Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Senshang Lin

Second Advisor

Bhagwan D Rohera

Third Advisor

Zhe-Sheng Chen

Abstract

Primary brain cancer cells grow within the brain or cancer cells can metastasis from different site of the body into brain. The major hurdle in the treatment of brain cancer is the presence of blood-brain barrier (BBB). Additionally, acquired multidrug-resistant (MDR) impedes the success of long-term chemotherapy. Therefore, the objective of this investigation is to evaluate the brain targeting potential of orally administered poly(butyl cyanoacrylate) nanoparticulate delivery systems (PBCA-NPDS), double-coated with Tween 80 and polyethylene glycol (PEG) 20000 for brain delivery of doxorubicin, that does not cross the BBB by itself. And, evaluate the MDR reversal potential of PBCA-NPDS. Doxorubicin-loaded PBCA-NPDS were prepared by the anionic polymerization method and were successively double-coated with Tween 80 and PEG 20000 in varied concentrations. Brain uptake study of double-coated doxorubicin-loaded PBCA-NPDS using bEnd.3 cell line suggested the role of clathrin-mediated endocytosis in the uptake of double coated doxorubicin-loaded PBCA-NPDS. When Transwell® permeable supports were used, significant transport of doxorubicin across the cell monolayer was observed by the double-coated formulations, in comparison to doxorubicin solution (p<0.05). Significant accumulation of doxorubicin in brain was achieved after oral administration of double-coated doxorubicin-loaded PBCA-NPDS in rats (p<0.05). Furthermore, simultaneously analyzing the pharmacokinetic data obtained after intravenous and oral administrations, revealed the role of lymphatics in absorption of double-coated doxorubicin-loaded PBCA-NPDS. When MDR reversal potential of PBCA-NPDS was evaluated by cell uptake in P-gp overexpressing cell line, significant uptake of doxorubicin was mediated by double-coated doxorubicin-loaded PBCA-NPDS (p<0.05). These results were verified by MTT assay in P-gp or BCRP overexpressing cell lines. MTT assays revealed that double-coated doxorubicin-loaded PBCA-NPDS significantly potentiated the sensitivity of doxorubicin in P-gp overexpressing cells, in comparison to doxorubicin solution, single-, and un-coated doxorubicin-loaded PBCA-NPDS (p<0.05 in all case), respectively. Further increase in concentration of Tween 80, significantly enhanced the sensitivity of doxorubicin in BCRP overexpressing cell line, in comparison to single- and double-coated doxorubicin-loaded PBCA-NPDS (with lower concentration of Tween 80) (p<0.05 in all case). Hence, it could be concluded that double-coated doxorubicin loaded PBCA-NPDS could be used for brain targeting of doxorubicin administered orally and overcome MDR.

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