Targeted delivery of lopinavir to HIV reservoirs in the mesenteric lymphatic system by lipophilic ester prodrug approach

We proposed a novel lipophilic ester prodrug approach, combined with oral lipid-based formulation, to efficiently deliver lopinavir to the mesenteric lymph and mesenteric lymph nodes

Chaolong Qin; YenJu Chu; Wanshan Feng; Christophe Fromont; Sijia He; Joseph Ali; Jong Bong Lee; Atheer Zgair; Mattia Berton; Sara Bettonte; Ruiling Liu; Lei Yang; Teerapong Monmaturapoj; Concepción Medrano-Padial; Allen Alonso Rodríguez Ugalde; Daria Vetrugno; Shi Ying Ee; Charles Sheriston; Yuntao Wu; Michael J. Stocks; Peter M. Fischer; Pavel Gershkovich

2020

Scholarcy highlights

  • The combined antiretroviral therapy can efficiently reduce viral load and keep it undetectable in the blood of HIV-infected patients for the duration of treatment
  • Following oral administration of activated ester prodrug 7 in lipid-based formulation, high concentrations of the prodrug were observed in mesenteric lymph and mesenteric lymph nodes, which is in line with its high affinity to CMs
  • Our results showed that the levels of LPV were below the limit of detection in both mesenteric lymph and MLNs when unmodified LPV was administered orally, even in conditions facilitating lymphatic transport
  • It seems that solid lipid nanoparticles can increase the concentrations of LPV in both mesenteric lymph and MLNs, it is unclear if LPV in these tissues is free or is still encapsulated within the SLNs flowing through the intestinal lymphatics to the systemic circulation
  • LPV has negligible CMs association, which results in the lack of substantial delivery of unmodified LPV to the mesenteric lymphatic system even when administered with lipids promoting intestinal lymphatic absorption
  • Simple alkyl ester prodrug approach resulted in substantially higher levels of the prodrug in mesenteric lymphatic system compared to plasma, but poor release of active drug within the lymphatic system
  • Acknowledgements The authors would like to thank the Bio-Support Unit team in University of Nottingham for excellent technical assistance

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