In vivo efficacy of dendrimer-methylprednisolone conjugate formulation for the treatment of lung inflammation.
Dendrimers are an emerging class of nanoscale intracellular drug delivery vehicles. Methylprednisolone (MP) is an important corticosteroid used in the treatment (through inhalation) of lung inflammation associated with asthma. The ability of MP-polyamidoamine (PAMAM) dendrimer conjugate to improve the airway delivery was evaluated in a pulmonary inflammatory murine model that was based on an 11-fold enhancement of eosinophil lung accumulation following five daily inhalation exposures of sensitized mice to the experimental allergen, ovalbumin. MP was successfully conjugated to PAMAM-G4-OH dendrimer yielding 12 MP molecules per dendrimer, and further solubilized in lysine carrier. Five daily trans-nasal treatments with the carrier alone, free MP, and MP-dendrimer at 5 mg kg(-1) (on a drug basis) did not induce additional lung inflammation, although free MP decreased baseline phagocytic cell recoveries by airway lavage and tissue collagenase dispersion. MP treatments alone decreased ovalbumin-associated airway and tissue eosinophil recoveries by 71 and 47%, respectively. Equivalent daily MP dosing with MP-dendrimer conjugate further diminished these values, with decreases of 87% and 67%, respectively. These findings demonstrate that conjugation of MP with a dendrimer enhances the ability of MP to decrease allergen-induced inflammation, perhaps by improving drug residence time in the lung. This is supported by the fact that only 24% of a single dose of dendrimer delivered to the peripheral lung is lost over a 3-day period. Therefore, conjugation of drugs to a dendrimer may provide an improved method for retaining drugs within the lung when treating such inflammatory disorders as asthma.
Inapagolla
R
R
Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202, USA.
Guru
B Raja
BR
Kurtoglu
Y E
YE
Gao
X
X
Lieh-Lai
M
M
Bassett
D J P
DJ
Kannan
R M
RM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D002626:Chemistry, Pharmaceutical; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D005260:Female; D005977:Glutarates / Q000138:chemical synthesis / Q000737:chemistry; D008775:Methylprednisolone / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry*; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000893:Anti-Inflammatory Agents; D050091:Dendrimers; D004337:Drug Carriers; D005977:Glutarates; D009757:Nylons; C520550:PAMAM-G4; D010047:Ovalbumin; C035736:glutaric acid; D008775:Methylprednisolone