Bread, chewing gum and pig semen: unconventional ways of delivering cancer therapeutics
It’s all well and good designing a novel therapeutic, but these efforts are futile if you’re unable to safely and effectively deliver the treatment at the right time and to the right location. As a result, drug delivery tactics are becoming increasingly offbeat, helping to enhance the accumulation of drugs at target sites, improve their cell-type specificity and reduce off-target toxicity – and cancer research is no exception.
Here, we explore some of the more unconventional (and sometimes unsavory) methods of delivering cancer therapeutics, ranging from the palatable – chewing gum and bread – to the downright unhinged – pig semen and snail-inspired robots.
Bread-based drug delivery for enhanced colon cancer vaccine efficacy
Creating a modified version of the bacterium Listeria monocytogenes (Lm) as a vaccine against colon cancer – administered via bread consumption – researchers from Stony Brook University (NY, USA) have generated a robust anti-tumor response in mice, targeting gastrointestinal tissues more effectively than traditional immunotherapy methods.
Colorectal cancer is a leading cause of cancer-related death worldwide and remains a significant global health challenge. Vaccines have shown themselves to be a promising immunotherapy for long-term tumor control, with Lm-based intravenous jabs eliciting potent innate and adaptive immune responses. However, clinical trial success has been limited.
In light of this, the team sought to investigate whether foodborne delivery of Lm cancer vaccines could better target gastrointestinal tissues and control tumor growth in murine models of colorectal cancer.
To do so, they engineered a strain of Lm with two virulence genes deleted and a mutation that allows epithelial cell invasion. Immunogenicity and safety were tested in C57Bl/6 mice, which consumed the bacterial vaccine via inoculated bread. Importantly, oral immunization induced a robust CD8 T cell response, Lm was contained to intestinal tissues and immunized mice did not lose weight.
Then, vaccine efficacy was evaluated with colorectal tumors delivered into the colon by colonoscopy-guided orthotopic transplantation. The vaccines limited colorectal cancer development when administered prophylactically and provided tumor control when administered therapeutically in combination with immune checkpoint inhibitors.
“This combination therapy led to profound tumor control in the model and suggests that the vaccine can effectively ‘turn on’ the immune system in tumors that were previously resistant to standard immune therapy,” explained lead author Brian Sheridan.
The findings underscore the potential of Lm as an oral cancer vaccine vector to target colorectal cancer: “Ultimately, such a strategy could significantly improve the prognosis for patients with advanced or metastatic colorectal cancer who have limited therapeutic options otherwise,” Sheridan added.
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Combating oral cancer with bioengineered chewing gum
An ex vivo study from the University of Pennsylvania (PA, USA) has revealed that bioengineered antiviral or antibacterial chewing gums can reduce the levels of carcinogenic microbes in the mouth, demonstrating their potential as part of a treatment strategy for head and neck squamous cell cancer (HNSCC).
HNSCC is a common and often aggressive cancer that develops in the lining of the mouth and throat. It is associated with several microbes – including oral human papilloma virus (HPV), Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn) – a higher abundance of which is correlated with worse survival of HNSCC patients.
Using HPV ELISA, the researchers detected viruses in 100% of saliva and 75% of oral-rinse samples from HNSCC patients, while cell culture studies showed there was 1000-fold higher Pg and Fn in patients’ saliva and 100-fold higher in oral-rinse samples, compared to non-cancer control participants.
Building on previous work that designed chewing gum made from lablab beans that contained the naturally antiviral protein FRIL, the team used ELISA to show that the gum aggregated 93% of HPV in saliva samples and 80% in oral rinse samples.
They then bioengineered the gum to contain protegrin, an antimicrobial peptide, finding that it lowered Pg and Fn levels by more than 99% in both saliva and oral-rinse samples. However, it did not kill capsule-forming bacteria, providing selectivity and protection of beneficial oral bacteria.
“Our findings support the value of advancing these therapies to clinical trials as adjuvants with current treatments or as prophylaxis to prevent infection and transmission,” lead researcher Henry Daniell concluded.
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Eye cancer drug delivery derived from pig semen
Semen-derived exosomes (SEVs) could transform retinoblastoma treatment – yes, you read that right. Scientists from Shenyang Pharmaceutical University (China) have engineered eye drops containing vesicles derived from pig semen, capable of penetrating ocular barriers and noninvasively delivering drugs to the posterior segment of the eye.
Retinoblastoma is the most prevalent intraocular malignancy in children. It is notoriously difficult to treat due to its location within the retina and the delicate nature of ocular tissues. Current therapies, such as injections, chemotherapy and radiotherapy, can have severe side effects and may result in ocular damage and vision loss.
Exosomes can cross biological barriers, meaning they could be an ideal means for delivering drugs to the posterior segment of the eye while minimizing collateral damage. Despite this promise, exosomes remain underexplored for noninvasive posterior ocular delivery.
To try to rectify this, the researchers turned to SEVs, which have evolved to facilitate sperm penetration through the female reproductive tract and are therefore encouraging candidates for getting past the ocular barrier. Combining SEVs isolated from pig semen with folic acid and a nanozyme system composed of carbon dots, manganese dioxide and glucose oxidase, they created eye drops with excellent penetration ability and precise targeting to retinoblastoma cells.
The drops were tested in cell cultures and in mouse models of retinoblastoma. In the in vivo experiments, the system effectively inhibited tumor growth while preserving retinal function.
“This groundbreaking study on SEVs marks a paradigm shift in posterior ocular disease therapeutics,” the study authors write. They hope it could lead to safer, more effective and less invasive treatments for eye cancers.
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’Trojan horse’ drug delivery system uses gold nanoparticles to enhance cancer therapy
University of Oklahoma (OK, USA) researchers have created a drug delivery system that uses gold nanoparticles to transport therapeutic mRNA inside cancer cells, improving a treatment’s ability to kill tumors.
mRNA therapies often struggle to infiltrate cancer cells, and the unavailability of effective delivery systems has meant that clinical translation has been limited, particularly in solid tumors.
Describing a new, gold nanoparticle-based mRNA delivery system, the scientists hope to overcome these challenges. “The delivery system is like a Trojan horse,” Joshua Seaberg, the doctoral student who created the system, explained. Once transported into cancer cells by a vehicle called an aurniosove, the gold nanoparticles bind to and inactivate two key proteins – PP2A and Rab7 – triggering a process that allows more nanoparticles and their associated mRNA to enter. “The end result is that we get a flood of the therapeutic inside the cell rather than individual pieces creeping in one at a time,” Seaberg added.
Through in vitro studies in p53-null ovarian and hepatocellular carcinoma cell lines, the team demonstrated that their drug delivery system improved uptake of tumor-suppressing p53 mRNA within tumors, resulting in enhanced protein expression and therapeutic efficacy. Studies in p53-null mouse models corroborated this, revealing that delivery of p53 mRNA can regulate tumor growth in vivo.
Taken together, the findings point to this ‘trojan horse’ method as a next-generation mRNA delivery system. “Our work shows that the delivery system can play an active role in treatment. This shift in thinking opens up entirely new possibilities,” study author Priyabrata Mukherjee concluded.
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Snail-inspired colorectal cancer drug delivery
Mini robots, inspired by snails, could be the next big thing in colorectal cancer drug delivery. A multidisciplinary team of University of Manchester (UK) researchers has been awarded almost £1 million in funding from the UK Research Institute (Swindon, UK) to invent a novel, highly targeted method of drug release directly at tumor sites.
While cancer therapies are becoming increasingly advanced, off-target effects are common and pose a serious risk for patients. Taking inspiration from snails, the researchers want to create teeny robots, starting at the centimeter scale, which can be guided through the gastrointestinal tract via magnetic fields to the site of colorectal cancer tumors, where they trigger a release of therapeutic agents without damaging other parts of the body.
“Gastropod molluscs such as snails use slime-based locomotion and can survive in extreme environments, including as intestinal parasites, and we believe this body plan is ideal for our application,” lead researcher Mostafa Nabawy told BioTechniques. “Their locomotor mechanism provides high precision, low speed, and substrate-independent body movement, which will enable regiospecific localised drug release, for enhanced bioavailability in malignant tumours.”
The first step on their quest to achieve this is to find out more about how snails move, by producing the first high-resolution data set on snail movement, food actuation and mucus interactions that they will then use to train digital simulations and machine-learning-based control systems. These will inform the design of biocompatible, peptide-based soft robots; meanwhile, a digital twin simulation framework will enable the rapid testing of designs in silico.
Nabawy is optimistic about the robots’ future: “By studying these remarkable organisms and translating their movement strategies into soft robotic systems, we hope to deliver a step change in how medicine is administered deep inside the body.”