ABSTRACT
Successful oral delivery of therapeutic proteins such as insulin can greatly improve the quality of life of patients. This study develops a bubble carrier system by loading diethylene triamine pentaacetic acid (DTPA) dianhydride, a foaming agent (sodium bicarbonate; SBC), a surfactant (sodium dodecyl sulfate; SDS), and a protein drug (insulin) in an enteric-coated gelatin capsule. Following oral administration to diabetic rats, the intestinal fluid that has passed through the gelatin capsule saturates the mixture; concomitantly, DTPA dianhydride produces an acidic environment, while SBC decomposes to form CO2 bubbles at acidic pH. The gas bubbles grow among the surfactant molecules (SDS) owing to the expansion of the generated CO2. The walls of the CO2 bubbles consist of a self-assembled film of water that is in nanoscale and may serve as a colloidal carrier to transport insulin and DTPA. The grown gas bubbles continue to expand until they bump into the wall and burst, releasing their transported insulin, DTPA, and SDS into the mucosal layer. The released DTPA and SDS function as protease inhibitors to protect the insulin molecules as well as absorption enhancers to augment their epithelial permeability and eventual absorption into systemic circulation, exerting their hypoglycemic effects.
Subject(s)
Microbubbles , Proteins/administration & dosage , Administration, Oral , Animals , Capsules/toxicity , Cell Line, Tumor , Diabetes Mellitus, Experimental/drug therapy , Drug Carriers/toxicity , Gelatin , Insulin/administration & dosage , Insulin/pharmacokinetics , Insulin/therapeutic use , Intestinal Absorption , Pentetic Acid , Permeability , Proteolysis/drug effects , Random Allocation , Rats , Rats, Wistar , Sodium Dodecyl Sulfate/administration & dosage , Sodium Dodecyl Sulfate/toxicity , Solubility , Tablets, Enteric-Coated , Tissue Distribution , Tomography, Emission-Computed, Single-PhotonABSTRACT
Eradicating subcutaneous bacterial infections remains a significant challenge. This work reports an injectable system of hollow microspheres (HMs) that can rapidly produce localized heat activated by near-infrared (NIR) light and control the release of an antibiotic via a "molecular switch" in their polymer shells, as a combination strategy for treating subcutaneous abscesses. The HMs have a shell of poly(d,l-lactic-co-glycolic acid) (PLGA) and an aqueous core that is comprised of vancomycin (Van) and polypyrrole nanoparticles (PPy NPs), which are photothermal agents. Experimental results demonstrate that the micro-HMs ensure efficiently the spatial stabilization of their encapsulated Van and PPy NPs at the injection site in mice with subcutaneous abscesses. Without NIR irradiation, the HMs elute a negligible drug concentration, but release substantially more when exposed to NIR light, suggesting that this system is suitable as a photothermally-responsive drug delivery system. The combination of photothermally-induced hyperthermia and antibiotic therapy with HMs increases cytotoxicity for bacteria in abscesses, to an extent that is greater than the sum of the two treatments alone, demonstrating a synergistic effect. This treatment platform may find other clinical applications, especially for localized hyperthermia-based cancer therapy.
Subject(s)
Abscess/therapy , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Drug Delivery Systems , Skin Diseases/therapy , Abscess/drug therapy , Animals , Anti-Bacterial Agents/pharmacology , Hot Temperature , Infrared Rays , Injections, Subcutaneous , Lactic Acid , Methicillin-Resistant Staphylococcus aureus/drug effects , Mice , Mice, Inbred BALB C , Microspheres , Nanoparticles , Photochemistry , Polyglycolic Acid , Polylactic Acid-Polyglycolic Acid Copolymer , Pyrroles , Skin Diseases/drug therapy , Tissue Distribution , Vancomycin/administration & dosage , Vancomycin/pharmacology , Vancomycin/therapeutic use , Wound Healing/drug effectsABSTRACT
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 hollow microspheres (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 poly(D,L-lactic-co-glycolic acid) (PLGA) and an aqueous core that contains vancomycin (Van) and NaHCO3. At neutral pH, the CP/HM cement elutes a negligible concentration of the drug. In an acidic environment, the NaHCO3 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.
