Local Delivery and Glioblastoma: Why Not Combining Sustained Release and Targeting?

Abstract

Glioblastoma is one of the most aggressive brain tumors and is associated with a very low overall median survival despite the current treatment. The standard of care used in clinic is the Stupp's protocol which consists of a maximal resection of the tumor when possible, followed by radio and chemotherapy using temozolomide. However, in most cases, glioblastoma cells infiltrate healthy tissues and lead to fatal recurrences. There are a lot of hurdles to overcome in the development of new therapeutic strategies such as tumor heterogeneity, cell infiltration, alkylating agent resistance, physiological barriers, etc., and few treatments are on the market today. One of them is particularly appealing because it is a local therapy, which does not bring additional invasiveness since tumor resection is included in the gold standard treatment. They are implants: the Gliadel® wafers, which are deposited post-surgery. Nevertheless, in addition to presenting important undesirable effects, it does not bring any major benefit in the therapy despite the strategy being particularly attractive. The purpose of this review is to provide an overview of recent advances in the development of innovative therapeutic strategies for glioblastoma using an implant-type approach. The combination of this local strategy with effective targeting of the tumor microenvironment as a whole, also developed in this review, may be of interest to alleviate some of the obstacles encountered in the treatment of glioblastoma.

Loco-regional treatment with temozolomide-loaded thermogels prevents glioblastoma recurrences in orthotopic human xenograft models

“…To work around this problem, implantable delivery systems have gained special attention to control the release of drugs and localize treatments in specific sites next to a targeted tissue to create much higher local drug concentrations. Importantly, a postoperative implant for locoregional treatment of GBM, i.e., Gliadel Wafers, has been already developed and FDA-approved, but important side effects, mainly ascribed to the stiffness of the support and the use of carmustine as active molecule, have strongly limited its use 33 . Therefore, formulation of a “soft” support consisting of biocompatible gels is currently regarded as a possible solution for some Gliadel’s side effects.…”

The immunosuppression pathway of tumor‐associated macrophages is controlled by heme oxygenase‐1 in glioblastoma patients

“…The local delivery of drugs has already been explored in glioma management 47 and our group has demonstrated a selective phagocytosis of lipid nanocapsules (LNCs) in both circulating and tumor‐associated myeloid cells from GBM patients. 48 ZnPPIX‐loaded nanoparticles could thus be proposed as a strategy to overcome GBM multifactorial immunosuppression and to increase antitumor immune responses by reprogramming immunosuppressive myeloid cells.…”

Intratarget Microdosing for Deep Phenotyping of Multiple Drug Effects in the Live Brain

“…Examples of such approaches include convection-enhanced delivery (Mehta et al, 2017), disruption of the BBB (e.g. by focused ultrasound) (Aryal et al, 2014), chemical or nanocarrier delivery systems (Finbloom et al, 2018), and the use of intracranial drug-eluting implants (Gazaille et al, 2021), among others. In such a scenario, the IMD may be used to identify the required concentration to induce a desired biological effect in the diseased tissue, and the clinician would choose an appropriate enhanced delivery technique in an attempt to achieve an effective local dose.…”