Intended and Unintended Targeting of Polymeric Nanocarriers: The Case of Modified Poly(glycerol adipate) Nanoparticles.

Biodegradable nanoparticles based on stearic acid-modified poly(glycerol adipate) (PGAS) are promising carriers for drug delivery. In order to investigate the impact of the particle interface characteristics on the biological fate, PGAS nanoparticles are covalently and noncovalently coated with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. HPMA copolymer-modified PGAS nanoparticles have similar particle sizes, but less negative zeta-potentials. Nanoparticles are double labeled with the fluorescent dyes DiR (noncovalently) and DYOMICS-676 (covalently bound to HPMA copolymer), and their biodistribution is investigated noninvasively by multispectral optical imaging. Both covalent and noncovalent coatings cause changes in the pharmacokinetics and biodistribution in healthy and tumor-bearing mice. In addition to the intended tumor accumulation, high signals of both fluorescent dyes are also observed in other organs, including liver, ovaries, adrenal glands, and bone. The unintended accumulation of nanocarriers needs further detailed and systematic investigations, especially with respect to the observed ovarian and adrenal gland accumulation.

In vitro toxicity of Stearoyl-poly(glycerol adipate) nanoparticles.

PURPOSE: Poly(glycerol adipate) (PGA)-based nanoparticles are promising carriers for drug delivery with a wide range of available structures. The biodegradable polymer with pendant free hydroxyl groups can be diversely functionalized. In this study, the toxicity of different Stearoyl-PGA nanoparticles with respect to erythrocytes and HepG2 cells was assessed. These cells are crucial test systems for intravenously injected biomedical particles. METHODS: For this work, a series of PGA polyesters with 0, 20, 50 and 65 mol% of converted hydroxyl groups was synthesized with stearic acid (PGABB, S20, S50, S65). Nanoparticles were prepared with these polymers by an optimized nanoprecipitation method. Physicochemical characterization was performed by photon correlation spectroscopy and zeta potential measurement. Cell compatibility was studied by a hemolysis assay with separated red blood cells as well as a QBlue viability test and a modified LDH cytotoxicity assay with HepG2 cells. RESULTS AND CONCLUSIONS: Different self-stabilizing nanoparticles with narrow size distributions in the range of 100-140 nm were prepared. All tested nanoparticle samples were nontoxic for HepG2 cells. In fact, increased metabolic activity and proliferation was observed after 24 h incubation with the Stearoyl-PGA particles. Apart from PGAS20, all samples did not show any hemolytic effect. Hemolysis of PGAS20 particles could be considerably decreased by adding Poloxamer 188 during the preparation process.

Poly(glycerol adipate)-fatty acid esters as versatile nanocarriers: From nanocubes over ellipsoids to nanospheres.

Poly(glycerol adipate) (PGA) is a biodegradable polymer with promising features for nanoparticulate drug carrier systems. By acylation of PGA with fatty acids, composite systems with amphiphilic properties can be obtained. Variation of the fatty acid (laurate, stearate and behenate) and their substitution degrees lead to a wide range of different polymer structures. This strongly influences the aggregation of the polymer and thus the nature of the resulting colloidal system. Based on the modification of the interfacial deposition method, various self-stabilizing nanoparticles with defined sizes and narrow size distributions could be prepared. Non-spherical shapes (squares, pentagons) with an internal lamellar-like structure were observed for low substituted PGA-stearates. Higher substitution degrees lead to ellipsoidal or spherical particles. The size, charge, fluidity and polarity of the nanoparticles have been studied comprehensively by PCS, AF4, zeta potential measurements, DSC, NMR, TEM and fluorescence spectroscopy. The chain lengths of the attached fatty acids as well as their substitution degree substantially influence the physicochemical properties of the bulk polymers and the nanoparticles. With their diverse particle shapes and internal structures as well as their different thermal behavior, aggregate states and polarities, the systems offer promising possibilities as delivery systems for lipophilic, amphiphilic and water soluble drugs.

Formation of structured polygonal nanoparticles by phase-separated comb-like polymers.

A simple approach using comb-like polymers that undergo nanophase separation between the polyester backbone and the stearoyl side chains is proposed for the preparation of structured non-spherical nanoparticles from a nanoemulsion. Depending on the degree of esterification of the OH groups of poly(glycerol adipate) differently ordered nanostructures is obtained. A perfect lamellar arrangement is obtained for polymers with a high degree of esterification and leads to spherical nanoparticles with an internal onion-like structure. However, when the degree of esterification is only 20 mol%, polygonal nanoparticles with an internal pseudo-hexagonal structure are obtained. The differences in the nanoparticle shapes are related to the volume fraction of the paraffinic pool.