Recent Advances in Medicinal Chemistry and Pharmaceutical Technology- Strategies for Drug Delivery to the Brain

Abstract

This paper provides a mini-review of some recent approaches for the treatment of brain pathologies examining both medicinal chemistry and pharmaceutical technology contributions. Medicinal chemistry-based strategies are essentially aimed at the chemical modification of low molecular weight drugs in order to increase their lipophilicity or the design of appropriate prodrugs, although this review will focus primarily on the use of prodrugs and not analog development. Recently, interest has been focused on the design and evaluation of prodrugs that are capable of exploiting one or more of the various endogenous transport systems at the level of the blood brain barrier (BBB). The technological strategies are essentially non-invasive methods of drug delivery to malignancies of the central nervous system (CNS) and are based on the use of nanosystems (colloidal carriers) such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, polymeric micelles and dendrimers. The biodistribution of these nanocarriers can be manipulated by modifying their surface physico-chemical properties or by coating them with surfactants and polyethylene-glycols (PEGs). Liposomes, surfactant coated polymeric nanoparticles, and solid lipid nanoparticles are promising systems for delivery of drugs to tumors of the CNS. This mini-review discusses issues concerning the scope and limitations of both the medicinal chemistry and technological approaches. Based on the current findings, it can be concluded that crossing of the BBB and drug delivery to CNS is extremely complex and requires a multidisciplinary approach such as a close collaboration and common efforts among researchers of several scientific areas, particularly medicinal chemists, biologists and pharmaceutical technologists.

Nanoparticle accumulation and transcytosis in brain endothelial cell layers

“…3 As a result, extensive research has been focused on the development of strategies to cross the BBB and deliver therapeutic agents efficiently in the CNS. 2,[4][5][6][7][8][9] Within this context, nanotechnology applied to medicine has the potential to lead to significant advances in the diagnosis and treatment of diseases; as a result of their unique properties, such as size, surface energy, large surface area to volume ratio and the possibility of introducing a variety of surface modifications, engineered nanoparticles offer enormous promise as drug delivery vehicles specifically targeting a range of human diseases. [10][11][12][13] Several nanoparticles have been reported to accumulate in the CNS, thus suggesting their ability to cross the BBB.…”

Insights into direct nose to brain delivery: current status and future perspective

“…This creates a considerable threat for the therapy of cerebral diseases (Chakraborty et al, 2009). It is increasingly clear that crossing of BBB and drug delivery to CNS is a complex and challenging task requiring close collaboration and common efforts among researchers of several scientific areas including pharmaceutical sciences, biological chemistry, physiology and pharmacology (Denora et al, 2009). Therefore, treatment of neurological diseases has become one of the most significant challenges.…”

Nanoscale drug delivery systems and the blood–brain barrier

“…Resistance to antiepileptic remedies may be explained by increased activity of P-gp because it can possibly transport phenytoin, levetiracetam, lamotrigine, and phenobarbital. 88 P-gp activity is increased after stroke, which influences therapy efficacy. 89,90 In the case of HIV infection, trans-activating transcriptor (TAT) proteins from virions are able to stimulate P-gp activity.…”

“…Administration of ABC transporter substrates combined with efflux inhibitors has been employed to increase EC permeability. 88 Thus, modulators of P-gp activity, such as verapamil and diltiazem, are used to increase brain delivery of viral protease inhibitors, antitumor substances (paclitaxel), and the antifungal agent itraconazole. Some polymers may suppress ABC transporter activity due to altered membrane fluidity.…”