| Resumo: |
Nano4Glio aims to develop a novel implantable device for the continuous treatment of glioblastoma multiforme (GBM). GBM is the most common and invasive type of brain cancerwith high mortality. Its gold standard treatment is resection followed by combination of radiotherapy (RT) and chemotherapy (CT) with temozolomide (TMZ) [1]. The limitations oftherapy with TMZ are associated with its high toxicity to the healthy tissues and its low bioavailability in the brain tumour cells, mainly related to its inability to cross the blood-brainbarrier (BBB). Its efficacy is also decreased by resistance mechanisms such as the DNA repair enzyme (MGMT) that can revert TMZ's effects and is overexpressed in about 40-60%GBM patients [2]. In clinical trials, the concomitant use of TMZ with O6-benzylguanine (O6BG) increased the efficacy and reduced resistance to TMZ (allowed for 50% TMZ dosereduction when combined with O6BG) in GBM patients by downregulating MGMT expression [3].
Here, we propose an innovative implantable device for the co-delivery of TMZ and O6BG through the BBB to the tumour over 6 weeks. This biodegradable implantable device will becomposed of a hydrogel incorporating TMZ and O6BG-loaded nanoparticles (NPs). The hydrogel will be degraded over time, releasing the NPs into the bloodstream. For braintargeting, the NPs surface will be modified with a transferrin receptor (TfR) targeting moeity, as TfR is overexpressed in the brain and in the brain tumour cells. Then, the drugs willbe released from the NPs in the brain tumour cells, thus achieving high drug levels at the target site (Figure 1). This implantable device will allow reducing the frequency ofadministration. While the current therapy requires daily administration of TMZ during the 6 week-cycle of RT [4], this device is expected to have a lifetime of 6 weeks, thus onlyrequiring a single administration. If the medical doctor decides to interrupt the treatment, e.g. due to toxic side effects, the device c  |
Resumo
Nano4Glio aims to develop a novel implantable device for the continuous treatment of glioblastoma multiforme (GBM). GBM is the most common and invasive type of brain cancerwith high mortality. Its gold standard treatment is resection followed by combination of radiotherapy (RT) and chemotherapy (CT) with temozolomide (TMZ) [1]. The limitations oftherapy with TMZ are associated with its high toxicity to the healthy tissues and its low bioavailability in the brain tumour cells, mainly related to its inability to cross the blood-brainbarrier (BBB). Its efficacy is also decreased by resistance mechanisms such as the DNA repair enzyme (MGMT) that can revert TMZ's effects and is overexpressed in about 40-60%GBM patients [2]. In clinical trials, the concomitant use of TMZ with O6-benzylguanine (O6BG) increased the efficacy and reduced resistance to TMZ (allowed for 50% TMZ dosereduction when combined with O6BG) in GBM patients by downregulating MGMT expression [3].
Here, we propose an innovative implantable device for the co-delivery of TMZ and O6BG through the BBB to the tumour over 6 weeks. This biodegradable implantable device will becomposed of a hydrogel incorporating TMZ and O6BG-loaded nanoparticles (NPs). The hydrogel will be degraded over time, releasing the NPs into the bloodstream. For braintargeting, the NPs surface will be modified with a transferrin receptor (TfR) targeting moeity, as TfR is overexpressed in the brain and in the brain tumour cells. Then, the drugs willbe released from the NPs in the brain tumour cells, thus achieving high drug levels at the target site (Figure 1). This implantable device will allow reducing the frequency ofadministration. While the current therapy requires daily administration of TMZ during the 6 week-cycle of RT [4], this device is expected to have a lifetime of 6 weeks, thus onlyrequiring a single administration. If the medical doctor decides to interrupt the treatment, e.g. due to toxic side effects, the device can be easily removed through a small surgeryrequiring only a very small incision.
Multiple NP types will be screened to identify the most suitable NP candidates based on their physicochemical properties. The NP candidates with the most suitable properties will beevaluated in terms of antitumour efficacy and brain targeting ability. The best NP candidate will be incorporated in an optimized hydrogel to produce the biodegradable andbiocompatible implantable device. The hydrogel should be suited for subcutaneous injection, which will be achieved by testing two different gel concepts. The hydrogel should also bebiodegradable to enable continuous release of NPs, that are excreted after drug release. Different polymer materials will be screened, and thermoresponsive polymers will be givenextra attention due to their ability to increase viscosity above polymer- and concentration-dependent threshold temperatures.
The physicochemical properties of the device will be studied, as well as its in vitro biodegradation and release kinetics. Its biological performance and therapeutic efficacy will beevaluated in an intracranial tumour mouse model. Its safety will be evaluated by assessing the interactions with the biological environment in terms of toxicity to healthy organs andinflammatory/immune response.
This project will deliver a suitable approach to improve GBM therapeutic efficacy by increasing TMZ's bioavailability and reducing toxicity to healthy tissues. This implantable devicewill allow a continuous therapy without the need for daily administration, enhancing the efficacy of the combined |