Optimization of Lipid-Indinavir Complexes for Localization in Lymphoid Tissues of HIV-Infected Macaques
In HIV-infected persons on highly active antiretroviral therapy, residual virus is found in lymphoid tissues. Indinavir concentrations in lymph node mononuclear cells of patients on highly active antiretroviral therapy were approximately 25% to 35% of those in blood mononuclear cells, suggesting that drug insufficiency contributes to residual virus in lymphoid tissues. Therefore, we developed novel lipid-indinavir nanoparticles targeted to lymphoid tissues. Given subcutaneously, these nanoparticles provided indinavir concentrations 250% to 2270% higher than plasma indinavir concentrations in both peripheral and visceral lymph nodes. Improved indinavir delivery was reflected in reduced viral RNA and CD4(+) T-cell rebound. This study optimized lipid nanoparticle formulation with respect to indinavir in lymphoid tissues of HIV-infected macaques. Regardless of lipid characteristic tested (charge, fluidity, and steric modification), indinavir binds completely to lipid at pH 7.4 but is reversed at pH 5.5 or lower. Compared with previous formulations, nanoparticles composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine (DSPC:mPEG-DSPE) provided 6-fold higher indinavir levels in lymph nodes and enhanced drug exposure in blood. Enhanced anti-HIV activity paralleled improved intracellular drug accumulation. Collectively, these data suggest that indinavir nanoparticles composed of DSPC:mPEG-DSPE provided the most effective lymphoid delivery and could maximally suppress the virus in lymphoid tissues.
Available from: Tomikazu Sasaki
- "L-α-Phosphatidylcholine extracted from eggs (EPC) was used to construct the liposome formulation for our initial showcase formulations NP109 (EPC + ADP109) and NPm109 (EPC + AMPm109). We prepared the liposome nanoparticles with the liquid-hydration-sonication method previously described , . Briefly, a 10-to-1 ratio of EPC and ADP109, both in chloroform, were mixed and dried down to form a thin film before rehydrated in 0.9× phosphate buffered saline (PBS) and sonicated to give a suspension of the nanoparticles at a concentration of 20 mM of lipid. "
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ABSTRACT: Artemisinin (ART) dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs) remained tightly associated with liposomal nanoparticles (NPs) at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1) declines in a triple negative breast cancer (TNBC) cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives.
Available from: Chanchal Deep Kaur
- "In addition, virostatic nature of drugs demands long-term administration for an effective treatment (Chien and Wearley 1989). In the early course of the disease, HIV colonizes the lymphoid organs (spleen, lymph nodes, and tonsils), which act as the reservoirs for the residual virus (Kinman et al. 2006). Even in the case of most potent antiviral therapy, which practically sterilizes the peripheral blood, latent virus still lurks in the lymphocytes of the lymphoid organs; hence, it is very difficult to eradicate. "
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ABSTRACT: The present investigation was aimed at lymphatic targeting of zidovudine (ZDV)-loaded surface-engineered liposomes (SE liposomes). Surface of liposomes was engineered by incorporation of charges (positive or negative) and site-specific ligand (mannose) in order to enhance localization to lymphatics, specifically to lymph node and spleen. Positively and negatively charged nanosized SE liposomes (120 +/- 10 nm) were prepared using stearylamine (SA) and dicetyl phosphate (DCP), respectively, while ligand-coated SE liposomes were prepared using mannose-terminated SA (mannose conjugate). The SE liposomes were characterized for shape and surface morphology, size, entrapment efficiency, and in vitro drug release. All the SE liposomes formulations showed biphasic ZDV release, whereas mannose-coated liposomes (MAN-Lip) significantly reduced (p < 0.05) drug release compared with conventional liposome (Lip). The organ distribution pattern of the SE liposomes exhibited significant reduction in free ZDV concentration in serum, whereas significantly increased quantity was detected in the spleen and lymph nodes (p < 0.05). Fluorescent microscopy suggested enhanced uptake and localization of the SE liposomes in the lymph nodes and spleen, which were in the order: mannose coated > negatively charged > positively charged > Lip. Thus, the SE liposomes appeared to be promising novel vesicular system for enhanced targeting of ZDV to lymphatics, in AIDS chemotherapy.
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ABSTRACT: We have investigated the ability of lipid-indinavir particles composed of 3-to-1 lipid-drug molar ratio to encapsulate an aqueous marker calcein and anti-HIV drug (3)H-phosphonylmethoxypropyl-adenine (PMPA). Even at a high density of indinavir associated to lipid-indinavir nanoparticles, they form an enclosed lipid membrane that allows encapsulation of calcein and PMPA in an aqueous compartment. At neutral pH, practically all indinavir was incorporated into lipid bilayer and lipid associated indinavir can be dissociated with half-maximum pH recorded between 5.2 and 5.5. pH-Dependent release of indinavir did not influence calcein release significantly. However, pH-dependent release of indinavir affected PMPA release. By lowering pH, PMPA release was enhanced in the presence of indinavir in the lipid bilayer. Collectively, these data indicate that indinavir incorporated in lipid particles provides (1) stable bilayers capable of encapsulating other hydrophilic drugs, (2) ability to dissociate indinavir (which is acid stable) from lipid membranes, by lowering the pH, and (3) enabling enhancement in pH-dependent release of aqueous contents. However, the degree of pH-dependent release could be related to the charge and size of an aqueous molecule.
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