari Esfahani M, Ghassemi S, Akbarzadeh A and Hassanshahi G. In vitro evaluation of the efficacy of liposomal and pegylated liposomal hydroxyurea. Indian J. Clin. Biochem. (2014) 29: 84-8.
    24. Gayam SR, Venkatesan P, Sung Y-M, Sung S-Y, Hu S-H, Hsu H-Y and Wu SP. An NAD (P) H: quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery in-vitro and in-vivo. Nanoscale (2016) 8: 12307-17.
    25. Feng S-S, Zhao L, Zhang Z, Bhakta G, Win KY, Dong Y and Chien S. Chemotherapeutic engineering: vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in-vivo. Chem. Eng. Sci. (2007) 62: 6641-8.
    26. Ghaferi M, Asadollahzadeh MJ, Akbarzadeh A, Ebrahimi Shahmabadi H and Alavi SE. Enhanced Efficacy of PEGylated Liposomal Cisplatin: In Vitro and In Vivo Evaluation. Int. J. Mol. Sci. (2020) 21: 559.
    27. Liu M, Zhang X, Yang B, Deng F, Ji J, Yang Y, Huang Z, Zhang XI and Wei Y. Luminescence tunable fluorescent organic nanoparticles from polyethyleneimine and maltose: facile preparation and bioimaging applications. RSC Adv. (2014) 4: 22294-8.
    28. Gan Q, Wang T, Cochrane C and McCarron P. Modulation of surface charge, particle size and morphological properties of chitosan–TPP nanoparticles intended for gene delivery. Colloids. Surf B. Biointerfaces (2005) 44: 65-73.
    29. Kashif PM, Madni A, Ashfaq M, Rehman M, Mahmood MA, Khan MI and Tahir N. Development of Eudragit RS 100 microparticles loaded with ropinirole: optimization and in vitro evaluation studies. AAPS. Pharm. Sci. Tech. (2017) 18: 1810-22.
    30. Prakobvaitayakit M and Nimmannit U. Optimization of polylactic-co-glycolic acid nanoparticles containing itraconazole using 2 3 factorial design. Aaps Pharmscitech. (2003) 4: 565-73.
    31. Ravi PR, Vats R, Dalal V, Gadekar N and NA. Design, optimization and evaluation of poly-ɛ-caprolactone (PCL) based polymeric nanoparticles for oral delivery of lopinavir. Drug. Dev. Ind. Pharm. (2015) 41: 131-40.
    32. Gajra B, Dalwadi C and Patel R. Formulation and optimization of itraconazole polymeric lipid hybrid nanoparticles (Lipomer) using box behnken design. DARU. (2015) 23: 3.
    33. Sahoo SK, Panyam J, Prabha S, Labhasetwar V. Residual polyvinyl alcohol associated with poly (D, L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake. J. Control. Release. (2002) 82: 105-14.
    34. Sun X, Shen J, Yu D and Ouyang Xk. Preparation of pH-sensitive Fe3O4@ C/carboxymethyl cellulose/chitosan composite beads for diclofenac sodium delivery. Int. J. Biol. Macromol. (2019) 127: 594-605.
    35. Ferreira M, Chaves LL, Lima SAC and Reis S. Optimization of nanostructured lipid carriers loaded with methotrexate: a tool for inflammatory and cancer therapy. Int. J. Pharm. (2015) 492: 65-72.
    36. Jain A, Kesharwani P, Garg NK, Jain A, Jain SA, Jain AK, Nirbhavane P, Ghanghoria R, Tyagi RK and Katare OP. Galactose engineered solid lipid nanoparticles for targeted delivery of doxorubicin. Colloids. Surf. B. Biointerfaces. (2015) 134: 47-58.
    37. Xu F, Yan TT and Luo YL. Studies on micellization behavior of thermosensitive PNIPAAm-b-PLA amphiphilic block copolymers. J. Nanosci. Nanotechnol. (2012) 12: 2287-91.
    38. Cheow WS and Hadinoto K. Factors affecting drug encapsulation and stability of lipid–polymer hybrid nanoparticles. Colloids. Surf. B. Biointerfaces (2011) 85: 214-20.
    39. Alavi SE, Muflih Al Harthi S, Ebrahimi Shahmabadi H and Akbarzadeh A. Cisplatin-loaded polybutylcyanoacrylate nanoparticles with improved properties as an anticancer agent. Int. J. Mol. Sci. (2019) 20: 1531.