The objective of this study was to develop a novel folate receptor-targeted drug delivery system for retinoblastoma cells using doxorubicin (DOX) as a model drug.
Methods:
Biodegradable DOX-loaded poly(d,l-lactide-co-glycolide)-poly(ethylene glycol)-folate (PLGA-PEG-FOL) micelles (DOXM) were prepared with various solvents (dimethylsulfoxide, acetone, and dimethylformamide). The effects of solvents on entrapment efficiency, particle size, and polydispersity were examined. The effects of thermosensitive gel structure on the release of DOX from the DOXM were also studied. Qualitative and quantitative uptake studies of DOX and DOXM were carried out in Y-79 cell line. Cytotoxicity studies of DOXM were performed on Y-79 cells.
Results:
Based on size, polydispersity, and entrapment efficiency, dimethylformamide was found to be the most suitable solvent for the preparation of DOXM. Dispersion of DOXM in PLGA-PEG-PLGA gel sustained drug release for a period of 2 weeks. Uptake of DOX was ∼4 times higher with DOXM than DOX in Y-79 cells overexpressing folate receptors. This was further confirmed from the quantitative uptake studies. DOXM exhibited higher cytotoxicity in Y-79 cells when compared with pure DOX.
Conclusion:
These polymeric micellar systems suspended in thermosensitive gels may provide sustained and targeted delivery of anticancer agents to retinoblastoma cells following intravitreal administration.
Get full access to this article
View all access options for this article.
References
1.
AlbertD.M.Historic review of retinoblastoma. Ophthalmology, 94:654–662. 1987.
2.
BishopJ.O., MadsonE.C.Retinoblastoma. Review of the current status. Surv. Ophthalmol., 19:342–366. 1975.
3.
HonavarS.G., SinghA.D.Management of advanced retinoblastoma. Ophthalmol. Clin. North Am., 18:65–73. 2005.
4.
Sanchez de ToledoJ.Retinoblastoma. Can we do more?Clin. Transl. Oncol., 10:525–526. 2008.
5.
PesinS.R., ShieldsJ.A.Seven cases of trilateral retinoblastoma. Am. J. Ophthalmol., 107:121–126. 1989.
6.
HenkesH.E., HenkesH.E., OosterhuisJ.A.Tumors of the eye. Doc. Ophthalmol., 43:341–342. 1977.
De PotterP.Current treatment of retinoblastoma. Curr. Opin. Ophthalmol., 13:331–336. 2002.
9.
ChintagumpalaM., Chevez-BarriosP., PaysseE.A., PlonS.E., HurwitzR.Retinoblastoma: review of current management. Oncologist, 12:1237–1246. 2007.
10.
EngC., LiF.P., AbramsonD.H., EllsworthR.M., WongF.L., GoldmanM.B., SeddonJ., TarbellN., BoiceJ.D.Jr.Mortality from second tumors among long-term survivors of retinoblastoma. J. Natl. Cancer Inst., 85:1121–1128. 1993.
11.
BeckM.N., BalmerA., DessingC., PicaA., MunierF.First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J. Clin. Oncol., 18:2881–2887. 2000.
12.
MurphreeA.L., VillablancaJ.G., DeeganW.F.3rd, SatoJ.K., MalogolowkinM., FisherA., ParkerR., ReedE., GomerC.J.Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch. Ophthalmol., 114:1348–1356. 1996.
13.
RizzutiA.E., DunkelI.J., AbramsonD.H.The adverse events of chemotherapy for retinoblastoma: what are they? Do we know?Arch. Ophthalmol., 126:862–865. 2008.
14.
GallieB.L., BudningA., DeBoerG., ThiessenJ.J., KorenG., VerjeeZ., LingV., ChanH.S.Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch. Ophthalmol., 114:1321–1328. 1996.
15.
ChinK.V., LiuB.Regulation of the multidrug resistance (MDR1) gene expression. In Vivo, 8:835–841. 1994.
16.
KuoM.T.Roles of multidrug resistance genes in breast cancer chemoresistance. Adv. Exp. Med. Biol., 608:23–30. 2007.
17.
ChanH.S., CantonM.D., GallieB.L.Chemosensitivity and multidrug resistance to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res., 9:469–474. 1989.
18.
KartnerN., Evernden-PorelleD., BradleyG., LingV.Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature, 316:820–823. 1985.
19.
LiB., GaoR., ZhangH., LiL.Q., GaoF., RenR.J.[Studies on multidrug resistance associated protein in retinoblastoma]Zhonghua Yan Ke Za Zhi, 45:314–317. 2009.
20.
JanoriaK.G., GundaS., BodduS.H., MitraA.K.Novel approaches to retinal drug delivery. Expert Opin. Drug Deliv., 4:371–388. 2007.
21.
PhylactosA.C., UngerW.G.Biochemical changes induced by intravitreally-injected doxorubicin in the iris-ciliary body and lens of the rabbit eye. Doc. Ophthalmol., 95:145–155. 1998.
22.
WeitmanS.D., LarkR.H., ConeyL.R., FortD.W., FrascaV., ZurawskiV.R.Jr., KamenB.A.Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res., 52:3396–3401. 1992.
23.
ShiokawaT., HattoriY., KawanoK., OhguchiY., KawakamiH., TomaK., MaitaniY.Effect of polyethylene glycol linker chain length of folate-linked microemulsions loading aclacinomycin A on targeting ability and antitumor effect in vitro and in vivo. Clin. Cancer Res., 11:2018–2025. 2005.
ZhaoH., YungL.Y.Selectivity of folate conjugated polymer micelles against different tumor cells. Int. J. Pharm., 349:256–268. 2008.
26.
ParkE.K., KimS.Y., LeeS.B., LeeY.M.Folate-conjugated methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery. J. Control. Release, 109:158–168. 2005.
27.
YooH.S., ParkT.G.Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. J. Control. Release, 70:63–70. 2001.
28.
KansaraV., PaturiD., LuoS., GaudanaR., MitraA.K.Folic acid transport via high affinity carrier-mediated system in human retinoblastoma cells. Int. J. Pharm., 355:210–219. 2008.
29.
DuvvuriS., JanoriaK.G., MitraA.K.Development of a novel formulation containing poly(d,l-lactide-co-glycolide) microspheres dispersed in PLGA-PEG-PLGA gel for sustained delivery of ganciclovir. J. Control. Release, 108:282–293. 2005.
30.
DuvvuriS., JanoriaK.G., PalD., MitraA.K.Controlled delivery of ganciclovir to the retina with drug-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres dispersed in PLGA-PEG-PLGA gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis. J. Ocul. Pharmacol. Ther., 23:264–274. 2007.
31.
AukunuruJ.V., SunkaraG., BandiN., ThoresonW.B., KompellaU.B.Expression of multidrug resistance-associated protein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel aldose reductase inhibitor. Pharm. Res., 18:565–572. 2001.
32.
TreupelL., PouponM.F., CouvreurP., PuisieuxF.[Vectorisation of doxorubicin in nanospheres and reversion of pleiotropic resistance of tumor cells]C. R. Acad. Sci. III, 313:171–174. 1991.
33.
GaudanaR., JwalaJ., BodduS.H., MitraA.K.Recent perspectives in ocular drug delivery. Pharm. Res., 26:1197–1216. 2009.
34.
JonesM., LerouxJ.Polymeric micelles—a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm., 48:101–111. 1999.
35.
BaeY.H., YinH.Stability issues of polymeric micelles. J. Control. Release, 131:2–4. 2008.
36.
ChenH., KimS., HeW., WangH., LowP.S., ParkK., ChengJ.X.Fast release of lipophilic agents from circulating PEG-PDLLA micelles revealed by in vivo forster resonance energy transfer imaging. Langmuir, 24:5213–5217. 2008.
37.
JeonH.J., JeongY.I., JangM.K., ParkY.H., NahJ.W.Effect of solvent on the preparation of surfactant-free poly(dl-lactide-co-glycolide) nanoparticles and norfloxacin release characteristics. Int. J. Pharm., 207:99–108. 2000.
38.
LiuS.Q., TongY.W., YangY.Y.Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(d,l-lactide-co-glycolide) with varying compositions. Biomaterials, 26:5064–5074. 2005.
39.
QiaoM., ChenD., MaX., LiuY.Injectable biodegradable temperature-responsive PLGA–PEG–PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. Int. J. Pharm., 294:103–112. 2005.
40.
HuangW., PrasadP.D., KekudaR., LeibachF.H., GanapathyV.Characterization of N5-methyltetrahydrofolate uptake in cultured human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci., 38:1578–1587. 1997.
