Biodistribution and renal clearance of biocompatible lung targeted poly(ethylene glycol) (PEG) nanogel aggregates

Abstract

A novel stabilized aggregated nanogel particle (SANP) drug delivery system was prepared for injectable passive lung targeting. Gel nanoparticles (GNPs) were synthesized by irreversibly cross-linking 8 Arm PEG thiol with 1,6-Hexane-bis-vinylsulfone (HBVS) in phosphate buffer (PB, pH 7.4) containing 0.1% v/v Tween™ 80. Aggregated nanogel particles (ANPs) were generated by aggregating GNPs to micron-size, which were then stabilized (i.e., SANPs) using a PEG thiol polymer to prevent further growth-aggregation. The size of SANPs, ANPs and GNPs was analyzed using a Coulter counter and transmission electron microscopy (TEM). Stability studies of SANPs were performed at 37 °C in rat plasma, phosphate buffered saline (PBS, pH 7.4) and PB (pH 7.4). SANPs were stable in rat plasma, PBS and PB over 7 days. SANPs were covalently labeled with HiLyteFluor™750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE-SANPs (30 μm, 4 mg in 500 μL PBS) in male Sprague-Dawley rats was compared to free HiLyteFluor™750 DYE alone (1 mg in 500 μL PBS) and determined using a Xenogen IVIS®100 Imaging System. Biodistribution studies demonstrated that free DYE was rapidly eliminated from the body by renal filtration, whereas DYE-SANPs accumulated in the lung within 30 minutes and persisted for 48 h. DYE-SANPs were enzymatically degraded to their original principle components (i.e., DYE-PEG-thiol and PEG-VS polymer) and were then eliminated from the body by renal filtration. Histological evaluation using H & E staining and broncho alveolar lavage (BAL) confirmed that these flexible SANPs were not toxic. This suggests that because of their flexible and non-toxic nature, SANPs may be a useful alternative for treating pulmonary diseases such as asthma, pneumonia, tuberculosis and disseminated lung cancer.

In situ tissue engineering with synthetic self-assembling peptide nanofiber scaffolds, PuraMatrix, for mucosal regeneration in the rat middle-ear

“…These results suggest that proper scaffolds are indispensable for cell transplantation and that PuraMatrix forms effective nanofiber scaffolds in in situ tissue engineering of middle-ear mucosal tissue in this animal model. Synthetic scaffolds with several biopolymers have been developed for biomedical and pharmaceutical applications, such as drug delivery 57,58 and tissue engineering. 8,20,[59][60][61] Injectable biodegradable polymer hydrogels are ideal for in situ tissue engineering, because cells can be easily incorporated into polymer solutions and rapidly convert into a gel under physiological conditions, comprising threedimensional hydrophilic polymeric networks.…”

Docetaxel-Loaded Lecithoid Nanoparticles with Enhanced Lung Targeting Efficiency and Reduced Systemic Toxicity: Developed by Solid Dispersion and Effervescent Techniques

“…For injectable administration, enhanced drug delivery efficacy to lung was confirmed and attributed mainly to the "mechanical trapping effect" of the pulmonary capillary network when the administrated particles diameter is larger than 7 µm. 23,24) However, the significant lung targeting ability of DTX-LN with the diameter less than 3 µm (as shown in Fig. 1C) could be not simply attributed to this trapping effect.…”

Pharmaceutical and Toxicological Properties of Engineered Nanomaterials for Drug Delivery

“…In addition, PEG is available in both branched and linear architectures, with the branched versions acting as though they are larger than the linear counterparts. Our lab has utilized both linear and branched versions of PEG as scaffolds for bioconjugates utilized in a variety of applications (47–56). …”

“…ENMs that are smaller than the size of serum albumin (~40–50 kDa or a diameter of ≲4–6 nm) are eliminated primarily through the kidneys (47, 50, 62, 79). Particles or aggregates of particles >10 μm become passively entrapped within the capillaries of the lung (47, 80–83). These particles persist within the lung until degraded to smaller components, whereas particles that are >3 μm are transiently entrapped in the lung and subsequently move to the liver (47).…”

“…Particles or aggregates of particles >10 μm become passively entrapped within the capillaries of the lung (47, 80–83). These particles persist within the lung until degraded to smaller components, whereas particles that are >3 μm are transiently entrapped in the lung and subsequently move to the liver (47). Particles that are in the range of 3–6 μm accumulate in the liver and spleen.…”