Challenges in drug delivery to tumors of the central nervous system: An overview of pharmacological and surgical considerations

Department of Neurological Surgery, University of California - San Francisco, San Francisco, CA 94158, United States.
Advanced drug delivery reviews (Impact Factor: 15.04). 01/2012; 64(7):590-7. DOI: 10.1016/j.addr.2012.01.004
Source: PubMed


The majority of newly diagnosed brain tumors are treated with surgery, radiation, and the chemotherapeutic temozolomide. Development of additional therapeutics to improve treatment outcomes is complicated by the blood-brain barrier (BBB), which acts to protect healthy tissue from chemical insults. The high pressure found within brain tumors adds a challenge to local delivery of therapy by limiting the distribution of bolus injections. Here we discuss various drug delivery strategies, including convection-enhanced delivery, intranasal delivery, and intrathecal delivery, as well as pharmacological strategies for improving therapeutic efficacy, such as blood-brain barrier disruption.

14 Reads
  • Source
    • "Examples of carriers include polymeric micelles [2e4], liposomes [5e7], microparticles [8], nanoparticles [9e11], nanogels [12] [13], drug polymer conjugates [14], inorganic conjugations [15], and other supramolecular assemblies [16]. However, challenges such as low specific targeting, insufficient cellular uptake, and low therapeutic efficiency still exist in regard to the delivery of clinically optimal levels of therapeutic molecules [17]. There is a great need for the development of approaches that can transport drugs precisely and safely to a target site with a controlled release to achieve the maximum therapeutic effect [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A protein delivery method using freeze concentration was presented with a variety of polyampholyte nanocarriers. In order to develop protein nanocarriers, hydrophobically modified polyampholytes were synthesized by the succinylation of ε-poly-l-lysine with dodecyl succinic anhydride and succinic anhydride. The self-assembled polyampholyte aggregated form nanoparticles through intermolecular hydrophobic and electrostatic interactions when dissolved in aqueous media. The cationic and anionic nanoparticles were easily prepared by changing the succinylation ratio. Anionic or cationic proteins were adsorbed on/into the nanoparticles depending on their surface charges. The protein-loaded nanoparticles were stable for at least 7 d. When L929 cells were frozen with the protein-loaded nanoparticles in the presence of a cryoprotectant, the adsorption of the protein-loaded nanoparticles was enhanced and can be explained by the freeze concentration mechanism. After thawing, proteins were internalized into cells via endocytosis. This was the first report that showed that the efficacy of protein delivery was successfully enhanced by the freeze concentration method. This method could be useful for in vitro cytoplasmic protein or peptide delivery to various cells for immunotherapy or phenotype transformations.
    Biomaterials 05/2014; DOI:10.1016/j.biomaterials.2014.04.030 · 8.56 Impact Factor
  • Source
    • "Noninvasive treatment to improve glioma-bearing survival is a promising direction of glioma therapy. However, most chemotherapy fails because of the limited blood–brain barrier (BBB) penetration and poor glioma targeting of the chemotherapeutics [1] [2] [3]. As a disease of the whole brain, effective treatment for brain glioma needs to conquer two barriers: the BBB and the brain–glioma barrier [3] [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dual targeting delivery system was developed to absolutely conquer the two barriers that glioma treatment faced: blood-brain barrier (BBB) and brain-glioma barrier. Recently, a system, AS1411 aptamer (for glioma targeting) and TGN peptide (for BBB targeting) modified nanoparticles (AsTNPs), was developed which can effectively target to brain glioma and improve survival of glioma bearing mice. However, the in vitro models currently used are far too different from the in vivo tumor microenvironment that the glioma targeting delivery system actually faced. In this study, the pharmacology mechanisms of AsTNPs were explored on several models that imitated the tumor microenvironment. AsTNPs can be selectively taken up by endothelial and glioma cells, effectively penetrate the BBB and brain-glioma barriers to reach glioma cells and displayed their anti-glioma effect. The cell monolayers, tumor spheroids and coculture systems were more suitable in vitro models for the pharmacology evaluation of targeted drug delivery systems.
    Acta biomaterialia 11/2013; 10(2). DOI:10.1016/j.actbio.2013.11.003 · 6.03 Impact Factor
  • Source
    • "Therapeutic strategies have targeted these transporters to increase delivery to the brain through the BBB (Hartz and Bauer, 2010). In some cases, injections of therapeutics directly into the subarachnoid space (intrathecal administration) are used as targeted treatments of diseases in the brain such as tumors and infections (Varelas et al., 2008; Serwer and James, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The choroid plexus epithelium (CPE) is located in the ventricular system of the brain, where it secretes the majority of the cerebrospinal fluid (CSF) that fills the ventricular system and surrounds the central nervous system. The CPE is a highly vascularized single layer of cuboidal cells with an unsurpassed transepithelial water and solute transport rate. Several members of the slc4a family of bicarbonate transporters are expressed in the CPE. In the basolateral membrane the electroneutral Na(+) dependent Cl(-)/HCO3 (-) exchanger, NCBE (slc4a10) is expressed. In the luminal membrane, the electrogenic Na(+):HCO3 (-) cotransporter, NBCe2 (slc4a5) is expressed. The electroneutral Na(+):HCO3 (-) cotransporter, NBCn1 (slc4a7), has been located in both membranes. In addition to the bicarbonate transporters, the Na(+)/H(+) exchanger, NHE1 (slc9a1), is located in the luminal membrane of the CPE. Genetically modified mice targeting slc4a2, slc4a5, slc4a7, slc4a10, and slc9a1 have been generated. Deletion of slc4a5, 7 or 10, or slc9a1 has numerous impacts on CP function and structure in these mice. Removal of the transporters affects brain ventricle size (slc4a5 and slc4a10) and intracellular pH regulation (slc4a7 and slc4a10). In some instances, removal of the proteins from the CPE (slc4a5, 7, and 10) causes changes in abundance and localization of non-target transporters known to be involved in pH regulation and CSF secretion. The focus of this review is to combine the insights gathered from these knockout mice to highlight the impact of slc4 gene deletion on the CSF production and intracellular pH regulation resulting from the deletion of slc4a5, 7 and 10, and slc9a1. Furthermore, the review contains a comparison of the described human mutations of these genes to the findings in the knockout studies. Finally, the future perspective of utilizing these proteins as potential targets for the treatment of CSF disorders will be discussed.
    Frontiers in Physiology 10/2013; 4:304. DOI:10.3389/fphys.2013.00304 · 3.53 Impact Factor
Show more

Similar Publications