Rational design of affinity-based peptide carriers and transport modeling
The transport and binding behavior of solutes inside tissues is a complex function of a wide range of parameters. This project focuses on determining the rules of combination of size, net electric charge and its spatial distribution, hydrophobicity, and effects of other binding interactions to design polypeptide-based carriers for targeting tissues of varying fixed charge density. We use both experiments and theoretical transport models to rationally design nanocarriers for delivery of wide range of biological entities including small molecules, protein growth factors, antibodies and gene materials that can penetrate through the dense negatively charged tissue matrix barriers and reach their target site.
Representative Papers
- Vedadghavami A, He T, Zhang C, Amiji SM, Hakim B, Bajpayee AG. Charge-based drug delivery to cartilage: Hydrophobic and not electrostatic interactions are the dominant cause of competitive binding of cationic carriers in synovial fluid. Acta Biomater. (2022) Read
- Warren MR, Vedadghavami A, Bhagavatula S, Bajpayee AG. Effects of polycationic drug carriers on the electromechanical and swelling properties of cartilage. Biophysical J. (2022) Read
- Vedadghavami A, Wagner EK, Mehta S, He T, Zhang C, Bajpayee AG. Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues. Acta Biomat. (2019) Read
Perspective Articles
- Mehta S, He T, Bajpayee AG. Recent advances in targeted drug delivery for treatment of osteoarthritis. Curr Opin Rheumatol. (2021) Read
- Vedadghavami A, Zhang C, Bajpayee AG. Overcoming negatively charged tissue barriers: Drug delivery using cationic peptides and proteins. Nano Today. (2020) Read
- Young CC, Vedadghavami A, Bajpayee AG. Bioelectricity for Drug Delivery: The Promise of Cationic Therapeutics. Bioelectricity. (2020) Read
Multi-arm avidin protein as a charge-based drug delivery platform
Targeted drug delivery to joint tissues like cartilage remains a challenge that has prevented clinical translation of promising osteoarthritis (OA) drugs. Local intra-articular (IA) injections of drugs suffer from rapid clearance from the joint space and slow diffusive transport through the dense, avascular cartilage matrix comprised of negatively charged GAGs. We have designed a multi-arm cationic nano-construct of Avidin (mAv) that can be covalently conjugated with small molecule drugs using hydrolysable linkers. The construct can rapidly penetrate through the full thickness of cartilage in high concentration and have long intra-cartilage residence time in both healthy and arthritic cartilage via weak-reversible binding with negatively charged aggrecans.
Representative Papers
- He T, Zhang C, Colombani T, Bencherif SA, Porter RM, Bajpayee AG. Intra-articular kinetics of a cartilage targeting cationic PEGylated protein for applications in drug delivery. Osteoarthritis Cartilage. (2022) Read
- He T, Shaw I, Vedadghavami A, Bajpayee AG. Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism. Cartilage. (2022) Read
- Wagner EK, Vedadghavami A, Jacobsen TD, Goel SA, Chahine NO, Bajpayee AG. Avidin grafted dextran nanostructure enables a month-long intra-discal retention. Sci Rep. (2020) Read
- Bajpayee AG, Quadir MA, Hammond PT, Grodzinsky AJ. Charge based intra-cartilage delivery of single dose dexamethasone using Avidin nano-carriers suppresses cytokine-induced catabolism long term. Osteoarthritis Cartilage. (2016) Read
Exosome-based carriers for targeting charged tissues like cartilage and mucin
Cationic exosomes for cartilage repair: MSC derived exosomes are emerging as promising therapeutics for OA as they carry proteins and genetic materials that induce regenerative processes like cell migration, proliferation, differentiation and matrix synthesis. The negative charge of exosome lipid bilayer, however, hinders their penetration into the negatively charged cartilage. Their intrinsic therapeutic potential can be enhanced by making them cartilage penetrating and binding such that they have longer joint residence time and can effectively reach cell targets. We have, for the first time, demonstrated charge reversal on exosome surface and shown significantly enhanced cartilage targeting.
Mucus penetrating milk exosomes for oral drug delivery: We have engineered high purity milk exosomes (mExo) with modular surface tunability for oral delivery of siRNA by utilizing a low- cost enrichment method combining casein chelation with differential ultracentrifugation. PEGylated mExo penetrated through the mucin and exhibited high uptake by intestinal epithelial cells and mediated functional intra-cellular delivery of siRNA.
Papers
- Warren MR, Zhang C, Vedadghavami A, Bokvist K, Dhal PK, Bajpayee AG. Milk exosomes with enhanced mucus penetrability for oral delivery of siRNA. Biomater Sci. (2021) Read
- In Progress