Poly(ethylene oxide)-block-polyphosphester-based paclitaxel conjugates as a platform for ultra-high paclitaxel-loaded multifunctional nanoparticles

Abstract

A new type of degradable, nanoscopic polymer assembly containing ultra-high levels of drug loading via covalent attachment within amphiphilic core-shell nanoparticle morphology has been generated as a potentially effective and safe anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-based paclitaxel drug conjugates (PEO-b-PPE-g-PTX) were synthesized by rapid, scalable and versatile approach that involves only two steps: organocatalyst-promoted ring-opening-polymerization followed by click reaction-based conjugation of a PTX prodrug. Variations in the polymer-to-PTX stoichiometries allowed for optimization of the conjugation efficiency, the PTX drug loading and the resulting water solubilities of the entire polymer and the PTX content. The PEO-b-PPE-g-PTX formed well-defined micelles in aqueous solution, with a PTX loading capacity as high as 65 wt%, and a maximum PTX concentration of 6.2 mg/mL in water, which is 25000-fold higher than the aqueous solubility of free PTX. The positive cell-killing activity of PEO-b-PPE-g-PTX against several cancer cell lines is demonstrated, and the presence of pendant reactive functionality provides a powerful platform for future work to involve conjugation of multiple drugs and imaging agents to achieve chemotherapy and bioimaging.

New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity

“…However, most hydrophobic chemotherapeutics alone cannot self-assemble into stable nanoprecipitates in aqueous media without the help of adjuvant matrices. By exploiting the innate hydrophobicity of therapeutics, various amphiphilic prodrugs covalently coupled with hydrophilic motifs [e.g., oligo(ethylene glycol) (17)(18)(19), polypeptides (20,21), and copolymers (22)(23)(24)(25)] have been leveraged to mimic the self-assembly behavior that ubiquitously occurs in nature. More intriguingly, several groups, including us, have recently demonstrated that the attachment of lipophilic moieties to anticancer agents conferred the prodrug amphiphiles with the ability to form colloidally stable nanoaggregates rather than precipitants, despite the enhanced overall lipophilicity of prodrugs (26)(27)(28)(29)(30)(31).…”

Self-assembling prodrugs

“…Wooley and coworkers demonstrated this by synthesizing an alkyne-bearing PEG-PPE (poly(phosphoester)) polymer through organocatalyzed ROP, to which they attached an azide-functionalized PTX by copper-mediated azide-alkyne cycloaddition (CuAAC). 74 These conjugates, PEO- b -(PPE- g -PTX), formed micellar nanoparticles with narrow size distributions (24 ± 7 nm by TEM) and a PTX loading capacity of 55% ( w/w ). However, while breakdown of the polymer occurred at pH 6, only ~5% of the conjugated PTX was released.…”

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

“…Zhang et al synthesized poly(ethylene oxide)-polyphosphoester-based PTX drug conjugates (PEO-PPE-PTX) in a two-step manner using organo-catalyst promoted ring-opening-polymerization, followed by click reaction based conjugation of a PTX prodrug. [157] The PEO-PPE-PTX formed well-defined core-shell nanoparticles in aqueous solution, containing ultra-high levels of drug loading. The Yu group developed a poly(L-γ-glutamyl glutamine)-PTX (PGG-PTX) conjugate.…”

“…In vitro biological evaluations confirmed that PTX-PEEP-FA, simultaneously acted as both a prodrug and drug delivery carrier, could achieve the aims of increased drug loading efficiency and enhanced targeting efficacy. [157]…”