15 research outputs found
A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model
Visceral leishmaniasis (VL) is a systemic form of a vector-borne parasitic disease caused by obligate intra-macrophage protozoa of the genus Leishmania. VL is always fatal in humans if left untreated and treatment options are limited. Amphotericin B (AmB), a polyene antibiotic, is the most active antileishmanial agent that currently exists. Liposomal AmB (AmBisome) is used as first-line treatment in developed countries [1], [7], [8], [9], [10]; however, the requisite parenteral administration and the high cost of the liposomal formulation prevents this treatment from reaching the majority of patients in developing nations [3]. A stable, efficacious oral treatment for VL that is able to withstand the rigors of tropical climates would overcome many of the current barriers to treatment that exist in countries with large VL-infected patient populations. In this study we have developed an oral formulation of AmB that is stable in tropical conditions and exhibits significant antileshimanial activity in mice
Biophysical characterization of catonic liposome/plasmid DNA complexes for gene therapy
The goal of gene therapy is to achieve expression of an exogenous gene that results in a
specific functional change. Cationic liposome-based carriers of plasmid DNA ("lipoplexes") are
the most widely used method of nonviral DNA delivery. Lipoplexes form through electrostatic
interactions between DNA and liposomes. This thesis investigates how lipid composition and
ionic environment affect the biophysical behavior of lipoplexes and their transfection ability.
A major concern regarding lipoplex development is their instability in a physiological
environment or salt solutions. Lipoplexes containing a cationic lipid and the transfection-helper
lipid dioleoylphosphatidylethanolamine (DOPE) exhibit heterogeneous morphology and variable
activity. A charge ratio near neutrality or the presence of salts promotes super-aggregation
(particle mean diameter > 1 Āµm). Cryo-transmission electron microscopy showed that liposome
morphology differs when plasmid, oligodeoxynucleotides or phosphate anions are added. In
conjunction with lipid mixing assays and particle size analysis, these observations demonstrate
that charge ratio and charge density are critical for lipoplex structure. The extent of lipid mixing
and aggregation, during or after lipoplex formation, is influenced by lipid composition as well as
the presence of salt or serum. A multi-step lipid-mixing assay to model in vitro transfection
demonstrated that lipoplexes with relatively high in vitro transfection undergo lipid-mixing
reactions after salt or serum interactions. Significantly, liposomal internal aqueous contents were
retained in the lipoplexes. This may allow the codelivery of drugs within the lipoplexes during
transfection of cells.
Smaller, salt-stable lipoplexes are desirable for systemic in vivo use. It was also of great
interest to pursue development of lipoplexes capable of trapping drugs for codelivery (e.g.
transfection enhancers). Such lipoplexes must be transfection-competent, possess a large trapped
volume and have the ability to maintain an ion gradient for drug loading. This was achieved by
replacing DOPE with cholesterol and including poly(ethylene glycol) to stabilize the lipoplexes
against aggregation. A model amine drug, vincristine, was loaded into lipoplexes via a pH
gradient. This research introduces the novel concept that salt-stable lipoplexes can be generated
which can be loaded with secondary compounds for codelivery, adding a new functionality to
cationic liposomes as carriers of DNA for gene therapy.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat
An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery
The focus of this review is to provide an overview of the chitosan based nanoparticles for various non-parenteral applications and also to put a spotlight on current research including sustained release and mucoadhesive chitosan dosage forms. Chitosan is a biodegradable, biocompatible polymer regarded as safe for human dietary use and approved for wound dressing applications. Chitosan has been used as a carrier in polymeric nanoparticles for drug delivery through various routes of administration. Chitosan has chemical functional groups that can be modified to achieve specific goals, making it a polymer with a tremendous range of potential applications. Nanoparticles (NP) prepared with chitosan and chitosan derivatives typically possess a positive surface charge and mucoadhesive properties such that can adhere to mucus membranes and release the drug payload in a sustained release manner. Chitosan-based NP have various applications in non-parenteral drug delivery for the treatment of cancer, gastrointestinal diseases, pulmonary diseases, drug delivery to the brain and ocular infections which will be exemplified in this review. Chitosan shows low toxicity both in vitro and some in vivo models. This review explores recent research on chitosan based NP for non-parenteral drug delivery, chitosan properties, modification, toxicity, pharmacokinetics and preclinical studies
Chitosan Nanoparticles at the Biological Interface: Implications for Drug Delivery
The unique properties of chitosan make it a useful choice for various nanoparticulate drug delivery applications. Although chitosan is biocompatible and enables cellular uptake, its interactions at cellular and systemic levels need to be studied in more depth. This review focuses on the various physical and chemical properties of chitosan that affect its performance in biological systems. We aim to analyze recent research studying interactions of chitosan nanoparticles (NPs) upon their cellular uptake and their journey through the various compartments of the cell. The positive charge of chitosan enables it to efficiently attach to cells, increasing the probability of cellular uptake. Chitosan NPs are taken up by cells via different pathways and escape endosomal degradation due to the proton sponge effect. Furthermore, we have reviewed the interaction of chitosan NPs upon in vivo administration. Chitosan NPs are immediately surrounded by a serum protein corona in systemic circulation upon intravenous administration, and their biodistribution is mainly to the liver and spleen indicating RES uptake. However, the evasion of RES system as well as the targeting ability and bioavailability of chitosan NPs can be improved by utilizing specific routes of administration and covalent modifications of surface properties. Ongoing clinical trials of chitosan formulations for therapeutic applications are paving the way for the introduction of chitosan into the pharmaceutical market and for their toxicological evaluation. Chitosan provides specific biophysical properties for effective and tunable cellular uptake and systemic delivery for a wide range of applications
Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model
Background:
The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010).
Methods:
BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of FungizoneĀ® 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected.
Results:
The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of FungizoneĀ® resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. FungizoneĀ® treatment induced necrotic changes in hepatic and kidney tissues.
Conclusions:
Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofPharmaceutical Sciences, Faculty ofReviewedFacult
In vitro cytotoxicity of two novel oral formulations of Amphotericin B (iCo-009 and iCo-010) against Candida albicans, human monocytic and kidney cell lines
Background: Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B) and azoles. Amphotericin B (AmpB) presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizoneā¢ a commercial AmpB formulation.
The purpose of this study was to determine the cytotoxicity of Fungizoneā¢, Ambisomeā¢ and two novel AmpB formulations (iCo-009 and iCo-010) against Candida albicans, human kidney (293T) cells and monocytic (THP1) cells.
Methods:
Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation.
Results:
None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizoneā¢ and Ambisomeā¢ showed cytotoxicity at 500 Ī¼g/L (n = 4-10, p < 0.05).
The calculated EC50 to Candida albicans for the different formulations was as follows: 26.8 Ā± 2.9 for iCo-010, 74.6 Ā± 8.9 for iCo-009, 109 Ā± 31 for Ambisomeā¢ and 87.1 Ā± 22 for Fungizoneā¢ (Ī¼g of AmpB/L, n = 6-12, p < 0.05).
Conclusions:
The AmpB formulations analyzed were not cytotoxic to 293T cells. Cytotoxicity in THP1 cells was observed for Fungizoneā¢ and Ambisomeā¢, but not with the novel AmpB formulations. iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model.
The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizoneā¢ and Ambisomeā¢ suggest that iCo-010 has potential in treating candidiasis.Pharmaceutical Sciences, Faculty ofOther UBCNon UBCReviewedFacult