Homer H. Chiang

Photoswitchable nanoparticles for in vivo cancer chemotherapy

Significance The importance of this research is in the demonstration of the effectiveness and improved safety of a nanoparticulate chemotherapeutic formulation that can be phototriggered to shrink in size at the tumor site. That shrinkage enhanced nanoparticle penetration into tumors and also triggered local drug release. The result was increased efficacy and reduced systemic toxicity. The phototriggered formulation also relieved the compression of tumor blood vessels, which is a recognized barrier to nanoparticle accumulation in tumors. There are many obstacles to effective cancer chemotherapy, including drug penetration and accumulation in tumors and drug systemic toxicity. The penetration of therapies into tumors is limited by the dense tumor matrix and by compression of the tumor vasculature. We have developed spiropyran-based nanoparticles that shrink from 103 to 49 nm upon irradiation at 365 nm. That shrinkage enhanced tissue penetration and drug release. Irradiation of s.c. HT-1080 tumors in nude mice administered i.v. docetaxel-containing nanoparticles was more effective treatment than free docetaxel or encapsulated docetaxel without irradiation. Irradiation at the tumor site also resulted in less systemic toxicity than if the nanoparticles were irradiated before injection, presumably because of less systemically distributed free drug. The enhanced efficacy of nanoparticles in irradiated tumors may have been related to the observed enhanced tumor penetration by nanoparticles and decompression of tumor blood vessels, which may also increase nanoparticle delivery into tumors.

Long-Lasting Antifouling Coating from Multi-Armed Polymer

We describe a new antifouling surface coating, based on aggregation of a short amphiphilic four-armed PEG-dopamine polymer into particles and on surface binding by catechol chemistry. An unbroken and smooth polymeric coating layer with an average thickness of approximately 4 μm was formed on top of titanium oxide surfaces by a single step reaction. Coatings conferred excellent resistance to protein adhesion. Cell attachment was completely prevented for at least eight weeks, although the membranes themselves did not appear to be intrinsically cytotoxic. When linear PEG or four-armed PEG of higher molecular weight were used, the resulting coatings were inferior in thickness and in preventing protein adhesion. This coating method has potential applicability for biomedical devices susceptible to fouling after implantation.

Formulations for trans-tympanic antibiotic delivery.

We have developed a drug delivery system for prolonged trans-tympanic antibiotic delivery from a single dose administration. Increased permeability to ciprofloxacin of the intact tympanic membrane (TM) was achieved by chemical permeation enhancers (CPEs--bupivacaine, limonene, sodium dodecyl sulfate); this was also seen by CPEs contained within a hydrogel (poloxamer 407) to maintain the formulation at the TM. The CPE-hydrogel formulation had minimal effects on auditory thresholds and tissue response in vivo. CPE-hydrogel formulations have potential for ototopical delivery of ciprofloxacin for the treatment of acute otitis media (AOM) and other middle ear diseases.

Hydroxyapatite for Keratoprosthesis Biointegration

PURPOSE Integration of keratoprosthesis with the surrounding cornea is very important in preventing bacterial invasion, which may cause ocular injury. Here the authors investigated whether hydroxyapatite (HAp) coating can improve keratoprosthesis (KPro) biointegration, using polymethyl methacrylate (PMMA)--the principal component of the Boston KPro--as a model polymer. METHODS HAp coatings were induced on PMMA discs after treatment with concentrated NaOH and coating with poly-dopamine (PDA) or polydopamine and then with 11-mercaptoundecanoic acid (11-MUA). Coatings were characterized chemically (Fourier transform infrared spectroscopy [FTIR], energy dispersive X-ray spectroscopy [EDX]) and morphologically (SEM) and were used as substrates for keratocyte growth in vitro. Cylinders of coated PMMA were implanted in porcine corneas ex vivo for 2 weeks, and the force required to pull them out was measured. The inflammatory reaction to coated discs was assessed in the rabbit cornea in vivo. RESULTS FTIR of the coatings showed absorption bands characteristic of phosphate groups, and EDX showed that the Ca/P ratios were close to those of HAp. By SEM, each method resulted in morphologically distinct HAp films; the 11-MUA group had the most uniform coating. The hydroxyapatite coatings caused comparable enhancement of keratocyte proliferation compared with unmodified PMMA surfaces. HAp coating significantly increased the force and work required to pull PMMA cylinders out of porcine corneas ex vivo. HAp coating of implants reduced the inflammatory response around the PMMA implants in vivo. CONCLUSIONS These results are encouraging for the potential of HAp-coated surfaces for use in keratoprostheses.

Duration and local toxicity of sciatic nerve blockade with coinjected site 1 sodium-channel blockers and quaternary lidocaine derivatives.

Background and Objectives Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the coapplication of extracellularly acting site 1 sodium-channel blocker, resulting in prolonged block duration but with minimal tissue toxicity. Methods Quaternary lidocaine derivatives (QX-314 or QX-222), site 1 sodium-channel blockers (tetrodotoxin [30 &mgr;M] or saxitoxin [12.5 &mgr;M]), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment. Results Coapplication of 25 mM QX-314 or 100 mM QX-222 with site 1 sodium-channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P < 0.05), compared with QLDs or site 1 blockers alone. Quaternary lidocaine derivatives elicited severe myotoxicity; this was not exacerbated by coinjection of the site 1 sodium-channel blockers. Conclusions Coadministration of site 1 sodium-channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.

Topical drug formulations for prolonged corneal anesthesia.

Purpose: Ocular local anesthetics currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect of the site 1 sodium channel blocker tetrodotoxin (TTX) on the duration of corneal anesthesia, applied with either proparacaine (PPC) or the chemical permeation enhancer octyl-trimethyl ammonium bromide (OTAB). The effect of test solutions on corneal healing was also studied. Methods: Solutions of TTX, PPC, and OTAB, singly or in combination, were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet–Bonnet esthesiometer, and the duration of corneal anesthesia was calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo after corneal debridement. Results: Combination of TTX and PPC resulted in corneal anesthesia that was 8 to 10 times longer in duration than that from either drug administered alone, whereas OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed after coadministration of TTX and PPC. Conclusions: Coadministration of TTX and PPC significantly prolonged corneal anesthesia, but in view of delayed corneal reepithelialization, caution is suggested in the use of the drug combination.

Photoactive electrospun fibers for inducing cell death.

A photoactive electrospun material producing reactive oxygen species (ROS) upon light irradiation is reported. The phototoxicity of the generated ROS is spatially restricted to the fiber-tissue interface by conjugation of the photosensitizer to a macromolecule. Photo-triggered ROS is produced on demand and repeatedly. It induces death of mammalian cells growing on the material surface with high spatial resolution.