Article

Drug-Initiated, Controlled Ring-Opening Polymerization for the Synthesis of Polymer-Drug Conjugates

Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Macromolecules (Impact Factor: 5.93). 03/2012; 45(5):2225-2232. DOI: 10.1021/ma202581d
Source: PubMed

ABSTRACT Paclitaxel, a polyol chemotherapeutic agent, was covalently conjugated through its 2'-OH to polylactide with 100% regioselectivity via controlled polymerization of lactide mediated by paclitaxel/(BDI-II)ZnN(TMS)(2) (BDI-II = 2-((2,6-diisopropylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-2-pentene). The steric bulk of the substituents on the N-aryl groups of the BDI ligand drastically affected the regiochemistry of coordination of the metal catalysts to paclitaxel and the subsequent ring-opening polymerization of lactide. The drug-initiated, controlled polymerization of lactide was extended, again with 100% regioselectivity, to docetaxel, a chemotherapeutic agent that is even more structurally complex than paclitaxel. Regioselective incorporation of paclitaxel (or docetaxel) to other biopolymers (i.e., poly(δ-valerolactone), poly(trimethylene carbonate), and poly(ε-caprolactone)), was also achieved through drug/(BDI-II)ZnN(TMS)(2)-mediated controlled polymerization. These drug-polylactide conjugates with precisely controlled structures are expected to be excellent building blocks for drug delivery, coating, and controlled-release applications.

0 Followers
 · 
114 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Continuing improvement in the pharmacological and therapeutic properties of drugs is driving the revolution in novel drug delivery systems. In fact, a wide spectrum of therapeutic nanocarriers has been extensively investigated to address this emerging need. Accordingly, this article will review recent developments in the use of nanoparticles as drug delivery systems to treat a wide variety of diseases. Finally, we will introduce challenges and future nanotechnology strategies to overcome limitations in this field.
    Nanomedicine 08/2012; 7(8):1253-71. DOI:10.2217/nnm.12.87 · 5.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To achieve a conjugated drug delivery system with high drug loading but minimal long-term side effects, a degradable brush polymer-drug conjugate (BPDC) was synthesized through azide-alkyne click reaction of acetylene-functionalized polylactide (PLA) with azide-functionalized paclitaxel (PTXL) and poly(ethylene glycol) (PEG). Well-controlled structure of the resulting BPDC and its precursors were verified by 1H NMR and gel permeation chromatography (GPC) characterizations. With nearly quantitative click efficiency, drug loading amount of the BPDC reached 23.2 wt%. Both dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) imaging indicated that the BPDC had a nanoscopic size around 10-30 nm. The significant hydrolytic degradability of the PLA backbone of the BPDC was confirmed by GPC analysis of its incubated solution. Drug release study showed that PTXL moieties can be released through the cleavage of the hydrolysable conjugation linkage in pH 7.4 at 37 ºC, with 50% release in about 22 h. As illustrated by cytotoxicity study, while the polymeric scaffold of the BPDC is non-toxic, the BPDC exhibited higher therapeutic efficacy towards MCF-7 cancer cells than free PTXL at 0.1 and 1 µg/mL. Using nile red as encapsulated fluorescence probe, cell uptake study showed effective internalization of the BPDC into the cells.
    Molecular Pharmaceutics 11/2012; 10(3). DOI:10.1021/mp3004868 · 4.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Small molecule chemotherapeutics often have undesired physiochemical and pharmacological properties, such as low solubility, severe side effect and narrow therapeutic index. To address these challenges, polymeric nanomedicine drug delivery technology has been routinely employed, in particular with the use of biodegradable and biocompatible polyesters, such as poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA). Here we review the development and use of PLA and PLGA for the delivery of chemotherapeutic agents in the forms of polymer-drug conjugates and nanoconjugates.
    Current Opinion in Solid State and Materials Science 12/2012; 16(6):323-332. DOI:10.1016/j.cossms.2013.01.001 · 7.17 Impact Factor
Show more

Preview

Download
1 Download