pH-triggered release of macromolecules from spray-dried polymethacrylate microparticles.
OBJECTIVE
pH-triggered microparticles release their therapeutic payloads at acidic pH (e.g., in the phagosome), making intracellular drug delivery more efficient. Here we modify lipid-based microparticles that are safe and efficacious in nerve and brain and are potentially inhalable, making them pH-triggerable by incorporating an acid-soluble polymethacrylate, Eudragit E100 (E100).


METHODS
Microparticles were produced by spray-drying and characterized by electron microscopy, Coulter counting, density measurement, and release kinetics of fluorescently labeled proteins. In addition, biocompatibility and cellular uptake were observed in rats.


RESULTS
Microparticles were spheroids 3 to 5 microm in diameter with densities of 0.12 to 0.25 g/L. Microparticles with 20% (w/w) or more E100 demonstrated slow release of fluorescently labeled proteins at pH 7.4 but rapid release at pH 5. pH-triggerability was maintained for over 2 weeks in solution. Protein loadings of 0.2-20% (w/w) were pH-triggerable. Histologic examination of particles in rat connective tissue near nerve and muscle demonstrated biocompatibility aside from muscle edema in the cell layers adjacent to the particles and a localized inflammatory reaction with macrophages laden with microparticles.


CONCLUSIONS
Microparticles containing E100 were pH-triggerable for many days and were taken up by macrophages, suggesting that they may be useful for intracellular drug delivery.
Kohane
Daniel S
DS
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Anderson
Daniel G
DG
Yu
Christine
C
Langer
Robert
R
D000179:Acrylates / Q000737:chemistry; D000418:Albumins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D000818:Animals; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000009:adverse effects / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007273:Injections, Intramuscular; D007768:Lactalbumin / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000009:adverse effects / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000179:Acrylates; D000418:Albumins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C477020:Eudragit E100; D005079:Excipients; D005456:Fluorescent Dyes; D011108:Polymers; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid; D007768:Lactalbumin; D016650:Fluorescein-5-isothiocyanate