Table 1.

Typical strategies used for delivery of selected therapeutic agents across tissue/cell barriers^*.

	Strategies	Drugs	Targeted Tissue Barrier(s)	References
The Paracellular Ap- proach	Attachment of surfactant-like agents to the drug (e.g., sodium caprate)	Berberine	Gut barrier	[135]
	Delivery of specific peptides to modulate tight junction proteins (e.g., synthetic peptide corresponding to the C-terminal ex tracellular loop 1 of rat claudin-1 that transiently perturbs the TJ- permeability barrier)	DAMGO, tetrodotoxin	Perineurial barrier	[50]
	Delivery of specific siRNA or shRNA that targets junction proteins (e.g., claudin-5 shRNA or siRNA)	Small molecules (<1 kDa) (e.g., sunitinib malate)	Blood-brain barrier, inner-blood- retina barrier	[44, 56, 136]
The Transcellular Ap- proach	Design of lipophilic drugs (e.g. ester-linked/acetylated prodrugs or drug-in-liposome)	Thiorphan	Blood-brain barrier, blood- cerebrospinal fluid barrier	[137, 138]
	Design of prodrugs that target specific protein transporters or receptors on the cell surface (e.g. valacyclovir that targets trans porter PEPT1 & 2 or a vitamin B12 based insulin conjugate)	Acyclovir Insulin	Renal epithelial barrier, Gut barrier	[139] [140]
	Drug particle microniztion (e.g., preparation of drugs using super- critical fluid technology)	Tetracycline	Gut barrier	[70]
	Nanoparticulate strategies (e.g., combination of lipid-based or polymer-based nanoparticles)	Nitrendipine Rivastigmine	Blood-brain Barrier	[141] [142]

^*This Table is not intended to be exhaustive. Only selective examples are shown herein to support discussion for delivery of male contraceptives (see text for detail). Thus, the use of different delivery routes such as nasal or transdermal delivery to circumvent biological barriers are not included. DAMGO, [D-Ala², N-MePhe⁴, Gly⁵-ol]-enkephalin; PEPT1 & 2, peptide transporter 1 and 2.