| Description |
As a nonimmunogenic biopolymer with diverse functions, immune-tolerant elastin-like polypeptides (iTEPs) have great potential to serve delivery systems for small molecules and for protein therapeutics. Lack of immunogenicity avoids possible neutralizing humoral immune responses that compromise therapeutic effects. iTEPs are composed of amino acids, which make iTEPs biocompatible and biodegradable. Flexible genetic engineering approaches allow introduction of functional amino acids or protein/peptide moieties. This dissertation describes delivery strategies of a small molecule chemotherapeutic drug, salinomycin, and production and characterization of an immunotherapy antibody, anti-programmed cell death protein 1 (αPD-1), by iTEPs for cancer treatments. To deliver salinomycin (Sali), two different strategies were employed with either salinomycin physically encapsulated in iTEP nanoparticles or covalently conjugated to an iTEP via a hydrazone bond. In the first strategy, salinomycin was encapsulated in iTEP nanoparticles formed by conjugating salinomycin to an iTEP via a nonreleasable amide bond. In the second strategy, salinomycin was conjugated to an iTEP via a releasable hydrazone bond, which released a derivative of salinomycin, Sali-ABA. Both delivery strategies showed therapeutic effects in 4T1 murine breast tumors. The second strategy, iv with salinomycin covalently conjugated to an iTEP, demonstrated a longer blood half-life than the first strategy and showed superior inhibition of primary tumors and tumor metastasis. In combination with paclitaxel, covalently conjugated salinomycin showed long-lasting inhibition of primary tumor growth and tumor metastasis surpassing monotherapies using paclitaxel or Sali-ABA. Delivery of an anti-PD-1 immunotherapeutic antibody was also explored by designing and generating a fusion protein between a αPD-1 single-chain variable fragment (scFv) and an amphiphilic block copolymer iTEP with a C-terminus cysteine tail. αPD-1 is presented on the particle surface when iTEP spontaneously forms micelle-like nanoparticles, which are stabilized by crosslinking of cysteine residues. This delivery strategy rescued the loss of binding affinity of αPD-1 scFv by multivalency effects and demonstrated similar PD-1-blocking efficiencies both in vivo and in vitro. |
