Nanomaterials are critical technological enablers of advanced anticancer therapies. Currently, nanomaterials are widely exploited as drug delivery vehicles to carry the cytotoxic anti-cancer drugs to the tumour. While the use of nano drug delivery system has led to a much-improved safety profile, the drugs' therapeutic efficacy did not significantly improve compared to standard therapies in clinical settings. This could be attributed to the inherent technical challenges that are associated to the nanocarrier paradigm which include low drug loading efficiency, risk of premature drug release in blood, suboptimal biodistribution, amongst others. Additionally, the use of mainstream anti-cancer drugs suffers from a wide-ranging of adversarial side-effects as a consequent of their cytotoxicity.

With the aim of making the cancer nanomedicine formulation less complex, coupled with the known amino acid metabolic liabilities and deregulated oxidative homeostasis of cancer cells, our lab has devised the nanoscopic L-phenylalanine (functionalized) porous amino acids mimic (Nano-pPAAM) – a “drug-free” anti-cancer nanomedicine.

The cancer-killing property of Nano-pPAAM is premised in large part by targeting the human large neutral amino acid transporter protein, LAT-1, encoded by SLC7A5. While expression of LAT-1 is usually limited in healthy organs, cancer cells are known to overexpress LAT-1 to enhance uptake of amino acids to fuel their growth. Studies by others have shown that “starving” the cancer cells of amino acids can slow or prevent tumour growth. This led to the idea of fighting cancer though dietary fasting. However, such approach would not be suitable for all patients, such as those who are at risk of malnutrition or those with cachexia.

To exploit the amino acid dependency of cancer cells but avoid the challenges of strict dietary regimes, Nano-pPAAM was developed. Once internalised into the cancer cells, the mesoporous silica nano-core generates cytotoxic reactive oxygen species (ROS) through a Fenton-like reaction, causing the cancer cells to self-destruct (undergo apoptosis). In this instance, the L-phenylalanine “cloak” serves as a trojan horse to mask the nanotherapeutic on the inside.

In lab experiments, Nano-pPAAM displayed good selectivity and efficacy (~80%) towards LAT-1-overexpressing human breast, gastric and skin cancer cells, while sparing the noncancerous cells. Conversely, the use of cisplatin resulted in the indiscriminate killing of both cancerous and noncancerous cells. Tumour growth in mice with human triple negative breast cancer cells was also significantly reduced with Nano-pPAAM treatment, compared to the untreated control group.

In summary, Nano-pPAAM is a novel and amongst the first-in-class nanomedicines that could achieve anti-cancer efficacy without the loading of additional therapeutic compounds nor need to externally activate the system – in other words, the nanomedicine is said to be ‘self-therapeutic’. Our lab is now looking to build on our findings, specifically to fine-tune the design and chemistry of the Nano-pPAAM for better precision in targeting specific cancer types, improved pharmacokinetics/ pharmacodynamics, and enhanced therapeutic efficacy.