Pulmonary administration of corticosteroids using lung surfactant at a delivering vehicle

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1 Pulmonary administration of corticosteroids using lung surfactant at a delivering vehicle Yi Zuo, Asst. Prof. Department of Mech. Engineering College of Engineering University of Hawaii at Manoa Charles R. Neal, Assoc. Prof. Department of Pediatrics JABSOM University of Hawaii at Manoa February,

2 Outline!! Background "!Premature birth and chronic lung disease (CLD) "!Clinical treatment of CLD "!Pulmonary drug delivery using surfactant as a vehicle!! Molecular probing the interaction between steroids and lung surfactant!! Translational values 2

3 Premature birth rate and ethnic disparities in Hawaii!! Estimated ~12,000 newborns in the USA develop CLD each year, associated with an overall cost of $2.4 billion, second only to the childhood asthma.!! In an average week in Hawaii, 44 babies are born preterm. Among them, 5 VLBW babies are at high risk of developing RDS or CLD.!! Premature infants admitted to the NSCU at Kapi olani Medical Center for Women and Children (KMCWC) show significant ethnic disparities. '&%$# $%&#!"# () *+*,*-. (/010**0- (2 0,0-343 (506704*0- (8 9:3;4 &'%&# &&%$# National Center for Health Statistics, final mortality data, Prince, C. B.; Song, L.; Quadri, N.; Baker, K. K., Californian Journal of Health Promotion 1 (2003)

4 State-of-the-art in treating CLD!! Postnatal corticosteroids (especially dexamethasone) are able to dampen the progression of CLD (Cummings et al. N. Engl. J. Med. 1989)!! Systemic corticosteroids cause significant adverse neurodevelopmental outcomes and hence are not recommended for routine use (AAP & CPS, Pediatrics 2002)!! Inhaled corticosteroids may provide effective antiinflammatory therapy locally and therefore fewer systemic adverse effects (Cole et al. N. Engl. J. Med. 1999)!! Intratracheal instillation of corticosteroids using natural lung surfactant as a delivering vehicle represents an alternative route for drug delivery (Yeh et al. Pediatrics 2008) 4

5 Gaps and objectives!! Gaps in clinical practice "!The mechanism of interaction between corticosteroid drugs and natural lung surfactant is unknown "!The type of corticosteroid and its dose have not been standardized and optimized!! Objectives "!Investigate the molecular mechanism of interaction between corticosteroids and lung surfactant "!Determine an optimal corticosteroid concentration at which it synergizes with the clinical lung surfactant 5

6 Clinical surfactant preparations Infasurf Curosurf Bovine lung lavage Porcine lung mince 6

7 Steroids Negative control Cholesterol Budesonide Beclomethasone!! All corticosteroids are biochemically derived from cholesterol!! Cholesterol differs from corticosteroids in having a unique alkyl side chain at C-17 of the cholesterol molecule!! It is known that a high concentration of cholesterol can inhibit the biophysical function of lung surfactant. Therefore, cholesterol was studied as a negative control 7

8 Methods!! Spectrophotometric bioassay: sample analysis and quantification!! Langmuir balance: in vitro reconstruction of lung surfactant films and measurements of surface activity!! Atomic force microscopy: probe lateral structure and molecular organization of surfactant films Spectrophotometric bioassay Langmuir balance Atomic force microscopy 8

9 Differential effects of cholesterol and budesonide on Curosurf mn/m + 10% Cho. + 10% Bud. 10 "m )! (! Cholesterol )! (! Budesonide '! '! * +,-./012,03 3 +, "! &! %! $! #!! 18 +,93 +,- 1:!;#< 18 => 1:#< => 1:#!< 118 => * +,-./012,03 3 +, "! &! %! $! #!! 18 +,93 +,- 1:!;#< 1=>? 1:#< 1111=>? 1:#!< 11=>?! "! #!! #"! $!! $"! %!! * +,-./01.,0.41/5 $ Curosurf + Cholesterol! "! #!! #"! $!! $"! %!! * +,-./01.,0.41/5 $ Curosurf + Budesonide Zhang, Wang, Neal, and Zuo, Pediatric Research (2012) doi: /pr

10 Differential effects of budesonide and budesonide on Infasurf mn/m + 10% BUD. + 10% BDP. 5 "m Budesonide Beclomethasone Infasurf + Budesonide Infasurf + Beclomethasone Wang, Zhang, Fan, Neal, and Zuo, Soft Matter 8 (2012) 504.

11 Translational values!! Our study suggests an optimal concentration range of corticosteroids for pulmonary delivery when using natural surfactant as a delivering vehicle. Beyond this concentration range, beneficial anti-inflammatory effect of corticosteroids may be counteracted by their deleterious effect on surfactant layering and consequently result in worsening lung mechanics.!! This optimal concentration depends both on the corticosteroid and the clinical surfactant preparation in use. Hence, optimal surfactant corticosteroid pairs exist for pulmonary steroid delivery.!! Cholesterol-free surfactant preparations (such as Curosurf) may be more suitable than cholesterolcontaining surfactant preparations (such as Infasurf) as a carrier of budesonide for intratracheal administration. 11

12 Acknowledgements!! Dr. Hong Zhang!! Yi Wang!! Ashley Fan!! Dr. Walter Klein at ONY Inc.!! Dr. Alan Roberts at Cornerstone Therapeutics Inc. (# U54RR026136) 12

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