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Improved drug delivery technologies and real-time protein monitoring through advancements in directed evolution techniques and biosensor optimization

  • Author(s): Fong, Faye
  • Advisor(s): Soh, Hyongsok T
  • et al.
Abstract

Whereas twentieth century medical research sought treatments to benefit as many individuals as possible, perhaps the watchword of the next century is “precision medicine”, which seeks to maximize the benefit of treatment for each individual. Every patient has a unique physiological and pathological profile. The effective dosage of a drug, the rate of disease progression, and even the risk of complications are determined by genetic and lifestyle factors specific to the individual. The next generation of medical innovation aims to customize healthcare to the unique needs of each patient.

One area of research in precision medicine is controlled drug delivery, which aims to precisely supply therapeutic molecules to the correct tissue and organ locations at the correct times. There is a universal general strategy: an engineered protective vehicle which reacts specifically to biological or physical triggers to release an encapsulated drug payload. Controlled drug delivery reduces toxic side effects, improves efficacy, and customizes therapy to the individual. Recently, there has been heightened interest in the development of pH-controlled drug delivery. A clinically significant pH gradient exists across the endocytosis pathway where the pH changes from 7.4 at the plasma membrane to 5.2 in the late endosome. Endocytosis is responsible for trafficking and modifying many important proteins and as such, triggered activation of drugs at specific pH corresponding to specific modules of endocytosis is a rich area for therapeutic targeting.

Towards these applications, we have developed an in vitro selection process to generate nanocarriers which switch structure in response to shifting the pH in order to release a drug payload. We have also adapted our selection process to generate pH-controlled aptamers whose affinity for ligands can be turned on or off by changing the pH. The ultimate goal is the rapid generation of useful pH-controlled nanovehicles for customized delivery of any therapeutic payload.

But to fulfill the promise of precision medicine, there is also a great need for new diagnostics which can more quickly and cost-effectively return data about the patient. Currently, the standard of care for biomarker monitoring is the enzyme linked immunosorbent assay (ELISA). Although ELISAs are highly accurate, they are time- and labor-intensive, requiring the expertise of a qualified medical lab technician in a centralized facility. The best way to meet the diagnostics needs for precision medicine in the next century is to develop real-time sensors which are rapid, fully-automated, and function at the point-of-care.

To that end, we have built a real-time electrochemical aptasensor for monitoring α-thrombin protein directly in human plasma. In our devices, protein detection is achieved by the binding of the target protein with methylene blue-modified aptamers, which alters the measured output current. In parallel, the incoming plasma sample stream is subjected to a pretreatment cocktail that blocks native inhibitors and prevents clot formation, thus amplifying the thrombin signal. Our platform could potentially be extended towards monitoring any protein of interest with results reported within minutes, directly at the patient’s bedside.

Controlled drug delivery and real-time biomarker monitoring are powerful complementary technologies in precision medicine. We envision the possibility of maximum patient benefit from therapy, where controlled drug delivery is further finetuned by closely monitoring the individual’s response to treatment.

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