Bioresponsive polymeric nanoparticles have been extensively pursued for the development of tumor-targeted drug delivery. A novel redox-sensitive biodegradable polymer with "trimethyl-locked" benzoquinone was synthesized for the preparation of paclitaxel-incorporated nanoparticles. The synthesized redox-sensitive nanoparticles released paclitaxel in response to chemically triggered reduction.

A class of thermosensitive biodegradable multiblock copolymers with acid-labile acetal linkages were synthesized from Pluronic® triblock copolymers (Pluronic® P85 and P104) and di-(ethylene glycol) divinyl ether. The novel polymers were engineered to form thermogels at body temperature and degrade in acidic environment. The Pluronic®-based acid-labile polymers were characterized using nuclear magnetic resonance, gel permeation chromatography and differential scanning calorimetry. In vitro biocompatibility of the synthesized polymers was evaluated using MTT assay. The polymers showed reverse thermogelling behavior in water around body temperature. The solgel transition temperatures of the polymers synthesized from Pluronic® P85 and P104 were lowered from 70.3 to 30 o C and from 68.5 to 26.9 o C, respectively, when the synthesized polymers were compared with corresponding Pluronic® block copolymers at a concentration of 25 wt%. The hydrophobic dye solubilization confirmed the formation of polymeric micelles in the aqueous solution. The sizes of multiblock copolymer increased upon a temperature rise indicating that thermal gelation was mediated by micellar aggregation. The thermally driven hydrogels showed preferential polymer degradation at acidic pH. At pH 5.0 and 6.5, the release of 40 kDa fluorescein isothiocyanate -dextran (FITC-dextran) from the thermally formed hydrogels was completed within 2 and 9 days, respectively. However, FITC-dextran was continuously released up to 30 days at neutral pH. The mechanism of FITC-dextran release at pH 5.0 was mainly an acid-catalyzed degradation whereas both diffusion and pH-dependent degradation resulted in FITC-dextran release at pH 6.5. The novel polymers hold great potential as a pH-sensitive controlled drug delivery system due to their interesting phase transition behavior and biocompatibility.

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Development of a successful bioresponsive drug delivery system requires exquisite engineering of materials so that they are able to respond to the signals stemming from the physiological environment. In this study, we proposed a new Pluronic® based thermogelling system containing matrix metalloproteinase-2 (MMP2) responsive peptide sequences. A novel thermosensitive multiblock copolymer comprising an MMP2-labile octapeptide (Gly-Pro-Val-Gly-Leu-Ile-Gly-Lys) was synthesized from Pluronic® triblock copolymer. The polymer was designed to form thermogel at body temperature and degrade in presence of MMP overexpressed in the tumor. The synthesized polymer was a multiblock copolymer with ~ 2.5 units of Pluronic®. The multiblock copolymer solutions exhibited a reverse thermal gelation around body temperature. The gelation temperatures of the multiblock copolymer solutions were lower than those of the corresponding Pluronic® monomer at a particular concentration. The cytotoxicity of the synthesized polymer was lower comparing to its monomer. The solubility of hydrophobic anticancer drug, paclitaxel, was enhanced in the polymer solutions via micelle formation. The synthesized polymer was preferentially degraded in presence of MMP. Paclitaxel release was dependent on the enzyme concentration. These findings suggest that the synthesized polymer has the potential as controlled drug delivery system due to its unique phase transition and bioresponsive behavior.

The principal aim of this study was to synthesize and characterize pH-sensitive biodegradable triblock copolymers containing a hydrophobic polyacetal segment for controlled drug delivery. Poly(ethylene glycol)-poly(ethyl glyoxylate)-poly(ethylene glycol) (PEG-PEtG-PEG) triblock copolymers with PEG molecular weights 500 (PEtG-PEG 500 ) and 750 (PEtG-PEG 750 ) were synthesized by PEtG end-capping with methoxy PEG via a carbamate linkage. Synthesized amphiphilic PEG-PEtG-PEG was characterized by 1 H-NMR spectroscopy. Molecular weights of PEtG-PEG 500 and PEtG-PEG 750 were determined to be 2,823 and 3,387, respectively, by gel permeation chromatography. The polymers with a biodegradable polyacetal block underwent pHdependent degradation via an acid-catalyzed hydrolysis. Paclitaxel (PTX)-loaded polymeric micelles were prepared by a dialysis method and the amount of PTX incorporated into the polymeric micelle formulations was 45,000 times greater than the water solubility of PTX at room temperature. The polymeric micelles prepared from the amphiphilic PEG-PEtG-PEG triblock copolymers have released the loaded PTX in a pH-dependent manner. The novel PEtG-based amphiphilic block copolymers can find applications for targeted and controlled drug delivery to the acidic environments found in tumors and intracellular compartments.