Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination

Anticancer drugs embedded in or conjugated with inert nanocarriers, referred to as nanomedicines, show many therapeutic advantages over free drugs, but the inert carrier materials are the major component (generally more than 90%) in nanomedicines, causing low drug loading contents and thus excessive uses of parenteral excipients. Herein, we demonstrate a new concept directly using drug molecules to fabricate nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release. Taking advantage of the strong hydrophobicity of the anticancer drug camptothecin (CPT), one or two CPT molecule(s) were conjugated to a very short oligomer chain of ethylene glycol (OEG), forming amphiphilic phospholipid-mimicking prodrugs, OEG-CPT or OEG-DiCPT. The prodrugs formed stable liposome-like nanocapsules with a CPT loading content as high as 40 or 58 wt % with no burst release in aqueous solution. OEG-DiCPT released CPT once inside cells, which sh...

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Prodrugs forming high drug loading multifunctional nanocapsules for intracellular cancer drug delivery.

Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications.

A simple method to achieve high doxorubicin loading in biodegradable polymersomes.

Nanoparticles and targeted drug delivery in cancer therapy.

Doxorubicin remains the first line of treatment for various cancers ever since its discovery in 1971. Cardiotoxicity and nephrotoxicity associated with unformulated doxorubicin triggered the development of doxorubicin nanocarriers. Although the therapeutic profile of doxorubicin is appreciably improved by entrapping in nanocarriers, they are largely taken up by organs of the reticuloendothelial system. Engineered nanocarriers of doxorubicin refer to carriers modified to escape recognition by reticuloendothelial system and/or functionalized with target specific ligands for selective accumulation at the target site. The first developments in engineered nanocarriers were the stealth carriers. These effectively bypassed the reticuloendothelial system and enhanced the therapeutic profile of doxorubicin by enabling passive accumulation in tumors. Stealth nanocarriers of doxorubicin revealed significant decrease in cardiotoxicity and nephrotoxicity, which led to the approval of liposomal doxorubicin for clinical applications. Success of liposomal doxorubicin was soon dulled by the appearance of newer toxicities like palmar-plantar erythrodysesthesia commonly referred as hand foot syndrome. The search for the magic bullet of doxorubicin has further intensified and resulted in design of engineered nanocarriers with high specificity for cancer cells. This review charts the progress from nanocarriers to engineered nanocarriers of doxorubicin, and highlights the current status of engineered nanocarriers of doxorubicin in clinical trials.

Engineered nanocarriers of doxorubicin: a current update.

Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting.

The present study demonstrates feasibility of preparation of nanoparticles using a novel polymer, polyethylene sebacate (PES), and its application in the design of drug-loaded nanocarriers. Silymarin was selected as a model hydrophobic drug for the present study. Two methods of preparation, viz., nanoprecipitation and emulsion solvent diffusion, were evaluated for preparation of nanoparticles. Effect of surfactants polyvinyl alcohol (PVA), lutrol F 68, and Tween 80 on the preparation of blank and silymarin-loaded PES nanoparticles was evaluated. Nanoprecipitation resulted in the formation of nanoparticles with all the surfactants (<450 nm). Increase in surfactant concentration resulted in decrease in entrapment efficiency and particle size except with PVA. The type and concentration of surfactant was critical to achieve low size and adequate drug entrapment. While increase in concentration of PES resulted in larger nanoparticles, inclusion of acetone in the organic phase resulted in particles of smaller size. In case of emulsion solvent diffusion, nanoparticles were obtained only with lutrol F 68 as surfactant and high surfactant concentration. The study revealed nanoprecipitation as a more versatile method for preparation of PES nanoparticles. Scanning electron microscopy studies revealed spherical shape of nanoparticles. Freeze-dried nanoparticles exhibited ease of redispersion, with a marginal increase in size. Differential scanning calorimetry and X-ray diffraction analysis revealed amorphous nature of the drug. The study demonstrates successful design of PES nanoparticles as drug carriers.

Nanoparticles of Polyethylene Sebacate: A New Biodegradable Polymer

The present study discusses evaluation of pullulan-functionalized doxorubicin nanoparticles for asialoglycoprotein receptor-mediated uptake in the Hep G2 cell line. Doxorubicin hydrochloride (DOX) nanoparticles using polymers of different hydrophobic character, polyethylene sebacate (hydrophobic) and poly (lactic-co-glycolic acid) (intermediate hydrophobicity) with high entrapment efficiency and particle size were prepared by modified nanoprecipitation, using Gantrez AN 119 as complexing agent. Nanoparticles of Gantrez AN 119 were also prepared to represent a hydrophilic polymer. Cell uptake of DOX nanoparticles was found to be comparable to DOX solution irrespective of DOX concentration, nanoparticles size, and pullulan concentration. Furthermore, uptake of nanoparticles functionalized with or without pullulan prepared with polymers of different hydrophobic character revealed comparable uptake. Comparable uptake of DOX solution and DOX nanoparticles functionalized with or without pullulan suggest extracellular release of DOX as the mechanism of uptake from the nanoparticles. In vivo evaluation in hepatic cancer model is therefore essential to confirm the role of pullulan as asialoglycoprotein receptors ligand.

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Swati A. Guhagarkar

Papers

Engineered nanocarriers of doxorubicin: a current update.

Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting.

Nanoparticles of Polyethylene Sebacate: A New Biodegradable Polymer

Evaluation of pullulan-functionalized doxorubicin nanoparticles for asialoglycoprotein receptor-mediated uptake in Hep G2 cell line.