Overcoming blood brain barrier with a dual purpose Temozolomide loaded Lactoferrin nanoparticles for combating glioma (SERP-17-12433)

Abstract

Targeted delivery of drugs to the brain is challenging due to the restricted permeability across the blood brain barrier (BBB). Gliomas are devastating cancers and their positive treatment outcome using Temozolomide (TMZ) is limited due to its short plasma half-life, systemic toxicity and limited access through the blood-brain barrier (BBB). Nanoparticles made of Lactoferrin (Lf) protein, have been shown to enhance the pharmacological properties of drugs. Here, we report the specific ability of Lf nanoparticles to cross BBB and target over-expressed Lf receptors on glioma for enhanced TMZ delivery. TMZ-loaded Lf nanoparticles (TMZ-LfNPs) were prepared by our previously reported sol-oil method. While the Lf protein in the NP matrix aids in transcytosis across the BBB and preferential tumor cell uptake, the pH responsiveness leads to TMZ release exclusively in the tumor microenvironment. Delivery through LfNPs results in an enhanced and sustained intracellular concentration of TMZ in GL261 cells in vitro along with improving its in vivo pharmacokinetics and brain accumulation. TMZ-LfNPs treatment results in a significant reduction of tumor volume, higher tumor cell apoptosis and improved median survival in glioma bearing mice. These results demonstrate that LfNPs present an efficient TMZ delivery platform for an effective treatment of gliomas.

Tomographic magnetic particle imaging of cancer targeted nanoparticles

“…27 Previous studies have shown that lactoferrin molecules can pass blood brain barrier (BBB) through a receptor-mediated transcytosis mechanism. 30 Therefore, future investigations using intracranially implanted brain tumor xenografts are required to validate facilitated BBB transport of these lactoferrin conjugated NPs. These proof of concept results hold promise for the safe clinical translation of our MPI contrast agents.…”

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

“…16 Furthermore, Lf has the ability to cross the BBB, and this property has been widely used for targeted delivery of several drugs to the brain. 15,18 Therefore, in the current study, we prepared Lf-modified rotigotine NPs (Lf-R-NPs) to investigate whether Lf can improve nose-to-brain delivery of R-NPs after intranasal administration. Lf-R-NPs should be able to rapidly and efficiently deliver rotigotine specifically into the brain.…”

“…Lactoferrin (Lf) is an iron-binding glycoprotein of 80 kDa belonging to the transferring family. 15 The Lf receptors (LfRs) are highly expressed on the apical surface of respiratory epithelial cells, brain endothelial cells, and neurons. 16,17 Previous studies demonstrated that neurons accumulate high concentrations of LfRs in PD.…”

All‐trans retinoic acid eluting poly(diol citrate) wafers for treatment of glioblastoma

“…Antiproliferative drugs including Carmustine (bis-chloroethylnitrosourea, BCNU) or other alkylating agents have some ability to cross the BBB and have been used clinically (Chamberlain, 2010;Kumari, Ahsan, Kumar, Kondapi, & Rao, 2017). Unfortunately, the survival benefit of these agents as a supplement to radiotherapy is modest at best, increasing median survival from 12.1 with radiation alone to 14.6 months (Kumari et al, 2017). Furthermore, these drugs can present serious toxicity problems when delivered systemically (Lee, 2017).…”