Selectively targeting cancerous cells to minimize side effects remains a critical challenge in the development of effective cancer therapies. The blood-brain barrier poses an additional challenge to delivering drugs into central nervous system tissues. One promising approach that has recently been explored is the use of positively charged cell-penetrating peptides to target negatively charged cell surfaces, which is a characteristic feature of many cancer cells. Therefore, a researchers' group, led by Assistant Professor Shailendra Joshi, at the College of Physicians and Surgeons, Columbia University Medical Center, developed an innovative drug delivery method that utilizes short TAT (trans-activating transcription factor) oligomers to deliver drug cargo across cell membranes.
Targeted drug delivery to tumours and central nervous system tissues is a crucial mechanism of different therapies. Computational modelling demonstrates that intra-arterial delivery is most efficient when the delivered drugs rapidly and avidly bind to the target site. The cell-penetrating peptide trans-activator of transcription (TAT) is a candidate carrier molecule that could mediate such specificity for brain tumour chemotherapeutics. TAT oligomers facilitate robust penetration of cell membranes
The developed technology demonstrates the use of short, positively charged TAT oligomers for more effective drug delivery targeted to negatively charged cancer cells. TAT peptides utilize cationic charge to penetrate across cell membranes and readily cross the blood-brain barrier. TAT dimers demonstrate robust tumour-selective uptake at half the concentration of conventional TAT monomers.
In addition, this innovative technology has been already validated in a rat tumour model and in several brain tumour and metastatic cancer cell lines. The team observed a robust uptake of TAT by all tumour cell lines in vitro. Flow cytometry and confocal microscopy revealed a rapid uptake of fluorescein-labelled TAT within 5 min of exposure to the cancer cells. IA injections are done under transient cerebral hypoperfusion (TCH) generated a four-fold greater tumour TAT concentration compared to conventional IV injections. Consequently, it is feasible to selectively target brain tumours with TAT-linked chemotherapy by the IA-TCH method.
Therefore, this method provides not only targeted drug delivery to solid tumours and cancerous cells but targeted drug delivery to apoptotic cells in stroke and to other negatively-charged cells. Furthermore, this technique enables to deliver drugs across the blood-brain barrier and the blood-retina barrier.