nanoparticle injection

what is amphotericin B

• broad-spectrum polyene antifungal agent

• first isolated from streptomyces nodosus in 1955

• big molecule and no charges → poor solubility

amphotericin B mechanism of action

• binds to ergosterol (cholesterol in fungal cell membranes)

• creates transmembrane channels and leads to cellular component

• binds to cholesterol in mammalian membranes → toxicity

describe toxicity of amphotericin B

• infusion related reaction: nausea, vomiting, rigors, fever, hyper- or hypotension, hypoxia

• nephrotoxicity

what are the marketed amphotericin B products in the US

• amphotericin B injection

• abelcet

• ambisome

describe amphotericin B injection

• colloidal dispersion

• composition: amphotericin B and sodium deoxycholate (solubilizer)

• micellar structure

• unstable in plasma so easy for AmpB to dissociate after administration but toxicity is higher

describe abelcet

• lipid complex

• composition: amphotericin B and DMPC/DMPG

• many connected micelles - ribbon like

• more stable and less toxic due to charge from DMPC/DMPG

describe ambisome

• liposomal

• composition: amphotericin B and HSPC/DSPG/cholesterol/tocopherol

• amphotericin B can interact with DSPG and form ionic complex

• stays stable in phospholipid bilayer of liposomes → reduced toxicity

describe ambisome pharmacokinetics

• larger AUC

• starting dose higher

• less nephrotoxicity

nanoparticles for tumors

• tumor targeting

• molecules of certain sizes (typically liposomes and nanoparticles) tend to accumulate in tumor tissue much more than they do in normal tissues

• leaky vasculature

• lower pH

• impaired drainage

describe taxol

• first paclitaxel product

• paclitaxel has very low water solubility

• required large amounts of surfactants and solvents → toxicities and impaired paclitaxel drug distribution

what is abraxane

• chemotherapy drug

• nanotechnology-based drug delivery that utilizes albumin to achieve solvent-free delivery

• less toxicity

characterization of abraxane

• multiple orthogonal techniques are required

• particle size (light scattering)

• surface charge (zeta potential)

• amorphous nature of paclitaxel in nanoparticle (xray diffraction)

• morphology (TEM and cryo-TEM)

• other specific tests defined by nature of nanoconstruct

abraxane mechanism of action

• active targeting provided by glycoprotein gp60 interaction

• albumin binds to gp60

• allows for diffusion and cell internalization of paclitaxel

abraxane vs taxol

• abraxane had improved response rate, increased time to tumor, and prolonged survival

• however, studies showed that disease progression and overall survival was better but not by much

what is doxil

• first lipid nanodrug approved

• anthracycline antibiotic

• treatment of a variety of human malignancies

• accumulates in tumor site

• cardiotoxicity is a major clinical handicap limiting cumulative dosage

describe the stealth liposome technology

• PEG coating

  • reduces uptake by cell

  • increase circulation time

  • plasma stability

• lipid shell/water core

• ~100 nm

describe manufacturing of liposome

• lipid soluble ingredients dissolved in ethanol and mixed with aqueous solution

• lipid components have higher transition temp so manufacturing should be carried out at high temp

• large micelles are formed and reduced with extruder

• load drug in using chemical gradient