Abstract
Poly(D,L-lactic-co-glycolic acid) (PLGA) has been extensively utilized as a carrier material for drug delivery, but in the absence of a triggering mechanism, the rate of release of a drug from a PLGA-based carrier is typically slow, resulting in a sub-effective drug concentration. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the drug and the bubble-generating agent. Upon injection of this system into inflamed tissues, environmental protons (H+) or H2O2 infiltrate the shell of the HMs and react with their encapsulated bubble-generating agent to form bubbles that trigger localized drug release. In study I, in the conventional treatment of osteomyelitis, the penetration of antibiotics into the infected bone is commonly poor. To ensure that the local antibiotic concentration is adequate, this work develops an injectable calcium phosphate (CP) cement in which is embedded pH-responsive HMs that can control the release of a drug according to the local pH. The HMs are fabricated using a microfluidic device, with a shell of PLGA and an aqueous core that contains vancomycin (Van) and sodium bicarbonate (SBC). At neutral pH, the CP/HM cement elutes a negligible concentration of the drug. In an acidic environment, the SBC that is encapsulated in the HMs reacts with the acid rapidly to generate CO2 bubbles, disrupting the PLGA shells and thereby releasing Van locally in excess of a therapeutic threshold. The feasibility of using this CP/HM cement to treat osteomyelitis is studied using a rabbit model. Analytical results reveal that the CP/HM cement provides highly effective local antibacterial activity. Histological examination further verifies the efficacy of the treatment by the CP/HM cement. The above findings suggest that the CP/HM cement is a highly efficient system for the local delivery of antibiotics in the treatment of osteomyelitis. In study II, this work proposes an ultra-sensitive ROS-responsive HM carrier that contains an anti-inflammatory drug, an acid-precursor of ethanol and FeCl2, and a bubble-generating agent (SBC). In cases of osteoarthritis, in inflamed tissues H2O2 in low concentrations diffuses through the HMs to oxidize their encapsulated ethanol in the presence of Fe2+ by the Fenton reaction, to establish an acidic milieu. In acid, SBC decomposes to form CO2 bubbles, disrupting the shell wall of the HMs and releasing the anti-inflammatory drug to the problematic site, eventually protecting against joint destruction. These results reveal that the proposed HMs may uniquely exploit the biologically relevant concentrations of H2O2 and thus be used for the site-specific delivery of therapeutics in inflamed tissues. In study III, Multidrug resistance (MDR) due to the overexpression of drug transporters such as P-glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable HM system that carries an anticancer agent (CPT-11) and a nitric oxide (NO)-releasing donor (NONOate). Upon injection of this system into acidic tumor tissues, environmental protons (H+) infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp-mediated MDR reversal agent. The site-specific drug release and the NO-reduced Pgp-mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell killing threshold, eventually inducing its antitumor activity. These results reveal that this pH-responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.