Intriguing possibilities and beneficial aspects of transporter-conscious drug design

Tashima, Toshihiko

doi:10.1016/j.bmc.2015.06.022

Cited by 27 publications

(29 citation statements)

References 85 publications

(102 reference statements)

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“…Accordingly, transporter-conscious drug design is an excellent tactic for effective cancer chemotherapy and good ADMET. In design of compounds transported by arbitrary SLC transporters, incorporated structural commonality of their substrates into designed compounds act as transporter recognition unit [3]. Compounds possessing peptide mimic as transporter recognition unit may enter into cancer cells overexpressing PEPT1.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the use of their transport systems overcomes the problems such as drug permeability into cancer cells and drug resistance through the overexpression of MDR1 (Figure 1) [1,2]. I have already described intriguing possibilities and beneficial aspects of transporter-conscious drug design [3]. In this review, I will introduce the effective method of cancer chemotherapy based on transporter-conscious drug design.…”

Section: Introductionmentioning

confidence: 99%

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Possibilities of Cancer Chemotherapy Based on Transporter-Conscious Drug Design

Tashima¹

2015

J Carcinog Mutagen

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Cancer chemotherapy is the treatment method which uses drugs to kill cancer cells or to inhibit their growth. In cancer drug discovery or development, not only anti-cancer drug delivery into target cancer cells across the cell membrane but also acquired anti-cancer drug resistance through the overexpression of ATP-binding cassette (ABC) transporters such as MDR1 (p-glycoprotein) in target cancer cells are serious problems to overcome. However, the use of transport system based on solute carrier (SLC) transporters can solve both problems, because it is wellknown that some types of SLC transporters are overexpressed in cancer cells. Thus, transporter-consciously designed drugs can be transported into cells by such overexpressed SLC transporters, so as not to be excreted by MDR1. Therefore, transporter-conscious drug design is very effective in absorption, distribution, excretion, and toxicity of drugs (ADMET) due to transport systems. In this paper, cancer chemotherapy based on transporterconscious drug design is described.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Possibilities of Cancer Chemotherapy Based on Transporter-Conscious Drug Design

Tashima¹

2015

J Carcinog Mutagen

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“…Certain N-containing compounds such as diphenhydramine and morphine are the substrates of the proton-coupled organic cation (H + /OC) antiporter, although its amino acid sequence and its topology have not been identified. 2,3) Thus, drugs designed based on such transporters, that is, transporterconsciously designed drugs, can be transported into the brain using SLC transporters expressed at the BBB. 4) In contrast, high-and middle-molecular compounds are too large to be transported by the transporters.…”

Section: Introductionmentioning

confidence: 99%

Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis

Tashima¹

2020

Chem. Pharm. Bull.

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Discriminatory drug delivery into target cells is essential to effectively elicit the drug activity and to avoid off-target side effects; however, transporting drugs across the cell membrane is difficult due to factors such as molecular size, hydrophilicity, intercellular adhesiveness, and efflux transporters, particularly, in the brain capillary endothelial cells. Drug delivery into the brain is blocked by the blood-brain barrier (BBB). Thus, developing drugs for the central nervous system (CNS) diseases remains a challenge. The approach based on receptor-mediated transcytosis (RMT) can overcome this impassable problem at the BBB. Well-designed molecules for RMT form conjugates with the ligand and drugs via linkers or nanoparticles. Cell penetrating peptides (CPPs), receptor-targeting peptides, and monoclonal antibodies (mAbs) are often used as ligands. The binding of ligand to the receptor on the endothelial cell surface induces endocytosis. Existing exosomes comprising the conjugates move in the cytoplasm and fuse with the opposite plasma membrane to release them. Subsequently, the transcytosed conjugate-loaded drugs or released drugs from the conjugates elicit activity in the brain. As receptors, transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (InsR) have been used to intendedly induce transcytosis. Presently, several clinical trials on CNS drugs for Alzheimer's and Parkinson disease are hindered due to poor drug distribution into the brain. Therefore, this strategy based on RMT is a promising method for CNS drugs to be transported into the brain. In this review, I introduce the practicality and possibility of drug delivery into brain across the BBB using RMT.

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“…Furthermore, receptor-mediated transcytosis (RMT) distributes the corresponding middleor high-molecular-weight ligands, such as insulin and transferrin, across the capillary endothelium to the brain. Therefore, carrier-mediated transport using arbitrary substrates with cargos could be a direct approach to bypass MDR1 and the tight junction-based physical boundary at the BBB [3]. Similarly, RMT using arbitrary ligands with cargos could be a direct approach to bypass tight junction-based boundary at the BBB [3].…”

Section: Introductionmentioning

confidence: 99%

Shortcut Approaches to Substance Delivery into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin

Tashima

2020

Molecules

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The direct delivery of central nervous system (CNS) drugs into the brain after administration is an ideal concept due to its effectiveness and non-toxicity. However, the blood–brain barrier (BBB) prevents drugs from penetrating the capillary endothelial cells, blocking their entry into the brain. Thus, alternative approaches must be developed. The nasal cavity directly leads from the olfactory epithelium to the brain through the cribriform plate of the skull bone. Nose-to-brain drug delivery could solve the BBB-related repulsion problem. Recently, it has been revealed that insulin improved Alzheimer’s disease (AD)-related dementia. Several ongoing AD clinical trials investigate the use of intranasal insulin delivery. Related to the real trajectory, intranasal labeled-insulins demonstrated distribution into the brain not only along the olfactory nerve but also the trigeminal nerve. Nonetheless, intranasally administered insulin was delivered into the brain. Therefore, insulin conjugates with covalent or non-covalent cargos, such as AD or other CNS drugs, could potentially contribute to a promising strategy to cure CNS-related diseases. In this review, I will introduce the CNS drug delivery approach into the brain using nanodelivery strategies for insulin through transcellular routes based on receptor-mediated transcytosis or through paracellular routes based on escaping the tight junction at the olfactory epithelium.

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Intriguing possibilities and beneficial aspects of transporter-conscious drug design

Cited by 27 publications

References 85 publications

Possibilities of Cancer Chemotherapy Based on Transporter-Conscious Drug Design

Possibilities of Cancer Chemotherapy Based on Transporter-Conscious Drug Design

Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis

Shortcut Approaches to Substance Delivery into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin

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