Sam Lai was born in Hong Kong and spent his childhood in both Hong Kong and Vancouver. After completing high school at Phillips Academy, Andover, he attended Cornell University and received his BS in chemical and biomolecular engineering in 2003. He then undertook doctoral studies at Johns Hopkins University, receiving his PhD in chemical and biomolecular engineering in 2007. Following a one-year postdoc, he became a research assistant professor at Johns Hopkins in fall 2008 before joining the UNC Eshelman School of Pharmacy in fall 2010. Lai’s previous research focused on nanoparticle-based delivery of bioactive molecules to mucosal tissues. He helped pioneer the development of mucus-penetrating particle technology, a breakthrough that formed the basis of Kala Pharmaceuticals, launched in 2009 based on funding from a syndicate of leading VC firms. Lai remains an adviser to Kala.
Industry Expertise (3)
Areas of Expertise (9)
PEG (polyethylene glycol)
Acute Respiratory Infections
Johns Hopkins University: PhD, Chemical and Biomolecular Engineering 2007
Cornell University: BS, Chemical and Biomolecular Engineering 2003
Media Appearances (1)
Pharmacy researchers show vaginal mucus may prevent HIV
The Daily Tar Heel online
A new study, led by UNC Pharmacy Professor Dr. Sam Lai, offers new prospects for protecting women from HIV. The key to this new discovery — a bacteria present in the cervical vaginal mucus of certain women. “The HIV was either highly mobile or effectively trapped. It was two extremes.” Lai said when the research team tried to find a connection between the samples and their ability to block HIV, they could not find a clear correlation.
Engineering polymer-binding bispecific antibodies for enhanced pretargeted delivery of nanoparticles to mucus-covered epitheliumAngewandte Chemie
Justin T. Huckaby, Christina L. Parker, Tim M. Jacobs, Alison Schaefer, Daniel Wadsworth, Alexander Nguyen, Anting Wang, Jay Newby, Samuel K. Lai
Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand‐conjugated particles often exhibit poor penetration across mucus. In this work, we explored a two‐step “pretargeting” approach through engineering a bispecific antibody that binds both cell‐surface ICAM‐1 and polyethylene glycol (PEG) on the surface of nanoparticles, thereby effectively decoupling cell targeting from particle design and formulation. When tested in a mucus‐coated Caco‐2 culture model that mimics the physiological process of mucus clearance, pretargeting increased the amount of PEGylated particles binding to cells by around 2‐fold or more compared to either non‐targeted or actively targeted PEGylated particles. Pretargeting also markedly enhanced particle retention in mouse intestinal tissues. Our work underscores pretargeting as a promising strategy to improve the delivery of therapeutics to mucosal surfaces.
Convolutional neural networks automate detection for tracking of submicron-scale particles in 2D and 3DProceedings of the National Academy of Sciences
Jay M. Newby, Alison M. Schaefer, Phoebe T. Lee, M. Gregory Forest, and Samuel K. Lai
The increasing availability of powerful light microscopes capable of collecting terabytes of high-resolution 2D and 3D videos in a single day has created a great demand for automated image analysis tools. Tracking the movement of nanometer-scale particles (e.g., virus, proteins, and synthetic drug particles) is critical for understanding how pathogens breach mucosal barriers and for the design of new drug therapies. Our advancement is to use an artificial neural network that provides, first and foremost, substantially improved automation. Additionally, our method improves accuracy compared with current methods and reproducibility across users and laboratories.
Herpes simplex virus binding IgG traps HSV in human cervicovaginal mucus across the menstrual cycle and diverse vaginal microbial compositionMucosal Immunology
Schroeder HA, Nunn KL, Schaefer A, Henry CE, Lam F, Pauly MH, Whaley KJ, Zeitlin L, Humphrys MS, Ravel J, Lai SK
IgG possesses an important yet little recognized effector function in mucus. IgG bound to viral surface can immobilize otherwise readily diffusive viruses to the mucin matrix, excluding them from contacting target cells and facilitating their elimination by natural mucus clearance mechanisms. Cervicovaginal mucus (CVM) is populated by a microbial community, and its viscoelastic and barrier properties can vary substantially not only across the menstrual cycle, but also in women with distinct microbiota. How these variations impact the “muco-trapping” effector function of IgGs remains poorly understood. Here we obtained multiple fresh, undiluted CVM specimens (n = 82 unique specimens) from six women over time, and employed high-resolution multiple particle tracking to quantify the mobility of fluorescent Herpes Simplex Viruses (HSV-1) in CVM treated with different HSV-1-binding IgG. The IgG trapping potency was then correlated to the menstrual cycle, and the vaginal microbial composition was determined by 16 s rRNA. In the specimens studied, both polyclonal and monoclonal HSV-1-binding IgG appeared to consistently and effectively trap HSV-1 in CVM obtained at different times of the menstrual cycle and containing a diverse spectrum of commensals, including G. vaginalis-dominant microbiota. Our findings underscore the potential broad utility of this “muco-trapping” effector function of IgG to reinforce the vaginal mucosal defense, and motivates further investigation of passive immunization of the vagina as a strategy to protect against vaginally transmitted infections.
A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchorsNature Communications
Newby J, Schiller J, Wessler T, Edelstein J, Forest MG, Lai SK
Biopolymeric matrices can impede transport of nanoparticulates and pathogens by entropic or direct adhesive interactions, or by harnessing “third-party” molecular anchors to crosslink nanoparticulates to matrix constituents. The trapping potency of anchors is dictated by association rates and affinities to both nanoparticulates and matrix; the popular dogma is that long-lived, high-affinity bonds to both species facilitate optimal trapping. Here we present a contrasting paradigm combining experimental evidence (using IgG antibodies and Matrigel®), a theoretical framework (based on multiple timescale analysis), and computational modeling. Anchors that bind and unbind rapidly from matrix accumulate on nanoparticulates much more quickly than anchors that form high-affinity, long-lived bonds with matrix, leading to markedly greater trapping potency of multiple invading species without saturating matrix trapping capacity. Our results provide a blueprint for engineering molecular anchors with finely tuned affinities to effectively enhance the barrier properties of biogels against diverse nanoparticulate species.
Modeling Neutralization Kinetics of HIV by Broadly Neutralizing Monoclonal Antibodies in Genital Secretions Coating the Cervicovaginal MucosaPLoS ONE
2014 ABSTRACT: Eliciting broadly neutralizing antibodies (bnAb) in cervicovaginal mucus (CVM) represents a promising “first line of defense” strategy to reduce vaginal HIV transmission. However, it remains unclear what levels of bnAb must be present in CVM to effectively reduce infection...
IgG in cervicovaginal mucus traps HSV and prevents vaginal Herpes infectionsMucosal Immunology
Wang YY, Kannan A, Nunn KL, Murphy M, Subramani DB, Moench TM, Cone RA, Lai SK
IgG is the predominant immunoglobulin in cervicovaginal mucus (CVM), yet how immunoglobulin G (IgG) in mucus can protect against infections is not fully understood. IgG diffuses rapidly through cervical mucus, slowed only slightly by transient adhesive interactions with mucins. We hypothesize that this almost unhindered diffusion allows IgG to accumulate rapidly on pathogen surfaces, and the resulting IgG array forms multiple weak adhesive crosslinks to mucus gel that effectively trap (immobilize) pathogens, preventing them from initiating infections. Here, we report that herpes simplex virus serotype 1 (HSV-1) readily penetrated fresh, pH-neutralized ex vivo samples of CVM with low or no detectable levels of anti-HSV-1 IgG but was trapped in samples with even modest levels of anti-HSV-1 IgG. In samples with little or no endogenous anti-HSV-1 IgG, addition of exogenous anti-HSV-1 IgG, affinity-purified from intravenous immunoglobulin, trapped virions at concentrations below those needed for neutralization and with similar potency as endogenous IgG. Deglycosylating purified anti-HSV-1 IgG, or removing its Fc component, markedly reduced trapping potency. Finally, a non-neutralizing IgG against HSV-gG significantly protected mice against vaginal infection, and removing vaginal mucus by gentle lavage abolished protection. These observations suggest that IgG-Fc has a glycan-dependent “muco-trapping” effector function that may provide exceptionally potent protection at mucosal surfaces.
Evading Immune Cell Uptake and Clearance Requires PEG Grafting at Densities Substantially Exceeding the Minimum for Brush ConformationMolecular Pharmaceutics
2014 ABSTRACT: Coating nanoparticles with polyethylene glycol (PEG), which reduces particle uptake and clearance by immune cells, is routinely used to extend the circulation times of nanoparticle therapeutics...
Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissuesAdvanced Drug Delivery Reviews
2009 ABSTRACT: Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates, including conventional particle-based drug delivery systems, are efficiently trapped in human mucus ...
Micro-and macrorheology of mucusAdvanced Drug Delivery Reviews
2009 ABSTRACT: Mucus is a complex biological material that lubricates and protects the human lungs, gastrointestinal (GI) tract, vagina, eyes, and other moist mucosal surfaces. Mucus serves as a physical barrier against foreign particles, including toxins, pathogens, and ...
Rapid transport of large polymeric nanoparticles in fresh undiluted human mucusProceedings of the National Academy of Sciences
2007 ABSTRACT: Nanoparticles larger than the reported mesh-pore size range (10–200 nm) in mucus have been thought to be much too large to undergo rapid diffusional transport through mucus barriers. However, large nanoparticles are preferred for higher drug ...