Perspectives on Nanodelivery to the Brain: Prerequisites for Successful Brain Treatment

Abstract

Nanocarriers (NCs) are promising tools to improve drug delivery across the blood–brain barrier (BBB) for more effective treatment of brain disorders, although there is a scarcity of clinical translation of brain-directed NCs. In order to drive the development of brain-oriented NCs toward clinical success, it is essential to understand the prerequisites for nanodelivery to be successful in brain treatment. In this Perspective, we present how pharmacokinetic/pharmacodynamic (PK/PD), formulation and nanotoxicity factors impact the therapeutic success of brain-specific nanodelivery. Properties including high loading efficiency, slow in vivo drug release, long systemic circulation, an increase in unbound brain-to-plasma concentration/exposure ratio ( K p,uu,brain ), high drug potency, and minimal nanotoxicity are prerequisites that should preferably be combined to maximize the therapeutic potential of a brain-targeted NC. The PK of brain-directed NCs needs to be evaluated in a more therapeutically relevant manner, focusing on the released, unbound drug. It is more crucial to increase the K p,uu,brain than to improve the ability of the NC to cross the BBB in its intact form. Brain-targeted NCs, which are mostly developed for treating brain tumors, including metastases, should aim to enhance drug delivery not just to tumor regions with disrupted BBB, but equally important to regions with intact BBB where the drugs themselves have problems reaching. This article provides critical insights into how a brain-targeted nanoformulation needs to be designed and optimized to achieve therapeutic success in the brain.

Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

“…Whereas providing interesting data, such studies have room for improvement to provide sufficient mechanistic insight 78 . A number of animal studies using microdialysis for time‐course information on unbound drug in plasma and brain provide such mechanistic information 78–84 …”

Emerging Nano-Carrier Strategies for Brain Tumor Drug Delivery and Considerations for Clinical Translation

“…Albumin, as previously mentioned, is unable to cross the healthy BBB in its blood plasma form. Albumin is a protein approximately 12 × 4 nm, and can be repurposed as a biomimetic nano-carrier which can carry chemotherapeutic drugs across the BBB [ 108 , 109 ]. Abraxane ® , approved by the US FDA in 2005, is a paclitaxel-albumin nanoparticle which is used clinically for breast cancer treatment, demonstrating the safety of this platform.…”

“…Generally, only the unbound drug present inside the brain parenchyma would be considered as therapeutically relevant. The unbound brain-to-plasma exposure ratio (K p,uu,brain ) can be used to evaluate brain uptake and make predictions about peripheral toxicity [ 109 ]. Since a successful nanomedicine would display greater BBB permeability than its naked counterpart, toxicity to brain tissue itself would also increase [ 158 ].…”

“…The term “nanotoxicity” describes the side effect of nanomaterials on human health and has been mostly studied in animal models. Adverse effects of nanoparticles can occur in many organs and often originate from disruption of cellular redox and subsequent ROS activation, or by disruption of cell membranes [ 31 , 109 ]. However, criteria for defining and measuring nanotoxicity are undefined, and great variation exists in the literature which relies on in vitro viability assays, ROS assays or electron microscopy of cell membranes—none of which are amenable to clinical measurement of nanotoxicity.…”

Nanocarriers for Biomedicine: From Lipid Formulations to Inorganic and Hybrid Nanoparticles

“…High interest of researchers in the design of different types of nanocontainers occurs, with a clear trend towards multifunctional and complicated formulations observed. Meanwhile, there are a number of recent comprehensive reviews in different specific aspects, in which drug delivery systems are classified based on the chemical nature and prescription of a medicine, the type of nanocarriers [9], the target site [3,23,24] and the administration route [25,26]. Alternatively, based on the above analysis, two distinct families of nanocarriers, namely, lipid formulations and silicon-containing nanoparticles (Figure 1), as well as intermediary cerasomes, have been chosen herein, with a focus on recent publications covering the drug encapsulation technique and emphasizing the aspects insufficiently highlighted elsewhere, e.g., development of hybrid formulations via non-covalent modification of nanocarriers aimed at the improving of their stability, targeting effects, multicentered drug loading and toxicity profile.…”