Novel approaches for the delivery of therapeutics in ischemic stroke

Highlights

• Ischemic stroke is one of the leading causes of death and disability worldwide.

• Current therapeutic options for stroke are use of tPA or endovascular thrombectomy.

• Multiple cellular and molecular mechanisms are involved in stroke pathophysiology.

• Recently novel approaches of drug delivery to the ischemic brain are being explored.

• Delivery of neuroprotectants to salvageable penumbra could improve stroke outcome.

Ischemic stroke, a prominent cause of mortality and disability, is a combination of neuronal and vascular disorders. Reperfusion techniques, such as administration of tissue-plasminogen activator (t-PA) and endovascular mechanical thrombectomy, are commonly used treatment approaches. In recent years, interest has focused on saving the salvageable penumbra using neuroprotective strategies to improve long-term stroke outcomes. However, insufficient drug delivery to the ischemic brain, especially to penumbra, remains one of the major obstacles. Several novel approaches have been investigated to improve brain delivery. In this review, we discuss different novel drug delivery approaches explored by researchers in recent years for improved treatment of ischemic stroke.

Introduction

Stroke continues to be one of the prominent causes of mortality and long-term disability among diseases in the USA [1]. Every 40 s, someone has a stroke in the USA. Stroke is primarily classified into two types: ischemic and hemorrhagic. Almost 86% of strokes result from cerebral ischemia, which occurs as a result of interrupted blood flow to the brain from a clot, which leads to oxygen and nutrient deficiency in the brain, ultimately resulting in primary brain injury [2]. After this, secondary injury cascades of the brain can initiate. Depletion of cellular energy leads to intracellular homeostasis impairment and increases intracellular calcium and neurotoxic levels of dopamine and glutamate. This can also lead to ion gradient dissipation because of the interruption of ATP-dependent ion channels, accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and excitotoxicity [3]. Brain edema, either cellular or vasogenic, are crucial factors that can worsen stroke outcome because of a cellular homeostasis imbalance and the blood–brain barrier (BBB) disruption. The latter increases the uptake of fluids into the brain tissue, raising the intracranial pressure [4]. Therefore, ischemic stroke is a combination of neuronal and vascular disorders. So far, r-tPA is the only US Food and Drug Administration (FDA)-approved drug for the treatment of acute ischemic stroke [5]. More recently, endovascular mechanical thrombectomy has also been used for ischemic stroke treatment in cases of large vessel occlusion. In addition to these reperfusion techniques, neuroprotective strategies have also been investigated in ischemic stroke to improve neuronal survival and stroke outcome [6]. Penumbra, the viable surrounding tissue of the lethally and irreversibly injured ischemic core, can be protected if appropriate treatments are administered quickly following an injury. This is possible because the cells within this area die slowly; therefore, progressively ongoing damage can be prevented with specific targeting. However, delivering neuroprotective therapeutics to the ischemic brain region has always been challenging (Box 1). Different physiological, chemical, and pharmacological approaches can be utilized to facilitate drug delivery in ischemic stroke. Some novel drug delivery strategies are also being investigated in stroke therapy, which could impact ischemic stroke outcome.