Enzyme-Prodrug Therapies

Targeted enzyme prodrug therapy, in which an exogenous enzyme is used to locally convert a non-toxic prodrug into a potent toxic agent at the site of a tumor, has been a conceptually attractive alternative to the toxicities that limit systemic chemotherapies. However, enzyme prodrug therapies have encountered numerous obstacles that have limited their development. These include targeting the enzyme to the cancer, identifying biologically compatible prodrug/drug/enzyme combinations, immunogenicity of foreign enzymes, and the need to clear the enzyme from the non-cancerous regions prior to prodrug administration. DevaCell’s novel nanoparticle carrier SHELS solves these problems by encapsulating the enzyme in a porous silica shell, initially synthesized with large pores that are sealed after enzyme loading, which allow diffusion of the prodrug and drug while preventing antibodies or other larger proteins from interacting with the enzyme.

The outside of the SHELS are decorated with PEG to extend circulation time as well as a peptide mimetope ligand for assisted clearance with a monoclonal antibody such as trastuzumab. When given intravenously (iv), SHELS accumulate in tumors through the enhanced permeation and retention phenomenon (EPR) associated with leaky tumor vasculature. Once sufficient accumulation obtained, SHELS still present systemically are cleared by addition of monoclonal antibody which binds to the mimetope peptide on SHELS surface and enhances their clearance by the reticuloendothelial system and tissue macrophages. Subsequently, prodrug is administered systemically where it is converted to cytotoxic drug by the enzymes within SHELS localized to tumor and metastatic lesions. For visible and accessible tumors, SHELS can also be administered intra-tumorally prior to prodrug administration. While cytotoxic drugs, when injected intra-tumorally quickly diffuse out from the tumor, SHELS get retained within tumor tissue for extended durations owing to their large size.

Nanoparticle-mediated enzyme delivery (for enzyme-prodrug therapy) offers significant advantages in comparison with the delivery of nanoparticles filled directly with cytotoxic drugs. First advantage is the enzymatic amplification; nanoparticles filled with enzymes, when localized to tumor, are capable of producing several orders more cytotoxic drug than can be delivered using drug-loaded nanoparticles. Secondly, systemically-administered prodrug regimen can be fine-tuned from patient to patient allowing a more personalized therapy. Third, off-target particles loaded with enzymes potentially cause reduced side effects because enzymes cleared by the macrophages substantially lose their activity within the endosomes.