Novel Self-Associating Poly(ethylene oxide)-block-poly(ε-caprolactone) Block Copolymers with Functional Side Groups on the Polyester Block for Drug Delivery

Abstract

The aim of this study was to develop micelle-forming poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL)-based block copolymers bearing functional side groups on the PCL block. Substituted monomer, i.e, α-benzyl carboxylate-ε-caprolactone, was synthesized by anionic activation of ε-caprolactone and further treatment with benzyl chloroformate. Successful substitution of benzyl carboxylate on ε-caprolactone monomer was evidenced by 1H NMR and mass spectroscopy. Ring-opening polymerization of α-benzyl carboxylate-ε-caprolactone with methoxy PEO (5000 g mol-1) as initiator and stannous octoate as catalyst was used to prepare PEO-b-poly(α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL). Further catalytic debenzylation of PEO-b-PBCL produced PEO-b-poly(α-carboxyl-ε-caprolactone) (PEO-b-PCCL). Ring-opening polymerization of a ε-caprolactone/α-benzyl carboxylate-ε-caprolactone mixture and further reduction of the product were also used to prepare block copolymers with various degrees of benzyl carboxylate or carboxyl group substitution. The calculated molecular weights determined by 1H NMR and gel permeation chromatography (GPC) for block copolymers were in good agreement with the theoretical values. The polydispersity of PEO-b-PBCL and PEO-b-PCCL block copolymers was 1.74 and 1.52, respectively. PEO-b-PBCL and PEO-b-PCCL block copolymers assembled to spherical micelles having average diameters of 62 and 20 nm based on dynamic light scattering (DLS) measurement, respectively. PEO-b-PBCL formed micelles at extremely low concentrations (cmc of 9.8 × 10-2 μM). The presence of carboxylic group on the PCCL block raised the cmc of PEO-b-PCCL to 1220 × 10-2 μM. For block copolymers with PCL-co-PCCL core structures, a decrease in cmc as well as an increase in size was observed as the level of PCL to PCCL was raised. Novel PEO-b-poly(ester) block copolymers with aromatic and reactive side groups on the polyester block have tremendous potential in the design of optimized carriers for the delivery of various therapeutic agents, as they can assemble to biodegradable nanoscopic micelles with chemically tailorable core structures.

Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors

“…PEO-b-PBCL micelles were found to be the most efficient vehicle for the solubilization of both cucurbitacins despite higher CMC of 5000-4700 PEO-b-PBCL compared to 5000-24,000 PEO-b-PCL (Mahmud et al, 2006;Aliabadi et al, 2005a). The presence of aromatic ring on PCL block increases the hydrophobicity and compatibility of core forming block with the hydrophobic structure of cucurbitacin derivatives.…”

“…PEO-b-PBCL block copolymer was also synthesized and characterized as described recently (Mahmud et al, 2006). A nomenclature, e.g., 5000-4700, 5000-5000 and 5000-24,000, in which the left number corresponds to the theoretical molecular weight of the shell forming block and the right number corresponds to the molecular weight of the core forming block, is used throughout the manuscript to distinguish between prepared block copolymers.…”

Polymeric micelles: authoritative aspects for drug delivery

“…The micellar disassembly is governed by the magnitude of the interactions in the micellar core which are dependent on the crystalline or amorphous state of the core-forming polymer, solvent in the micellar core, hydrophilic and hydrophobic balance of the copolymer, and presence of loaded hydrophobic compound [113,201]. Therefore, to improve the thermodynamic and the kinetic stability of drug-loaded micelles several strategies have emerged that include enhanced compatibility of the drug and polymer [74,206], cross-linking of the micelle core/corona [207,208], preparation of stereocomplex micelles [209,210], and reduction in CMC by altering the polymer [211,212].…”

Synthesis and Ring Opening Polymerization of a New Functional Lactone, α‐Iodo‐ε‐caprolactone: A Novel Route to Functionalized Aliphatic Polyesters

“…In polymer chemistry, Lavasanifar et al used this strategy to prepare a poly (a-carboxy-e-caprolactone). [10] Substituted monomer, a-benzyl carboxy-e-caprolactone, was synthesized by the treatment of enolate with benzyl chloroformate. Poly (a-benzyl carboxy-e-caprolactone) was prepared by ring opening polymerization of the monomer, and deprotected to afford poly(a-carboxy-e-caprolactone).…”