Ring‐Opening Polymerization of Prodrugs: A Versatile Approach to Prepare Well‐Defined Drug‐Loaded Nanoparticles

Abstract

We report a new methodology for the synthesis of polymer-drug conjugates from "compound"-all in one-prodrug monomers that consist of a cyclic polymerizable group that is appended to a drug through a cleavable linker. We show that organocatalyzed ring-opening polymerization can polymerize these monomers into well-defined polymer prodrugs that are designed to self-assemble into nanoparticles and release drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s) to initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a polyethylene glycol macroinitiator yields amphiphilic diblock copolymers that spontaneously self-assemble into micelles with a long plasma circulation, which is useful for systemic therapy. KeywordsPolymerizable prodrug; Ring-opening polymerization; Polymer-drug conjugate; Nanoparticle; Cancer therapy Most small-molecule drugs utilized in the clinic have poor bioavailability and suboptimal pharmacokinetics because of their hydrophobicity and low molecular weight. Polymeric drug delivery systems can improve the efficacy of these drugs by increasing their water solubility, prolonging their circulation time, increasing the amount of drug deposited in the target tissue, and decreasing their exposure to normal tissues. [1] Conjugation of hydrophobic drugs to hydrophilic polymers can address these problems, [2] and is typically carried out by separate synthesis of the polymer, drug and linker, and sequential conjugation of the three entities to create the polymer-drug conjugate. This conventional strategy requires multiple reaction steps with limited yield, and has limited control of the site and degree of drug loading. New methods are hence needed to synthesize polymer-drug conjugates that have the following attributes: (1) are compatible with a structurally diverse set of drugs; (2) enable more than one drug to be conjugated to the same polymer with tunable control of the * chilkoti@duke.edu. Supporting information for this article is given via a link at the end of the document. Motivated by this rationale, we report herein a new method to synthesize polymer-drug conjugates by living ring-opening polymerization (ROP) of prodrugs (Scheme 1). This scheme inverts the conventional approach of conjugating a drug to a polymer post-synthesis, and instead directly incorporates the drug during synthesis of the polymer. These polymer prodrugs are composed of a "compound" monomer that consists of three covalently linked moieties: (1) a cyclic group that can undergo ROP to yield a biodegradable main chain, that is attached to (2) a cleavable linker, and which is attached to (3) a drug of interest. Living ROP of the compound monomer leads to the synthesis of a polymer with a biodegradable main chain with pendant drug molecules th...

Anticancer nanoparticulate polymer‐drug conjugate

“…The “conjugation through” method could address the drawbacks in the “conjugation to” strategy, such as inconsistent and uncontrolled site conjugation along the polymer backbone . The drug loading can be controlled by adjusting the feed ratio of monomer‐drug conjugates; and the drug release can be controlled by the judicious selection of the linker between the drug and the monomer, which could be stimulus‐responsive (Figure b) . Such method thus allows for even higher drug‐loadings than the “conjugation to” approach, by avoiding steric hindrance and accessibility limitation during the conjugation.…”

“…Similarly, the reversible addition fragmentation transfer (RAFT) polymerization is reported for “conjugation through” method; for example, Cpt‐tethered acrylate with redox‐sensitive disulfide linker was polymerized by RAFT to formulate redox‐sensitive NPs . However, PDCs synthesized by the ROMP or RAFT had non‐biodegradable polymer backbones, which limits their potential clinical application . Alternatively, the ring‐opening polymerization (ROP) is applied in “conjugation through” method.…”

“…For instance, a campothecin‐tethered cyclic carbonate monomer was prepared with the disulfide linker between the drug and carbonate. The ROP of such drug‐carbonate conjugates resulted in a biodegradable polycarbonate PDC which can be further formulated to redox‐responsive NPs …”

One-component nanomedicine

“…However, this popular strategy may suffer from some potential drawbacks, such as low yield due to multi-step reactions involved, limited control of the conjugation sites, and relatively low drug loading [139–141]. To overcome these limitations, direct polymerization of polymerizable drugs has been pursued.…”

“…Their in vitro and in vivo results suggested that the staggered lamellae are superior to the other three nanostructures. Very recently, Chilkoti and co-workers used the ring-opening polymerization to homo or hetero-polymerize both CPT and chlorambucil (CL) prodrugs, initiated by a PEG macroinitiator [139]. These amphiphilic diblock copolymers can spontaneously self-assemble into nanoparticles, where drugs are sequestered in the core that is coated with a PEG corona.…”