Magnetic targeting of paclitaxel-loaded poly(lactic-<em>co</em>-glycolic acid)-based nanoparticles for the treatment of glioblastoma

Abstract

IntroductionGlioblastoma (GBM) therapy is highly challenging, as the tumors are very aggressive due to infiltration into the surrounding normal brain tissue. Even a combination of the available therapeutic regimens may not debulk the tumor completely. GBM tumors are also known for recurrence, resulting in survival rates averaging <18 months. In addition, systemic chemotherapy for GBM has been challenged for its minimal desired therapeutic effects and unwanted side effects.PurposeWe hypothesized that paclitaxel (PTX) and superparamagnetic iron oxide (SPIO)-loaded PEGylated poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs; PTX/SPIO-NPs) can serve as an effective nanocarrier system for magnetic targeting purposes, and we aimed to demonstrate the therapeutic efficacy of this system in an orthotopic murine GBM model.Materials and methodsPTX/SPIO-NPs were prepared by emulsion–diffusion–evaporation method and characterized for physicochemical properties. In vitro cellular uptake of PTX/SPIO-NPs was evaluated by fluorescence microscopy and Prussian blue staining. Orthotopic U87MG tumor model was used to evaluate blood–brain barrier disruption using T1 contrast agent, ex vivo biodistribution, in vivo toxicity and in vivo antitumor efficacy of PTX/SPIO-NPs.ResultsPTX/SPIO-NPs were in the size of 250 nm with negative zeta potential. Qualitative cellular uptake studies showed that the internalization of NPs was concentration dependent. Through magnetic resonance imaging, we observed that the blood–brain barrier was disrupted in the GBM area. An ex vivo biodistribution study showed enhanced accumulation of NPs in the brain of GBM-bearing mice with magnetic targeting. Short-term in vivo safety evaluation showed that the NPs did not induce any systemic toxicity compared with Taxol® (PTX). When tested for in vivo efficacy, the magnetic targeting treatment significantly prolonged the median survival time compared with the passive targeting and control treatments.ConclusionOverall, PTX/SPIO-NPs with magnetic targeting could be considered as an effective anticancer targeting strategy for GBM chemotherapy.

Dendrimer size effects on the selective brain tumor targeting in orthotopic tumor models upon systemic administration

“…Compared to other types of dendrimers injected via tail vein in flank tumor models, our hydroxyl‐terminated PAMAM dendrimer results exhibit similar levels of tumor accumulation despite needing to overcome physical transport barriers in orthotopic brain tumors that flank tumors lack 49‐51 . Compared to other types of nanoparticles explored in orthotopic brain tumors, G6 shows a ~100‐fold greater in tumor accumulation than liposomal 52 nanoparticles and ~10‐fold greater than G4 and reported tumor levels of gold 53,54 and PEGylated iron oxide 55 nanoparticles. Studies based on traditional polymeric nanoparticles with ~135 nm size showed only a 50% improvement in the delivery of temozolomide in a rat brain tumor model 56 .…”

“…This is in contrast to free drug administration of chemotherapies, which quickly clear from tumor tissue while accumulating in the liver at much greater concentrations 60,76 . These PAMAM dendrimers also compare favorably to gold nanoparticles, PEGylated iron oxide nanoparticles, and other classes of dendrimers, which exhibit slightly higher kidney levels but a significantly greater liver accumulation of 2–70% of the initial dose retained 49,50,54,55,77 . Taken together with their tumor accumulation results, this biodistribution profile indicates that these dendrimers may yield a large therapeutic window for effective and safe treatments for brain cancers.…”

“…At 24 hr after injection, G6 dendrimers exhibited ~10‐fold and ~15‐fold greater accumulation in tumor compared to the contralateral hemisphere in the 9L and GL261 models, respectively, while G4 dendrimers exhibited a ~5‐fold greater tumor accumulation in tumor compared to contralateral hemisphere in both models. In comparison, gelatin‐conjugated polylysine dendrimers and PEGylated iron oxide nanoparticles exhibited <3‐fold specificity 51,55 . In addition to tumor specificity, these PAMAM dendrimers also specifically target TAMs, with >80% of the dendrimer signal in the tumor localized within TAMs (Figure S2a).…”

Immunoengineering in glioblastoma imaging and therapy

“…Paclitaxel and superparamagnetic iron oxide nanoparticle (SPION)‐loaded PEGylated poly(lactic‐co‐glycolic acid) (PLGA)‐based nanoparticles were designed for magnetic targeting of glioma. In an orthotopic U87MG tumor model, magnetic targeting enhanced brain accumulation of therapeutic agent and prolonged the survival rate of mice (Ganipineni et al, ).…”

Sustained in vitro interferon-beta release and in vivo toxicity of PLGA and PEG-PLGA nanoparticles

“…Paclitaxel-and superparamagnetic iron oxide-loaded PLGA and PEG-PLGA nanoparticles with size >200 nm were injected intravenously into mice. 33 In that study aspartate aminotransferase and alanine aminotransferase for hepatic function, blood urea nitrogen for kidney function and creatine kinase isoenzyme as cardiac marker levels were analysed, whilst none of them indicated toxic effect of the nanoparticles. However, nanoparticles prepared using monomethoxy(polyethyleneglycol)-poly(D,L-lactic-co-glycolic acid)monomethoxy polymer with average size of 50 nm caused signicant immunotoxicity at low or high doses in Wistar rats aer intravenous administration, while the same doses of 200 nm nanoparticles did not exert any toxicity.…”