Multifunctional Liposomal Carriers Encapsulating Temozolomide, RG7388 and Elacridar for Targeted Glioblastoma Multiforme Therapy

Glioblastoma multiforme is a grade IV brain tumour that is highly malignant and has a very low patient survival rate. A hurdle in glioblastoma therapy is bypassing the blood brain barrier. Thus, this study was aimed at designing and comparing two multifunctional liposomal therapies for the delivery of multiple agents to address limitations in therapy like tumour resistance and efflux through the simultaneous delivery of temozolomide, RG7388 and elacridar in a single nano-carrier system. Two liposomal systems were characterized including a multilamellar system and nanoparticles in liposome system (PLL) were designed for this purpose.|The liposomes were surface modified by a folic acid conjugate for the tumour cell targeting. An HPLC technique was developed and validated for the simultaneous detection and quantification of temozolomide, elacridar and RG7388 and it was found to obey USP validation parameters for specificity, linearity, accuracy and precision. This method was applied for the determination of encapsulation efficiency, in vitro release, cell uptake and permeability studies. The folic acid conjugate was successfully characterized for its purity with a high yield of 89.6 ± 4.91% and the folic acid content was 86.5 ± 2.63%w/w. All liposomal systems were found to be below 200 nm with a negative charge. The effect of freeze thaw cycles on liposome bilayer characteristics was tested and it was found that increasing freeze thaw cycles to unilamellar vesicles caused an increase in the liposomal bilayer. The encapsulation efficiency for the surface modified multilamellar liposomes was found to be was found to be approximately 12, 47 and 86%w/w for RG7388, TMZ and elacridar respectively, whereas it was 33, 37 and 79% w/w respectively for the surface modified PLL systems. Sustained release was observed from the PLL system as compared to the multilamellar liposomal system.|In vitro characterization for cellular toxicity in BBB and glioblastoma models revealed that the liposomes showed lower toxicity in MDCK cells, while the toxicity for U87 and GBM 108 cells for the liposomal systems was higher than that of the drug solutions. Higher uptake for the folate decorated liposomes was seen in the U87 and GBM108 cell lines. The permeability of the systems was affected with the TEER values for the MDCK monolayer and in most cases, higher permeability was observed for the folate decorated liposomes upon prolonged treatment exposure.|Thus, the liposomal systems offer a unique carrier system for brain delivery of drugs, specifically for targeting glioblastoma. Additionally, sustained release can be achieved using PLGA nanoparticle in liposomes. However, the in vitro results need to be investigated in vivo.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2018

Author dc:creator

• Arsiwala, Tasneem

Advisor dc:contributor.advisor

• Dash, Alekha K.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10504/118849

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/118849