How do barriers like the skin and blood–brain barrier affect drug entry?
Executive summary
The skin and the blood–brain barrier (BBB) are deliberately selective physical and biochemical barriers that block most drugs: the BBB excludes roughly 95% of potential therapeutics and only allows small, lipophilic molecules (≈≤400 Da) to passively cross, while its tight junctions, efflux pumps (P‑gp, BCRP) and supporting cells enforce low paracellular permeability (<10−8 cm s−1 for sucrose) [1] [2]. Researchers are responding with two broad strategies: exploit existing transport routes (receptor-mediated “Trojan horses”, transporters, vesicles) or transiently/modestly open the barrier (focused ultrasound, RF/hyperthermia, modulators), but each approach carries trade‑offs in selectivity, safety and translatability [3] [4] [5] [2].
1. The fortress: how the BBB’s structure blocks drugs
The BBB is a multilayered, dynamic interface formed by brain microvascular endothelial cells joined by high‑resistance tight junctions (claudin‑5, occludin), surrounded by pericytes, a basement membrane and astrocytic end‑feet; this architecture enforces extremely low paracellular leak and concentrates efflux pumps that actively eject xenobiotics, so most pharmaceuticals cannot reach brain tissue from blood [2] [6]. Reviews and experimental metrics routinely quantify that the BBB’s paracellular permeability for markers like sucrose is <10−8 cm s−1 and that only small, lipid‑soluble molecules (~≤400 Da) cross efficiently by passive diffusion — a practical cutoff that rules out most biologics and large molecules [2] [1] [7].
2. Skin vs. BBB: different barriers, similar problem
The skin is not emphasized in these sources, but available sources do not mention detailed skin barrier mechanisms in the context of this query; reporting focuses on the BBB as the archetypal drug delivery bottleneck. For the BBB, the combined effect of tight junctions, specialized endothelial features, and efflux transporters is what prevents drugs from entering the CNS — a problem repeatedly cited as a core reason CNS drug development has lower success rates and longer timelines than other fields [7] [1] [8].
3. “Trojan horses” and transporters: tricking existing pathways
Researchers attempt to hijack physiological transport systems by attaching therapeutic cargos to molecules the BBB recognizes — for example, ligands for transferrin or other receptors — so the complex undergoes receptor‑mediated transcytosis into the brain. Journalistic summaries call these approaches “Trojan horses,” and they are an active area of investment and clinical translation, with engineered capsids, antibody shuttles and optimized receptor binders emerging in recent papers and partnerships [3] [9] [4] [10]. These strategies preserve barrier integrity but require precise engineering so the drug remains attached until crossing and avoids being routed to lysosomes or effluxed [3] [4].
4. Physically opening the barrier: gains, risks, and specificity
A second strategy is to transiently increase BBB permeability — options include focused ultrasound, RF pulses or mild hyperthermia and pharmacologic modulators (e.g., bradykinin agonists) — enabling higher CNS drug exposure but risking off‑target entry of toxins and systemic side effects if control is imperfect [5] [11] [12]. Literature notes the need to define safe parameters for reversible openings and to target diseased regions (e.g., blood‑tumor barrier) where selective modulation might be possible [5] [11].
5. The translational bottleneck and the commercial race
The scientific challenge has become an industrial one: companies and big pharma are investing in BBB‑penetrant platforms and licensing deals to field antibodies, AAV capsids and delivery modules that claim improved CNS access, signaling that technical solutions are maturing into commercial strategies — but these deals also reflect high technical and regulatory risk and large milestone structures [9] [13]. Nature and review pieces emphasize that despite progress, success requires matching mechanism to disease biology and demonstrating safety in humans [8] [4].
6. Nuance and open questions reporters should watch
Key unresolved issues noted in the literature include how aging, genetics (e.g., APOE genotype) and disease‑driven glycocalyx or tight‑junction changes alter BBB permeability and drug response; researchers are exploring extracellular vesicles, intranasal vectors and engineered microbes to bypass or exploit alternate routes, but those approaches remain under active investigation [14] [10] [6]. Studies highlight that the BBB is not a static wall but a regulated interface — both an obstacle and a set of possible “choke points” for rational drug delivery [2] [1].
Limitations: sources here focus heavily on the BBB and drug‑delivery research; specific, sourced detail on skin barrier mechanisms for drugs is not present in the provided reporting (available sources do not mention detailed skin barrier mechanisms).