Design and Application of Innovative Local Treatments in Glioblastoma and Other Cancers

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Background

While contributing to the failure of conventional therapy of certain solid tumors, among which glioblastoma is a typical example, the treatment resistance ascribed to cancer cell heterogeneity and to their intrinsic adaptation to environmental cues and sub-optimal delivery of active principles are two major limitations. Hence an essential de facto objective of glioblastoma treatment is the exclusive eradication of tumor cells infiltrated in the central nervous system (CNS).

Facing the tumor in place, inoperable, or the resected tumor, systematically associated with recurrence, current developments to the bed of the patient, which associate surgery and radiochemotherapy, have had little effect in reducing the disease in 40 years. Glioblastoma prognosis remains dramatic with a median survival not exceeding 15 months after diagnosis and a 5-year survival of less than 5%.

As surgery of these tumors remains invasive and since the brain, seat of our consciousness, is isolated from the rest of the organism by the blood-brain barrier (BBB), glioblastoma appears as an interesting pathological situation for the development of new locoregional therapeutic strategies, for which new micro-nanomedicines and medical technologies are particularly suited. Indeed, crossing the BBB remains a challenge and the enhanced permeation and retention (EPR) effect often described faces a non-permissive reality (tissue pressure, reduced convective transport, dense matrix network). The aims of locoregional delivery of drug and treatments can be defined as: i) increasing the loco-regional concentration of the radio/chemotherapeutic agent, with a minimum of loco-regional toxicity ii) reducing the systemic toxicity, and iii) reach pharmacological sanctuaries. Although excellent results were obtained in several clinical situations (eg. perfusions for melanoma, intra-arterial infusions for tumors in the head and neck and in the liver) for many other indications the responses were quite disappointing.

However, recent major breakthrough may emerge as so many solutions. Indeed, new technical equipment, more rationale on drug choice thanks to advances in pharmacology, particular vectorization and micro-nanomedicine for pharmacologic enhancement and new combination concepts such as the tumor cell trap are now resulting in more systematic designs for further preclinical and clinical evaluation.

The aim of this Research Topic, is to introduce the evolution of those different approaches regarding their possible significance in humans and to better apprehend how these systems behave at the local micro-nano-biological interface. Three investigation fields will be apprehended: i) innovation in terms of locoregional internal radiation therapy and new radiopharmaceutical development (with a particular emphasis to rationale between dosimetry and biological efficacy, choice of molecular or particular radiopharmaceuticals, targeting moieties, modalities of administration, radiobiological responses and product synthesis), ii) innovation in terms of target-related loco-regional micro-nanomedicine (related to anticancer drug delivery, RNAi or therapeutic proteins) and iii) innovation in the development of local bio-implant associated with environmental decoy (mechanical or biological) for the control of cancer cell fate decisions, confinement, trapping and killing.

Such new strategies may overcome key biological and technological barriers limiting cancer tissue homing and cellular and subcellular targeting of biomimetic vectors in the future toward the emergence of an optimized minimally invasive medical technologies treating gliomas, as well as other solid tumors.

Keywords: Glioblastoma, Locoregional drug delivery, Nanobiotechnology, Bio-implants & tumor traps, Radiopharmaceuticals and radiobiology, Therapeutic proteins, Genetics and RNAi, Medical technology

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