# Wheat Germ Agglutinin--From Toxicity to Biomedical Applications
## 5 WGA Biomedical Perspectives
### Overcoming Physiological Barriers  
Drug delivery usually involves crossing specific biological barriers. Nonspecific distribution and inadequate accumulation of therapeutics remain formidable challenges for drug developers. The blood-brain barrier (BBB) might also be overcome with WGA incorporation on nanoparticles [63; 64; 65]. PEGylated (Polyethylene glycol modified) fourth-generation poly(amidoamine) (PAMAM) dendrimer-based nanocarrier containing doxorubicin (DOX) inside and WGA with transferrin (Tf) as targeting molecules were developed for BBB crossing. A PA-MAM-WGA-Tf nanocarrier increased DOX delivery through BBB by 13.5% compared to free doxorubicin. Experiments also showed increased DOX accumulation in the tumor site due to dual targeting mechanisms. Accumulation led to the complete breakage of the avascular C6 glioma spheroids in vitro [66]. Recent studies suggest a novel intranasal nanoparticle delivery strategy to overcome BBB. WGA-modified PEG-poly(lactic acid) (PLA) nanoparticles with miR132 were administered to rodents. Transmission electron microscopy results demonstrated that the accumulation of WGA-modified nanoparticles in the brain was significantly higher than that of unmodified nanoparticles. Moreover, the results of Morris water maze analysis showed that the intranasal delivery of WGA-PLA-miR132 improved the learning and memory function of APP/PS1 mice [67]. These results suggest novel drug delivery through BBB strategies, which might overcome treatment-resistant intracranial tumors and neurodegenerative diseases, such as Alzheimer's disease. WGA-incorporated nanoparticles also demonstrate promising features for targeting drugs to bladder cancer cells. Due to the urothelial barrier, constant active drug substance washout, and short dwelling time, bladder cancers and urinary tract infections are another difficulty for efficient drug delivery. Surgical tumor resection is usually followed by repeated intravesical chemotherapy. WGA alone demonstrates high binding to 5637 bladder cancer cells [68]. Later investigations in flow-cytometric and fluorometric experiments with single cells and cell monolayers showed fluorescein (Fc)-labeled poly-l  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Carier Particle** & **Drug** & **Exipients** & **Animal/Cell Line** & **Outcome** & **Reference** \\ \hline \multirow{3}{*}{Polymer nanoparticles} & \multirow{3}{*}{Paclitaxel} & Poly & A549 & \multirow{3}{*}{Demonstrated higher cytotoxicity} & \multirow{3}{*}{[54]} \\  & & (lactic-co-glycolic acid) & & H1299 & \\  & & Isopropyl myristrate & & CCL-186 cell lines & \\ \hline \multirow{3}{*}{Polymer nanoparticles} & \multirow{3}{*}{Paclitaxel} & Poly & \multirow{3}{*}{Caco-2} & \multirow{3}{*}{H-29 cell lines} & \multirow{3}{*}{Demonstrated higher cytotoxicity} & \multirow{3}{*}{[5  
glutamic acid (PGA)-WGA drug delivery system binding and the internalization of high molecular weight (>100 kDa) conjugates. Results of specificity studies showed that the interaction between the Fc-PGA-WGA conjugates and the cell surface depended solely on the WGA component [69]. A recent study by [PERSON] and colleagues demonstrated poly(d,l-lactic-co-glycolic acid) (PLGA)-WGA nanoparticles' inherent adhesion capability to immortalized human uroepithelial cells. A slight adhesion capacity increase was WGA biospecificity-dependant [70]. WGA-liposome-cyclodextrinin complexes were bioengineered for oral cell therapeutics [71]. The designed carrier showed fast attachment to oral cells and sustained co-drug release of ciprofloxacin and betamethasone in saliva in vitro. The complex significantly increased oral cell survival against _Aggregatibacter actinomycetemomitans_, a bacterial pathogen responsible for chronic periodontal disease, and simultaneously reduced the inflammation. Crucially, WGA-facilitated cell-binding prevented complex degradation and loss due to salivary flushing and/or mucus turnover and allowed for sustained 24 h drug release. These promising results might eventually bring some breakthroughs in medicine.