Nanoparticle-based drug delivery for the treatment of traumatic brain injury.

INTRODUCTION: Traumatic brain injuries (TBIs) impact the breadth of society and remain without any approved pharmacological treatments. Despite successful Phase II clinical trials, the failure of many Phase III clinical trials may be explained by insufficient drug targeting and retention, preventing the proper attainment of an observable dosage threshold. To address this challenge, nanoparticles can be functionalized to protect pharmacological payloads, improve targeted drug delivery to sites of injury, and can be combined with supportive scaffolding to improve secondary outcomes. AREAS COVERED: This review briefly covers the pathophysiology of TBIs and their subtypes, the current pre-clinical and clinical management strategies, explores the common models of focal, diffuse, and mixed traumatic brain injury employed in experimental animals, and surveys the existing literature on nanoparticles developed to treat TBIs. EXPERT OPINION: Nanoparticles are well suited to improve secondary outcomes as their multifunctionality and customizability enhance their potential for efficient targeted delivery, payload protection, increased brain penetration, low off-target toxicity, and biocompatibility in both acute and chronic timescales.

Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.

Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.

Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment.

Despite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.

Biocompatibility of nanomaterials and their immunological properties.

Nanomaterials (NMs) have revolutionized multiple aspects of medicine by enabling novel sensing, diagnostic, and therapeutic approaches. Advancements in processing and fabrication have also allowed significant expansion in the applications of the major classes of NMs based on polymer, metal/metal oxide, carbon, liposome, or multi-scale macro-nano bulk materials. Concomitantly, concerns regarding the nanotoxicity and overall biocompatibility of NMs have been raised. These involve putative negative effects on both patients and those subjected to occupational exposure during manufacturing. In this review, we describe the current state of testing of NMs including those that are in clinical use, in clinical trials, or under development. We also discuss the cellular and molecular interactions that dictate their toxicity and biocompatibility. Specifically, we focus on the reciprocal interactions between NMs and host proteins, lipids, and sugars and how these induce responses in immune and other cell types leading to topical and/or systemic effects.