In this article we report on the development of polymeric micelles that can integrate multiple functions in one system, including the capability to accommodate a combination of therapeutic entities with different physicochemical properties (i.e., siRNA and doxorubicin; DOX), passive and active cancer targeting, cell membrane translocation, and pH-triggered drug release. A micellar system was constructed from degradable poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with functional groups on both blocks. The functional group on the PCL block was used to incorporate short polyamines for complexation with siRNA or to chemically conjugate DOX via a pH-sensitive hydrazone linkage. A virus mimetic shell was conferred by attaching two ligands, i.e., the integrin αvβ3-specific ligand (RGD4C) for active cancer targeting and the cell-penetrating peptide TAT for membrane activity. This system was used to improve the efficacy of DOX in multidrug-resistant MDA-MB-435 human tumor models that overexpress P-glycoprotein (P-gp), by simultaneous intracellular delivery of DOX and siRNA against P-gp expression. The carrier was tagged with near-infrared fluorescent imaging probes to provide a means to follow the fate of the system in vivo upon intravenous administration. Dy677-labeled siRNA was also used to assess the in vivo stability of the siRNA carrier. This multifunctional polymeric micellar system was shown to be capable of DOX and siRNA delivery to their intracellular targets, leading to the inhibition of P-gp-mediated DOX resistance in vitro and targeting of αvβ3-positive tumors in vivo.

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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.

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