Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors

Abstract

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drug-loaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(ω-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co-DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors.

Neuronanomedicine: An Up-to-Date Overview

“…Specifically, poly(lactide- co -glycolic) acid nanoparticles containing doxorubicin, cisplatin, and boldine resulted in an efficient internalization into the glioma cells, inducing cytotoxic effects [86] and an effective target-specific delivery [87]. Other polymeric nanocarriers for the treatment of brain cancer include polyethylene glycol and poly(ω-pentadecalactone- co - p -dioxanone) [88] or polyethylene glycol and poly(lactic- co -glycolic) acid [89] block copolymer nanoparticles which led to an improved drug release efficiency and a decrease in tumor size. Moreover, the administration of amphiphilic polymer-lipid nanoparticles containing docetaxel led to the in vivo accumulation at the tumor site, with an enhanced tumor growth inhibition and increased median survival compared to the equivalent clinical dose of docetaxel solution [90].…”

Impact of Nanoparticles on Brain Health: An Up to Date Overview

“…The results showed a considerably higher translocation across the blood brain barrier, both for in vitro brain tumor models [40] and for numerical simulations using a three-dimensional brain tumor model reconstructed from magnetic resonance images [41]. Moreover, poly(lactic-co-glycolic acid) nanoparticles [42], block copolymer nanoparticles consisting of polyethylene glycol and poly(ω-pentadecalactone-co-p-dioxanone) [43], or of polyethylene glycol and poly(lactic-co-glycolic acid) [44], and hybrid nanoparticles using poly(lactic-co-glycolic acid), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(carboxy-poly(ethylene glycol)), and charged 1,2-dioleoyl-3-trimethylammonium-propane [45] have been used for the delivery of various anti-cancer drugs, all showing improved targeting and drug release efficiency, with a decrease in brain tumor size.…”

Nanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma

“…To overcome these limitations, we propose to use polymeric nanoparticles (NPs) in combination with CED to achieve sustained and local delivery of agents that inhibit miR-21. In prior work, we have shown that this strategy is effective for sustained delivery of chemotherapy drugs [20][21][22] and radiosensitizers [23,24].…”