Anales RANF

Nannocannabinoids for brain tumor drug delivery @Real Academia Nacional de Farmacia. Spain 199 1. INTRODUCTION Brain diseases should be considered a major health challenge as brain drug delivery is truly hindered by the blood-brain barrier (BBB) (1). The BBB consists of the endothelium of brain capillaries. The key features of the brain endothelium that severely restrict brain drug delivery are both the lack of fenestrations and the presence of tight intercellular junctions. Hence, there is a dire need for developing effective brain drug delivery strategies that overcome the biodistribution limitations that account for treatment failure (2). Some of the described delivery strategies to circumvent the BBB such as the intracerebral administration and the artificial disruption of the tight junctions involve high risk of neurological damage and even of widespread tumor dissemination in the case of brain tumors. Therefore, the use of targeted drug nanocarriers arises as a promising alternative to achieve efficient transport across the brain endothelium following minimally-invasive intravenous injection (3-5). Unfortunately, the global translational impact of nanomedicine remains modest. In this context, we have analyzed the possibilities and technological challenges ahead to improve the chances of success in the development of nanomedicines for brain pathologies. Certainly, whereas the empirical development of delivery systems and their subsequent application to a specific disease has led to high attrition rates in clinical trials, the transition towards a disease-driven approach, whereby the nanomedicine features are rationally defined beforehand based on the pathophysiology of a specific disease is more likely to succeed. One of the major features that influence the in vivo behaviour of nanocarriers is particle size as their effect mainly relies on the unique interactions of materials at the nanoscale with biological structures. For instance, a size- driven extravasation at tumor and/or inflammatory sites based on their pathophysiological features (namely, the enhanced permeation and retention (EPR) effect) has been sought. However, the EPR effect in brain diseases is relatively weak due to the presence of the BBB, with a cut- off size of only 10-100 nm (6). In these cases, a much finer control over particle size will certainly improve the potential therapeutic benefits. Hence, rational disease- driven design of nanocarriers can only be achieved by determining the parameters that accurately control their size distribution. Under this assumption, we have thoroughly studied which parameters control the size distribution of lipid nanocapsules (LNCs) prepared by the phase inversion temperature (PIT) method. The PIT method is a low- energy nanoemulsification method wherein the physicochemical properties of surfactants are exploited to lower the required energy input for nanoemulsification according to the Young-Laplace equation for a spherical drop. To this end, the PIT method profits from the negligible interfacial tension achieved when the surfactant curvature is inverted by changes in temperature. At the “phase inversion temperature”, the affinity for both phases is balanced and the minimum in interfacial tension is achieved (7). As the final formulation is obtained following a thermal quench below the surfactant melting point, nanoemulsions eventually adopt the form of nanocapsules with a liquid oily core stabilized by a rigid surfactant shell. With around a quarter of a million new cases of brain tumors every year, these brain diseases could take great advantage of LNCs. Brain tumors are stratified according to a ‘malignancy scale’ (8). Malignant primary brain tumors typically originate from glial cells (being thus referred to as gliomas). The current standard approach in high grade gliomas combines maximal surgical resection (if eligible) with radiotherapy and chemotherapy; as well as symptomatic treatment. Unfortunately, the efficacy of this treatment remains questionable, since recurrence happens within months after diagnosis, with a median survival of 14.6 months (9). In the search for novel antitumor agents, the therapeutic potential of several cannabinoids has become a research hotspot as they have been reported to not only palliate cancer-related symptoms (such as nausea, pain or anorexia) but also promote apoptotic cancer cell death, impair tumor angiogenesis and reduce cell migration (10, 11). Cannabinoids are pharmacologically-active terpenophenols that can be ascribed to three distinct categories: phytocannabinoids (produced by the glandular trichomes of the herbaceous plant Cannabis sativa (12)), endocannabinoids (produced naturally by animals and humans) and synthetic cannabidomimetics (13). However, the therapeutic potential of cannabinoids has been truly constrained heretofore due to their strong psychoactive effects and their high lipophilicity. Precisely due to the lack of these psychoactive effects, cannabidiol (CBD) arises as the phytocannabinoid with the greatest potential to widen the therapeutic armamentarium for the treatment of gliomas thanks to its synergism with the currently available chemo and radiotherapy (14). As a proof of it, CBD has reached the clinical trials stage as adjuvant therapy for patients with glioblastoma (ClinicalTrials.gov identifiers: NCT01812616, NCT01812603, NCT03246113 and NCT03529448). Moreover, cannabinoids can take great advantage of nanomedicine-based formulation strategies to overcome the dosing problems traditionally associated with their high lipophilicity. Accordingly, several studies on nanocarriers encapsulating different kinds of cannabinoids have been published for distinct therapeutic purposes (Table 1). Notwithstanding that for cannabinoids to achieve high translational impact they should be devoid of psychoactive effects; the focus so far has been mainly put on 9-delta-tetrahydrocannabinol (Δ 9 -THC) and its analogues. Hence, we have evaluated herein LNCs as biocompatible carriers for CBD.