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Published on: November 17, 2015
Preparation of nucleoside-LDL-conjugates for the study of cell-selective internalization: stability characteristics
H W Schultis1, H von Baeyer, H Neitzel
1Institut für Biochemie, Freie Universität Berlin, Germany.
Abstract:
Antiviral therapy of human immunodeficiency virus (HIV) infection is currently based on inhibition of reverse transcriptase by dideoxynucleosides, such as azidothymidine. Because of widespread toxicity it is reasonable to selectively target these drugs to infected cells. This may be accomplished utilizing drug-LDL conjugates, which are internalized via cell specific receptor pathways. With respect to HIV infection, scavenger receptors of the macrophage system seems to offer a hopeful perspective. This pathway requires chemical modification of surface polarity of the LDL. Cell experiments were conducted in HepG2 hepatocytes, which express apolipoprotein B receptors, and in P388 macrophages, which express scavenger receptors. LDL particles to be conjugated were isolated from blood donor plasma and from LDL-apheresis waste material. Non-covalent LDL conjugation with amphiphilic nucleoside derivatives produced only an unspecific nucleoside transfer to cell membranes, due to instability of the LDL conjugates. An experimental method (coincubation test) was developed to identify those conjugates that are stable in the presence of other lipophilic compartments. Covalent coupling of nucleosides to the apolipoprotein B moiety of LDL particles resulted in stable conjugates. As a consequence, the surface charge became negative, and the LDL displayed scavenger receptor affinity rather than apolipoprotein B receptor affinity. Selective targeting of nucleosides to macrophages can be accomplished by covalent coupling to LDL.
Insights
Targeting antiviral drugs to HIV-infected cells is crucial. Covalently coupling nucleosides to low-density lipoprotein (LDL) particles enables selective delivery to macrophages via scavenger receptors, reducing toxicity.
Area of Science:
- Biomedical Engineering
- Virology
- Drug Delivery
Background:
- Current antiviral therapy for human immunodeficiency virus (HIV) relies on reverse transcriptase inhibitors like azidothymidine.
- Widespread toxicity necessitates targeted drug delivery to infected cells.
- Low-density lipoprotein (LDL) conjugates offer a potential strategy for cell-specific internalization via receptor pathways.
Purpose of the Study:
- To investigate the selective targeting of antiviral nucleosides to HIV-infected cells using LDL conjugates.
- To explore the potential of scavenger receptors on macrophages for targeted drug delivery.
- To develop stable LDL-nucleoside conjugates for enhanced therapeutic efficacy.
Main Methods:
- Isolation of LDL particles from human plasma and LDL-apheresis waste.
- Chemical modification of LDL surface polarity for receptor targeting.
- Development of a coincubation test to assess conjugate stability.
- Covalent coupling of nucleosides to the apolipoprotein B moiety of LDL particles.
- Evaluation of conjugate affinity for apolipoprotein B receptors (HepG2 hepatocytes) and scavenger receptors (P388 macrophages).
Main Results:
- Non-covalent LDL conjugation resulted in unstable conjugates and unspecific nucleoside transfer.
- Covalent coupling of nucleosides to LDL created stable conjugates with altered surface charge.
- These modified LDL conjugates exhibited scavenger receptor affinity, not apolipoprotein B receptor affinity.
- Selective targeting of nucleosides to macrophages was achieved through covalent LDL coupling.
Conclusions:
- Covalent coupling of nucleosides to LDL particles is an effective method for creating stable conjugates.
- This approach enables selective targeting of antiviral nucleosides to macrophages via scavenger receptors.
- Targeted drug delivery using LDL conjugates holds promise for improving HIV therapy and reducing systemic toxicity.
