# BC-mediated delivery of thromboprophylaxis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $666,613

## Abstract

No anti-thrombotic agent (ATA) is safe and effective in the many patients at a combined risk of
acute thrombosis and bleeding, e.g., in the early post-surgery period. To address this unmet need, we
develop drug delivery systems (DDS) executing two main functions: A) Block access of ATA to off-
target sites, e.g., hemostatic plugs formed after surgery, while B) Optimize pharmacokinetics and
deliver ATA into subsequent thrombi, where ATA is activated by thrombin. ATA fused with single-
chain fragments (scFv) targeted to red blood cells (RBC) bind to these carriers that execute dual
blocking/delivering function. Proof-of-concept is emerging in models of pre-existing and nascent clots
in animals. Here we devise humanized scFv/ATA targeted to human RBC and will test them in a
humanized microfluidic system (HMF), in transgenic (TG) mice expressing humanized target epitopes
on blood cells, and in the perfusion of isolated human lungs. We will pursue three aims. Aim 1. RBC
loading. We will characterize scFv/ATA loading onto RBC: A) Binding (copies/cell, on/off kinetics); B)
Effect on RBC functionality, biocompatibility and biomechanics; and, B) Regulation of distribution of
scFv/ATA between RBC in circulation. We also will characterize biomechanical factors modulating
RBC/ATA delivery and effect on clot dynamics and structure, in particular, impact of RBC
rigidification, caused by either drug loading or by intrinsic pathophysiological changes in patient's
blood. Aim 2. Mechanistic insights. We will interrogate previously unrecognized yet critically
aspects of the RBC/ATA workings, in particular their interaction with vascular endothelium and
transfer of the drug cargo to these and other vascular cells. In this Aim we will use standard mouse in
vivo models, microfluidic model and perfusion of isolated human lungs model. Aim 3. Appraisal of
benefit/risk ratio. We are developing TM mice expressing human RBC determinants in mouse EBC,
in order to study scFv/ATA loaded on "human RBC" in vivo: A) PK/BD, complement activation,
phagocyte uptake and vascular adhesion of RBC/ATA in TG mice; B) Define the time window/extent
of anti-thrombotic effect of human RBC/ATA in models of arterial vs venous thrombosis in TG mice;
B) Affirm the safety of RBC/ATA. We will detect adversities of scFv/ATA including abnormalities of
RBC. To defuse potential issues, if necessary, we will use more benign loading regimen. Together,
these studies will advance mechanistic insights and clinical translation of a novel way to mitigate
thrombosis in currently unprotected patients by providing a new and tractable approach to
understanding thrombus development and a rational approach to deliver cell-directed therapeutics

## Key facts

- **NIH application ID:** 10475755
- **Project number:** 5R01HL159256-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vladimir R Muzykantov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $666,613
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475755

## Citation

> US National Institutes of Health, RePORTER application 10475755, BC-mediated delivery of thromboprophylaxis (5R01HL159256-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10475755. Licensed CC0.

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