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Researchers overcome challenge of oral absorption of large molecules using bioinspired drug delivery approach

As biotechnology advances, large-molecule drugs such as peptides, proteins, and nucleic acids are increasingly gaining widespread clinical applications. These macromolecular agents display superior targeting and therapeutic efficacy compared to small-molecule drugs, and are applicable to a variety of diseases that threaten human health, including cardiovascular diseases, diabetes, and cancer. However, one significant obstacle is their susceptibility to degradation in the gastrointestinal tract and their large molecular size, which hampers effective oral absorption.

Despite considerable research investment in developing new delivery technologies over the past decades, very few orally administered peptide-based drugs have received FDA approval. For instance, the oral formulation of semaglutide, Rybelsus, approved by the FDA in 2020, still has a bioavailability of less than 1%, even after the addition of a multitude of absorption-promoting agents. To address this challenge, recent research efforts have sought to develop devices that can directly inject the drug into the gastrointestinal mucosa. However, the stability and safety of these technologies remain under scrutiny.

 

A team led by Associate Professor Zhi Luo of the Department of Biomedical Engineering at the Southern University of Science and Technology (SUSTech) has recently published a study inspired by the unique structure and efficient absorptive properties of octopus suckers, that leverages 3D printing technology to design a non-invasive oral drug delivery device.

Their research paper, entitled “Boosting systemic absorption of peptides with a bioinspired buccal-stretching patch”, has been published in the journal Science Translational Medicine.

The technology created by the researchers mimics the three-dimensional structure and muscle arrangement of octopus suckers to achieve gentle but effective adhesion and stretching on the oral mucosa. This mechanical force can reversibly disrupt the epithelial cell structure and destroy the lipid barrier, thereby facilitating the efficient diffusion of peptide molecules. Furthermore, this delivery device can be loaded with various types of excipients, including absorption promoters and release modifiers, to achieve controlled release of peptide drugs. Thus, through the synergistic action of mechanical stretching and chemical absorption enhancers, this formulation method efficiently diffuses the drug into the highly vascularized mucosal tissue, promoting its entry into the systemic circulation.

This work also marked improvement in bioavailability: In in vivo studies using a large animal model (beagle dogs), the bioinspired suction patch demonstrated two orders of magnitude increase in the bioavailability of desmopressin, a peptide drug whose oral bioavailability is only 0.1%, compared to commercial tablet formulations. For semaglutide, this formulation showed bioavailability comparable to the FDA-approved Rybelsus tablets.

Representing a novel oral peptide drug formulation, a PCT patent application has been submitted for this work. The formulation is a non-invasive drug delivery technology with a simple, highly flexible process suitable for the delivery of various large-molecule drugs. Human trials involving 40 healthy participants verified the high acceptability of the new formulation, indicating substantial clinical translational potential.

The study offers a novel and practical approach to resolving the challenges of oral absorption of large-molecule drugs. The synergistic effect of mechanical stretching and chemical absorption enhancers introduces a novel mechanism for the oral delivery of macromolecular drugs. This delivery modality has the potential to become a platform technology for various types of macromolecular drug formulations, providing more convenient and effective treatment options for patients.

Assoc. Prof. Zhi Luo is the first and corresponding author of this paper, and SUSTech is the first affiliation unit. Prof. Jean-Christophe Leroux at the Swiss Federal Institute of Technology in Zurich is a co-corresponding author.

This work was supported by the National Key Research and Development Program of the Ministry of Science and Technology and the Guangdong Provincial Key Laboratory of Biomaterials, among other projects.

 

Paper link: https://www.science.org/doi/10.1126/scitranslmed.abq1887

Researchers develop portable SARS-CoV-2 variant monitoring technology

The continuous mutations of the novel coronavirus (SARS-CoV-2) are complicating public health responses and vaccination strategies. Portable assays for the rapid identification of lineages of SARS-CoV-2 are needed to aid large-scale efforts in monitoring the evolution of the virus.

Virus mutations remain a significant challenge for both scientific research and public health, especially as the global pandemic continues to spread. Traditional detection methods, like RT-qPCR, have limitations in identifying multiple viral mutations. Given the rapid mutation of the coronavirus and the varying efficacy of vaccines against new variants, more precise detection techniques are critical.

In response to this urgent situation, Associate Professor Bo Zhang’s group from the Department of Biomedical Engineering (BME) at the Southern University of Science and Technology (SUSTech), in collaboration with Professor Hongjie Dai from Stanford University, Director Jing Yuan from the Third People’s Hospital of Shenzhen, the Microfluidic-Biomaterials Lab at SUSTech, and Dr. Meijie Tang from Nirmidas Biotech, have developed a novel SARS-CoV-2 variant detection technology called FEMMAN. This technology uses advanced methods combining nanotechnology and biosensors, allowing not just accurate detection but differentiation among dozens of different mutations.

Their research work, entitled “Multiplexed discrimination of SARS-CoV-2 variants via plasmonic-enhanced fluorescence in a portable and automated device”, has been published in the journal Nature Biomedical Engineering, offering a potential game-changer in the diagnosis and monitoring of COVID-19 variants.

FEMMAN Technology

FEMMAN integrates various cutting-edge technologies, such as plasmonic gold nanomaterials, DNA microarrays, and microfluidic chips, to successfully identify SARS-CoV-2 and its multiple variants with high sensitivity and specificity. The technology’s flexibility and accuracy make it a powerful tool for future pandemic control efforts. Moreover, FEMMAN can rapidly adapt to newly emerging virus variants, substantially enhancing the accuracy and efficiency of pandemic responses and helping in precise risk assessment and resource allocation worldwide.

Figure 1. FEMMAN achieves single-RNA copy sensitivity with Asy-RT–RPA for the detection of SARS-CoV-2 and the simultaneous discrimination of viral variants with SNV distinction

Unique Features

The unique feature of FEMMAN technology lies in its multiplex detection capabilities. Prof. Zhang’s team further optimized the technique to adapt to newly emerging virus variants. In essence, FEMMAN is not only a highly sensitive and specific detection tool but also a highly flexible and scalable platform for multiplex nucleic acid detection.

Figure 2. Comprehensive identification of SARS-CoV-2 lineages by FEMMAN

The breakthrough was made possible by interdisciplinary and inter-institutional collaborations. The project team solved multiple key scientific challenges by drawing upon their years of professional expertise. In collaboration with Director Jing Yuan’s team from the Third People’s Hospital of Shenzhen, thousands of clinical trials were conducted, allowing FEMMAN technology to move quickly from the lab to the clinic and to potentially be widely applied in various settings, including hospitals, airports, schools, and communities.

Figure 3. SARS-CoV-2 detection and viral-lineage discrimination of clinical samples with FEMMAN

Societal Impact

When asked about the social implications of the research, the first author of the paper, Dr. Ying Liu, said: “The emergence of FEMMAN technology gives us a much more robust weapon against the constant mutations of the novel coronavirus. This is particularly crucial as many regions globally face insufficient testing resources and immense pressures on healthcare systems.”

The scalability of FEMMAN technology also means it has broad application prospects. Aside from COVID-19, it could potentially be used to detect a variety of other viruses and microbes, including but not limited to influenza, Ebola, and Zika viruses.

Research Assistant Professor Ying Liu from the Department of BME at SUSTech is the first author of this paper. Yang Yang, Guanghui Wang, and Dou Wang are co-first authors. Associate Professor Bo Zhang from the Department of BME at SUSTech, Academician Hongjie Dai from Stanford University, Director Jing Yuan from the Third People’s Hospital of Shenzhen, and Dr. Meijie Tang from Nirmidas are the corresponding authors.

SUSTech is the primary institution for this research, and collaborating institutions include Stanford University, Third People’s Hospital of Shenzhen, Nirmidas Inc., and Guangzhou Medical University.

This work was supported by the National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Shenzhen Science and Technology Programme Project, Guangdong Provincial Key Laboratory of Advanced Biomaterials, National Key R&D Program of China, National Science and Technology Major Project, and the Shenzhen High-Level Hospital Construction Fund. Technical support for this research was provided by the Core Research Facilities at SUSTech.

 

Paper link: https://www.nature.com/articles/s41551-023-01092-4