Poly (propyleneimine) dendrimer based nanocontainers for targeting of efavirenz to human monocytes/macrophagesin vitro

Abstract

Cells of the mononuclear phagocytic system, in particular monocytes/macrophages (Mo/Mac) serve as a reservoir for human immunodeficiency virus (HIV) and are believed to be responsible for its dissemination throughout the body and especially into the brain. Treatment of HIV infection, therefore, must reach these cells in addition to the lymphocytes. The purpose of the present study is to develop poly(propyleneimine) (PPI) dendrimer-based nanocontainers for targeting of efavirenz (EFV) to Mo/Mac. Fifth generation PPI dendrimer, t-Boc-glycine conjugated PPI dendrimer (TPPI) and mannose conjugated dendrimers were synthesized and characterized. While the haemolytic activity and cytotoxicity of PPI dendrimer was found to be very high, the toxicity of t-Boc-glycine conjugated dendrimer and mannose conjugated dendrimers were found to be negligible. The entrapment efficiency of mannose conjugated dendrimer was found to be 47.4%, followed by that of PPI dendrimer (32.15%) and t-Boc-glycine conjugated dendrimer (23.1%). The in vitro drug release profile shows that while PPI dendrimer releases the drug by 24 h, the dendrimer-based nanocontainers prolong the release rate up to 144 h (83 +/- 0.4% in case of t-Boc-glycine conjugated dendrimer and 91 +/- 0.3% in mannose conjugated dendrimer). The cellular uptake of EFV was found to be both concentration and time dependent. Significant increase in cellular uptake of EFV by Mo/Mac cells were observed in case of mannose conjugated dendrimer which is 12 times higher than that of free drug and 5.5 times higher than that of t-Boc-glycine conjugated dendrimer. While mannose conjugated dendrimer was taken up by the lectin receptors of the cells, phagocytosis of t-Boc-glycine conjugated dendrimer might be responsible for its enhanced uptake. Results suggest that the proposed carriers hold potential to increase the efficacy and reduce the toxicity of antiretroviral therapy.

Potential Oral Delivery of 7-Ethyl-10-Hydroxy-Camptothecin (SN-38) using Poly(amidoamine) Dendrimers

“…Patri et al (23) have reported more than 70% release of free methotrexate within first 2.5 h from non covalent methotrexate-dendrimer inclusion complex. Complete release of efavirenz within first 24 h from drug containing polypropylenimine (PPI) dendrimers while significantly slower release from t-Boc glycine conjugated and mannose conjugated PPI dendrimers was reported by Dutta et al (24). Drug release was also found to be controlled by molecular architecture (25) of dendrimer and introducing poly(ethylene oxide) chains on the periphery of the dendrimer (26,27).…”

Dendrimers in Anti-HIV Therapy

“…As demonstrated for complexes of coupled tuftsin and zidovudine, antiretroviral activity of each separate compound was not enough for them to be considered anti-HIV agents in isolation, but when conjugated they represent a good method and are likely to enter phase I clinical trials [Fridkin et al, 2005]. Modifying dendrimers with tuftsin revealed them as the most biocompatible carriers, demonstrating striking results in studies concerning infected macrophages [Dutta et al, 2007]. Tuftsin is a tetrapeptide (Thr-Lys-ProArg) related to macrophage activation, and it binds specifically to macrophages, monocytes and polymorphonuclear leukocytes.…”

“…Development of non-toxic targeting nanocarriers could be vital in overcoming this problem. Modified PPI dendrimers have been used for the aim of targeted delivery into cells involved in highly conserved retention, and mannosylated PPI dendrimers possess double the effect in terms of viral attack, improving biological properties of drugs and displaying antiviral activity themselves owing to specific binding and their penetrating ability via cell receptors [Dutta & Jain, 2007]. As demonstrated for complexes of coupled tuftsin and zidovudine, antiretroviral activity of each separate compound was not enough for them to be considered anti-HIV agents in isolation, but when conjugated they represent a good method and are likely to enter phase I clinical trials [Fridkin et al, 2005].…”

Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations

“…A range of novel strategies are currently being developed for efficient delivery of antiretroviral drugs. Several delivery systems have been reported for the delivery of ARV drugs including bioadhesive coated matrix tablets (Betagiri et al, 2001;Govender et al, 2005), ceramic implants (Benghuzzi, 2000), liposomes Makabi-Panzu et al, 1998;Jin et al, 2005;Ramana et al, 2010), solid colloidal nanoparticles (Kuo & Su, 2007;Chattopadhyay et al, 2008;Kaur et al, 2008;Mainardes et al, 2009), microparticles by supercritical antisolvent method (Sanganwar et al, 2010), dendrimers (Dutta et al, 2007), micelles & microemulsion (Griffin & Driscoll, 2006), nanopowders (Erdenburgh et al, 2007) and suspensions/nanosuspension (Kinman et al, 2003;Yang et al, 2011).…”