Drug-Initiated Ring-Opening Polymerization of O-Carboxyanhydrides for the Preparation of Anticancer Drug–Poly(O-carboxyanhydride) Nanoconjugates

Abstract

We report a novel synthetic strategy of polymer-drug conjugates for nanoparticulate drug delivery: hydroxyl-containing drug (e.g., camptothecin, paclitaxel, doxorubicin and docetaxel) can initiate controlled polymerization of phenyl O-carboxyanhydride (Phe-OCA) to afford drug-poly(Phe-OCA) conjugated nanoparticles, termed drug-PheLA nanoconjugates (NCs). Our new NCs have well-controlled physicochemical properties, including high drug loadings, quantitative drug loading efficiencies, controlled particle size with narrow particle size distribution, and sustained drug release profile over days without “burst” release effect as observed in conventional polymer/drug encapsulates. Compared with polylactide NCs, the PheLA NCs have increased non-covalent hydrophobic inter-chain interactions and thereby result in remarkable stability in human serum with negligible particle aggregation. Such distinctive property can reduce the premature disassembly of NCs upon dilution in blood stream, prolong NCs' in vivo circulation with the enhancement of intratumoral accumulation of NCs, which have a bearing in therapeutic effectiveness.

Photo‐responsive amphiphilic poly(α‐hydroxy acids) with pendent o‐nitrobenzyl ester constructed via copper‐catalyzed azide‐alkyne cycloaddition reaction

“…[44] The CCL micelles not only improved the structural stability but also allowed the controlled release of cargo molecules in response to the reducing reagent. [45,46] In this work, we developed a versatile method to prepared photo-responsive poly(α-hydroxy acids) with pendent o-NB ester group. The photolabile o-NB ester group was introduced into the side chain of the hydrophobic poly(α-hydroxy acids) via coppercatalyzed azide-alkyne cycloaddition (CuAAC) reaction between 2-nitrobenzyl 6-azidohexanoate and amphiphilic mPEG-b-Poly(-Tyr) (Scheme 1).…”

Nanosized Camptothecin Conjugates for Single and Combined Drug Delivery

“…Tong (Figure 3a), predefined drug loadings and controlled drug release kinetics (48,49). Nanoparticles with diameter range from 70nm to 200nm can be fabricated depending on different polymer-CPT ratio.…”

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

“…They prepared the drug-poly(Phe-OCA) conjugates (Cpt-PheLA n , where n is the degree of polymerization) by nanoprecipitation followed by self-assembly of Cpt-PheLA n conjugates in water to form nanoconjugates with well controlled physicochemical properties. They reported that poly(PheLA-OCA)-Cpt nanoconjugates exhibited 100% drug loading efficiency at PheLA-OCA/Cpt ratios of 25:1; 50:1 and 100:1 with narrow particle size distribution (100 -125 nm), sustained drug release profiles without 'burst' drug release, remarkable stability in human serum with negligible aggregation and controlled cytotoxicity compared with PLA nanoconjugates (225). In this case it is possible to predict the drug loading efficiency from the PheLA-OCA/Cpt ratio used during polymerization.…”

“…Presently there is limited application of QbD principles to systematic development of nanoconjugates in literature. However in order to address these problems, many researchers have focused on ring opening polymerization (ROP) of lactide (LA) followed by nanoprecipitation of the resulting PLA-drug conjugate (223)(224)(225). The drug release from the nanoconjugate was tuned by controlled cleavage of the lactate ester bond between the drug and polymer by hydrolysis in the physiological solution.…”