(Patho)physiologic pathways to drug targeting: artificial viral envelopes.
The goal of this study was to exploit molecular recognition of cell surface receptors by viral surface glycoproteins as a means for the selective intracellular delivery of macromolecules. To accomplish this, artificial viral envelopes (AVE) resembling the human immunodeficiency virus-1 (HIV-1) were designed as a model system. Recombinant HIV-1 surface glycoprotein gp160 (HIV-1 rgp160) was inserted in the artificial envelope by a two-step detergent dialysis process. The artificial HIV-1 envelope recognized the CD4 cell surface receptor. FITC-dextran and ricin A were employed as model macromolecules as they cannot passively diffuse across cell membranes. Selective transfer of FITC-dextran encapsulated in HIV-1 rgp160 AVE into a CD4-positive cell line (REX-1B) versus a CD4-negative cell line (KG-1) was demonstrated. Ricin A at concentrations as low as 2 ng/ml arrested cell growth of CD4-positive MOLT-4 cells, whereas 8 ng/ml ricin A in solution had no effect on cell growth. The arrest of cell growth was reverted in the presence of excess anti-gp120 monoclonal antibody. Naked envelopes (without HIV-1 rgp160 inserted) were also found to interact with cells and transfer material, although less efficiently and in a non-specific manner. Viral mimicry using AVE may be a means for targeted intracellular delivery of peptides, proteins, enzymes, toxins, oligodeoxynucleotides, gene constructs, and other non-diffusive, labile or toxic macromolecules.
Schreier
H
H
Center for Lung Research, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-2650, USA.
Ausborn
M
M
Günther
S
S
Weissig
V
V
Chander
R
R
D015704:CD4 Antigens / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003911:Dextrans; D004337:Drug Carriers; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008081:Liposomes; D010743:Phospholipids; D011498:Protein Precursors; D011994:Recombinant Proteins; D012276:Ricin / Q000008:administration & dosage* / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins
D015704:CD4 Antigens; D003911:Dextrans; D004337:Drug Carriers; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D008081:Liposomes; D010743:Phospholipids; D011498:Protein Precursors; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C015219:fluorescein isothiocyanate dextran; D012276:Ricin; D016650:Fluorescein-5-isothiocyanate