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.

A Smart Nano‐Prodrug Platform with Reactive Drug Loading, Superb Stability, and Fast Responsive Drug Release for Targeted Cancer Therapy

“…As compared to polymer–drug conjugates, physically loaded drug formulations are usually less stable and more prone to premature drug release that would largely reduce their tumor targetability . Polymer–drug conjugates are, however, often perplexed by their multistep synthesis and/or inefficient activation at the site of action …”

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

“…In order to synthesize nanocarriers of GEM based on a biodegradable, dendritic polymer, we used hyperbranched PG‐ co ‐PCL as the macroinitiator core. To include a drug‐bearing domain along with a release trigger, we first grafted a pentafluorophenyl ester appended polycarbonate from PG‐ co ‐PCL to yield compound 3 , using cyclic carbonate as the monomer and 1,8‐diazabicyclo [5.4.0] undec‐7‐ene (DBU) as the catalyst . The hyperbranched PG‐ co ‐PCL macroinitiator provided multiple reaction sites from which the polycarbonate (PC) block was generated.…”

“…We have also investigated the potential of using PG‐ co ‐PCL to non‐covalently stabilize GEM, taking the advantage of the strong hydrogen bond–forming capacity of the latter. Polycarbonate blocks synthesized from macroinitiators such as PEG have been established by Hedricks et al, which have also found applications in the delivery of combination chemotherapy . Incorporation of wide varieties of tertiary amines as acid‐sensitive units in block copolymers has been used by Hammond et al to address delivery challenges in triple‐negative breast cancer .…”

Self-assembling prodrugs

“…To precisely control drug loading, one strategy to synthesize polymer-drug conjugates is to use hydrophobic drugs as initiators for the polymerization. 60–66 Cheng and co-workers initially reported drug-initiated polymerization using a number of anticancer drugs such as paclitaxel and doxorubicin. 61–63 …”