Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies

Abstract

Purpose.-This study was carried out to determine the biodistribution profiles and tumor localization potential of poly(ethylene oxide) (PEO)-modified poly (β-amino ester) (PbAE) as a novel, pH-sensitive biodegradable polymeric nanoparticulate system for tumor-targeted drug delivery.Methods.-The biodistribution studies of PEO-modified PbAE and PEO-modified poly(ɛ-caplactone) (PCL), a non-pH sensitive polymer, nanoparticle systems were carried out in normal mice using 111 indiumoxine [ 111 In] as a lipophilic radiolabel encapsulated within the polymeric matrix and the distribution of the nanoparticles was studied in plasma and all the vital organs following intravenous administration. Solid tumors were developed on nude mice using human ovarian carcinoma xenograft (SKOV-3) and the change in concentrations of tritium [ 3 H]-labeled paclitaxel encapsulated in polymeric nanoparticles was examined in blood, tumor mass and liver.Results.-Study in normal mice with a gamma-emitting isotope [ 111 In] provided a thorough biodistribution analysis of the PEO-modified nanoparticulate carrier systems, while the 3 H-paclitaxel was useful to understand the change in concentration and tumor localization of anticancer compound directly in major sites of distribution. Both PEO-PbAE and PEO-PCL nanoparticles showed long systemic circulating properties by virtue of surface modification with PEO-containing triblock block copolymer (Pluronic ® ) stabilizer. While the PCL nanoparticles showed higher uptake by the reticuloendothelial system (RES), the PbAE nanoparticles effectively delivered the encapsulated payload into the tumor mass.Conclusions.-PEO-modified PbAE nanoparticles showed considerable passive tumor targeting potential in early stages of biodistribution via the enhanced permeation and retention (EPR) mechanism. This prompts a detailed biodistribution profiling of the nanocarrier for prolonged periods of time to provide conclusive evidence for superiority of the delivery system.

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

“…Cationic surface charge is desirable as it promotes interaction of the nanoparticles with the cells and thus augments the rate and extent of internalization (Shenoy et al, 2005;Kumari et al, 2010). PLGA nanoparticles have negative charges which can be changed to neutral or positive charges by surface modification, for instance by PEGylation of the PLGA polymer or chitosan coating respectively (Tahara et al, 2009;Danhier et al, 2010;Danhier et al, 2012).…”

Smart Drug Delivery Strategies Based on Porous Nanostructure Materials

“…The pH-sensitive micelles demonstrated the long residence time and improved half-life typical of micellar nanoparticles in animal models. Comparing to non-pH-sensitive micelles, the pH-sensitive micelles achieved a satisfying effect in tumors [97]. It reveals that the potential of pH-sensitive micelles could increase drug delivery to cancerous tumors.…”

Recent Advances in Drug Delivery Systems

“…Moreover, using a hydrazonecholesteryl hemisuccinate linkage to the PEG which could be cleaved by esterases showed pH-response at pH 5.5 (with a t 1/2 of 6.7 h) and was stable at physiological pH (with a t 1/2 of 40.9 h) and thus can be used for tumor targeting [86]. Additionally, PEO (poly(ethylene glycol) and its derivates also promote stealth shielding and prolonged circulation [7,78,87] and have been extensively used as biomaterials due to excellent biocompatibility and low toxicity [78]. PLA and PLGA have also demonstrated some stealth shielding [16].…”

“…In addition, the lower pH observed (pH 6.5) in some tumors create a pH gradient that hinders the permeation of drugs and constitutes one of the causes of chemotherapy failure. PbAE-PEO, a pH sensitive polymer shows a 5.2 fold higher concentration of Paclitaxel when compared to the aqueous solution [87]. Thus, it can be considered as an ideal carrier to overcome the pH gradient barrier.…”