Paclitaxel-loaded multifunctional nanoparticles for the targeted treatment of glioblastoma.

INTRODUCTION: We hypothesised that the active targeting of αvß3 integrin overexpressed in neoangiogenic blood vessels and glioblastoma (GBM) cells combined with magnetic targeting of paclitaxel- and SPIO-loaded PLGA-based nanoparticles could improve accumulation of nanoparticles in the tumour and therefore improve the treatment of GBM. METHODS: PTX/SPIO PLGA nanoparticles with or without RGD-grafting were characterised. Their in vitro cellular uptake and cytotoxicity was evaluated by fluorospectroscopy and MTT assay. In vivo safety and anti-tumour efficacy of different targeting strategies were evaluated in orthotopic U87MG tumour model over multiple intravenous injections. RESULTS: The nanoparticles of 250 nm were negatively charged. RGD targeted nanoparticles showed a specific and higher cellular uptake than untargeted nanoparticles by activated U87MG and HUVEC cells. In vitro IC50 of PTX after 48 h was ∼1 ng/mL for all the PTX-loaded nanoparticles. The median survival time of the mice treated with magnetic targeted nanoparticles was higher than the control (saline) mice or mice treated with other evaluated strategies. The 6 doses of PTX did not induce any detectable toxic effects on liver, kidney and heart when compared to Taxol. CONCLUSION: The magnetic targeting strategy resulted in a better therapeutic effect than the other targeting strategies (passive, active).

Magnetic targeting of paclitaxel-loaded poly(lactic-co-glycolic acid)-based nanoparticles for the treatment of glioblastoma.

INTRODUCTION: Glioblastoma (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. PURPOSE: We 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 METHODS: PTX/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. RESULTS: PTX/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. CONCLUSION: Overall, PTX/SPIO-NPs with magnetic targeting could be considered as an effective anticancer targeting strategy for GBM chemotherapy.

Post-resection treatment of glioblastoma with an injectable nanomedicine-loaded photopolymerizable hydrogel induces long-term survival.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Despite available therapeutic options, the prognosis for patients with GBM remains very poor. We hypothesized that the intra-operative injection of a photopolymerizable hydrogel into the tumor resection cavity could sustain the release of the anti-cancer drug paclitaxel (PTX) encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles and prevent GBM recurrence. The tumor was resected 13 days after implantation and a pre-gel solution composed of polyethylene glycol dimethacrylate (PEG-DMA) polymer, a photoinitiator and PTX-loaded PLGA nanoparticles (PTX PLGA-NPs) was injected into the tumor resection cavity. A solid gel filling the whole cavity was formed immediately by photopolymerization using a 400 nm light. PTX in vitro release study showed a burst release (11%) in the first 8 h and a sustained release of 29% over a week. In vitro, U87 MG cells were sensitive to PTX PLGA-NPs with IC50 level of approximately 0.010 µg/mL. The hydrogel was well-tolerated when implanted in the brain of healthy mice for 2 and 4 months. Administration of PTX PLGA-NPs-loaded hydrogel into the resection cavity of GBM orthotopic model lead to more than 50% long-term survival mice (150 days) compared to the control groups (mean survival time 52 days). This significant delay of recurrence is very promising for the post-resection treatment of GBM.

Drug delivery challenges and future of chemotherapeutic nanomedicine for glioblastoma treatment.

Glioblastoma (GBM) is one of the most aggressive and deadliest central nervous system tumors, and the current standard treatment is surgery followed by radiotherapy with concurrent chemotherapy. Nevertheless, the survival period is notably low. Although ample research has been performed to develop an effective therapeutic strategy for treating GBM, the success of extending patients' survival period and quality of life is limited. This review focuses on the strategies developed to address the challenges associated with drug delivery in GBM, particularly nanomedicine. The first part describes major obstacles to the development of effective GBM treatment strategies. The second part focuses on the conventional chemotherapeutic nanomedicine strategies, their limitations and the novel and advanced strategies of nanomedicine, which could be promising for GBM treatment. We also highlighted the prominence of nanomedicine clinical translation. The near future looks bright following the beginning of clinical translation of nanochemotherapy for GBM.