Preparation and characterization of dox loaded pla-peg-fa copolymer containing superparamagnetic nanoparticles for cancer treatment

Mohammad Khaledian,1 Seyed mohammad sadegh nourbakhsh,2 Reza saber,3 Hadi hashemzade,4 Mohammad hasan darvishi,5,*

1. M.A student of Semnan University
2. Assistant Professor of Biomedical Engineering Faculty of New Sciences and Technology Semnan University
3. Research Center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran
4. Ph.D. student at Tarbiat Modares University
5. Nanobiotechnology Research Centre, Baqiyatallah University of Medical Sciences, Tehran, Iran

Abstract

Introduction

Iron oxide nanoparticles have potential for various biomedical applications, including hyperthermia, targeted drug delivery, magnetic resonance imaging(mri) contrast enhancement, biological separation. the therapeutic concept of superparamagnetic iron oxide nanoparticles (spions) to cancer treatment is based on the evidence that cancer cells are more sensitive than normal cells to temperatures higher than 41-42° c. the delivery of hyper thermic spions to a specific target site with minimal side effects is an important challenge in cancer cells hyperthermia. poly lactic acid(pla) is a linear polymer, due to good biodegradability, low toxicity and good biocompatibility, low immunity has been confirmed by the food and drug administration of the united states(fda) for use in tissue engineering and pharmaceutical carriers. hydrophilic polymers such as pegs are used to reduce the high hydrophobicity of pla and to protect it from being removed by a macrophage system. on the other hand, targeted drug delivery using nano carriers is achieved by functionalizing the carrier surface with a tissue recognition ligand. among these ligands, vitamins have frequently been used due to their small size and ease of handling and conjugation. moreover, the vitamin receptors are usually overexpressed in a wide variety of human tumors. folic acid a member of b-vitamin family is a growth promoter of cells. cancer cells often overexpress folic acid receptors on the cell surface. interestingly, the presence of folic acid on the particle surface not only does not increase surface potential, while it is sufficient to increase the particle uptake by cancer cells. one of the most commonly used chemotherapy drugs in the world is doxorubicin(dox). its use in a wide range of cancers includes small cell lung cancer, breast, ovarian, bone, gastric, liver and kidney cancers have been approved by the fda. in this study, the pla-peg-fa/spions nano carrier containing dox is used for targeted chemotherapy and hyperthermia, simultaneously.

Methods

Poly lactic acid(pla), nh2-peg-oh (bi-functional peg), folic acid were obtained from sigma aldrich, fecl3.6h2o, fecl2.4h2o were purchased from merk, dox was purchased from ebeve pharma. the synthesis of iron oxide nanoparticles by co-precipitation of ferrous and ferric ions was optimized in aqueous medium and the optimum size range required for magnetic fluid hyperthermia (mfh) was considered. bi-functional peg during the ring-opening polymerization process as an intermediary, from one side attached to fa ligand and then from other hand establishes chemical bond with pla monomers. the pla-peg-fa-coated magnetic nanoparticles were prepared as carriers of doxorubicin (pla-peg-fa–dox mnps) through water-in-oil-in-water (w/o/w) emulsification method.

Results

The synthesized fe3o4 nanoparticles and pla-peg-fa/spion nanoparticles have an average size of 41.98(nm) and 238.5(nm) in dls analysis, respectively. meanwhile, the drug content and encapsulation efficiency of nanoparticles can be achieved by varying the feed weight ratios of pla-peg-fa and dox. the results indicate that drug loading content(dlc) and encapsulation efficiency(ee) for (10:1), (20:1), (50:1) copolymer:drug samples were 4.86%, 2.81%, 1.5% and 48.62%, 61.17%, 75.29, respectively. these pla-peg-fa-dox mnps also demonstrated sustained release of dox at 37° c in buffer solution during the dialysis bag process. accordingly, the release of the drug in 120 hours for (10:1), (20:1), (50:1) copolymer:drug samples were 85%, 63%, 65% than the only dox that was equal to 95% in 2 hours. also the heat produced by fe3o4 nanoparticles with concentrations of 10, 12.5, 17.5, 20(mg/ml) were 40.6, 41.2, 45.1, 48.4° c and for fe3o4 loaded pla-peg-fa nanoparticles (pla-peg-fa/spion nanoparticles) with the same fe3o4 concentrations were 34.7, 37.3, 41.4, 44.1° c.

Conclusion

The delivery of spion nanoparticles to a specific target site with minimum side effects and heating is an important challenge in targeted hyperthermia. moreover, much higher therapeutic outcomes can be reached with combinatorial treatment of cancer cells by employing lower doses of chemotherapeutic drugs and hyperthermia incorporated in the developed delivery system. the results showed that pla-peg-fa-dox mnps have the ability to generate sufficient heat for killing cancer cells under magnetic field and sustained drug release in a week. therefore, pla-peg-fa/spion would be promising delivery system for combinational targeted cancer therapy with hyperthermia and chemotherapy.

Keywords

Poly lactic acid(pla), folic acid(fa), doxorubicin(dox), hyperthermia, targeted delivery