Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation?
Lymphocytes are central to the progression of autoimmune disease, transplant rejection, leukemia, lymphoma and lymphocyte-resident viral diseases such as HIV/AIDs. Strategies to target drug treatments to lymphocytes, therefore, represent an opportunity to enhance therapeutic outcomes in disease states where many current treatment regimes are incompletely effective and promote significant toxicities. Here we demonstrate that highly lipophilic drug candidates that preferentially access the intestinal lymphatics after oral administration show significantly enhanced access to lymphocytes leading to improved immunomodulatory activity. When coadministered with such drugs, lipids enhance lymphocyte targeting via a three tiered action: promotion of drug absorption from the gastrointestinal tract, enhancement of lymphatic drug transport and stimulation of lymphocyte recruitment into the lymphatics. This strategy has been exemplified using a highly lipophilic immunosuppressant (JWH015) where coadministration with selected lipids led to significant increases in lymphatic transport, lymphocyte targeting and IL-4 and IL-10 expression in CD4+ and CD8+ lymphocytes after ex vivo mitogen stimulation. In contrast, administration of a 2.5-fold higher dose of JWH015 in a formulation that did not stimulate lymph transport had no effect on antiinflammatory cytokine levels, in spite of equivalent drug exposure in the blood. The current data suggest that complementary drug design and delivery strategies that combine highly lipophilic, lymphotropic drug candidates with lymph-directing formulations provide enhanced selectivity, potency and therapeutic potential for drug candidates with lymphocyte associated targets.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, Australia.
Natalie L
NL
Trevaskis
William N
WN
Charman
Christopher J H
CJ
Porter
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000096:biosynthesis; D003634:DDT / Q000032:analysis / Q000276:immunology / Q000494:pharmacology; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D056747:Immunomodulation; D007211:Indoles / Q000032:analysis / Q000276:immunology / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008934:Mitogens / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D010616:Phenanthrenes / Q000032:analysis / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000032:analysis / Q000276:immunology / Q000494:pharmacology
D016207:Cytokines; D007211:Indoles; D008934:Mitogens; D010616:Phenanthrenes; D003634:DDT; C023768:halofantrine; D020123:Sirolimus; C402944:JHW 015