Clinical development of a poly(2-oxazoline) (POZ) polymer therapeutic for the treatment of Parkinson’s disease – Proof of concept of POZ as a versatile polymer platform for drug development in multiple therapeutic indications

Moreadith, Randall W.; Viegas, Tacey X.; Bentley, Michael D.; Harris, J. Milton; Fang, Zhihao; Yoon, Kunsang; Dizman, Bekir; Weimer, Rebecca; Rae, Brendan P.; Li, Xiuling; Rader, Christoph; Standaert, David G.; Olanow, Warren

doi:10.1016/j.eurpolymj.2016.09.052

Cited by 143 publications

(94 citation statements)

References 52 publications

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“…Our data clearly show that in mice POx-vismo is less a toxic and more effective, parenteral alternative to conventional vismodegib. Phase 1 trials to test the safety of POx-micelles loaded with other agents are currently on-going and early results of one phase 1 trial showed that poly(2oxazoline) nanoparticles similar to POx micelles in this study were well tolerated (34). The improved efficacy of POx-vismo and the need for more effective treatments for SHH-driven cancers support the testing of POx-vismo in humans.…”

Section: Discussionmentioning

confidence: 62%

Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Hwang

Dismuke²,

Tikunov³

et al. 2020

Preprint

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We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and doselimiting extraneural toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHHsubgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and bone toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.

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Section: Discussionmentioning

confidence: 62%

Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Hwang

Dismuke²,

Tikunov³

et al. 2020

Preprint

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“…Moreadith, Viegas and colleagues designed a polymer-peptide conjugate based on PEtOx and rotigotine for the treatment of Parkinson's disease. [35] This article is expected to stimulate the interest of further researchers in POx as it highlights the enormous potential of POx for future nanomedicines. Excitingly, for the first time a POx-therapeutic has entered human clinical trials, Phase I, and the authors provide preclinical safety and pharmacology, early clinical safety, tolerability and pharmacokinetic data of this conjugate.…”

Section: Versatility and Properties Of Poly(2-oxazoline)s (Poxs)mentioning

confidence: 99%

Chain and Step Growth Polymerizations of Cyclic Imino Ethers: From Poly(2‐oxazoline)s to Poly(ester amide)s

Kempe

2017

Macromol. Chem. Phys.

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Cyclic imino ethers (CIEs), such as 2‐oxazolines and 2‐oxazines are a unique class of monomers, which because of their manifold reactivities can be polymerized via multiple techniques. Most prominent, the living cationic ring‐opening polymerization (CROP) of CIEs enables the synthesis of well‐defined tailor‐made poly(CIEs), which have tremendous importance as functional and biocompatible polymers. On the other hand, CIEs are also powerful monomers in polyadditions resulting in the formation of a variety of biodegradable polyamide‐based systems. In this contribution, the enormous potential of CIEs as functional building blocks is discussed, which goes well beyond the CROP. Besides trends in the CROP of CIEs, recent developments in step‐growth polymerizations of CIEs are highlighted, including the spontaneous zwitterionic copolymerization (SZWIP) which provides access to functional alternating N‐acylated poly(amino ester)s (NPAEs) and polyadditions of multifunctional CIEs which give main‐chain poly(ester amide)s (PEAs).

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“…[8] Furthermore,(orthogonally) functionalized polymers can be prepared using functional initiators,t erminating agents and/or functional monomers. [11] Besides biomedical applications, PAOx are also popular for the development of responsive and smart materials as the monomer side chain and the copolymerization of different 2-oxazoline monomers allows accurate tuning of the overall hydrophilic-hydrophobic balance and, thus,t he thermoresponsive lower critical solution temperature behaviour in water. [11] Besides biomedical applications, PAOx are also popular for the development of responsive and smart materials as the monomer side chain and the copolymerization of different 2-oxazoline monomers allows accurate tuning of the overall hydrophilic-hydrophobic balance and, thus,t he thermoresponsive lower critical solution temperature behaviour in water.…”

mentioning

confidence: 99%

Defined High Molar Mass Poly(2‐Oxazoline)s

et al. 2018

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Poly(2-alkyl-2-oxazoline)s (PAOx) are regaining interest for biomedical applications.H owever,t heir full potential is hampered by the inability to synthesise uniform high-molar mass PAOx. In this work, we proposed alternative intrinsic chain transfer mechanisms based on 2-oxazoline and oxazolinium chain-end tautomerisation and derived improved polymerization conditions to suppress chain transfer,allowing the synthesis of highly defined poly(2-ethyl-2-oxazoline)s up to ca. 50 kDa (dispersity () < 1.05) and defined polymers up to at least 300 kDa ( < 1.2). The determination of the chain transfer constants for the polymerisations hinted towards the tautomerisation of the oxazolinium chain end as most plausible cause for chain transfer.Finally,the method was applied for the preparation of up to 60 kDa molar mass copolymers of 2-ethyl-2-oxazoline and 2-methoxycarbonylethyl-2-oxazoline.

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Clinical development of a poly(2-oxazoline) (POZ) polymer therapeutic for the treatment of Parkinson’s disease – Proof of concept of POZ as a versatile polymer platform for drug development in multiple therapeutic indications

Cited by 143 publications

References 52 publications

Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Chain and Step Growth Polymerizations of Cyclic Imino Ethers: From Poly(2‐oxazoline)s to Poly(ester amide)s

Defined High Molar Mass Poly(2‐Oxazoline)s

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