Nanoparticle targeting of neutrophil improves cancer therapy

Xutong Shi

doi:10.7273/000003954

In recent years, nanoparticle-based drug delivery systems have gained remarkable attention for cancer treatment since they can improve the safety of highly toxic anti-cancer agents. Conventionally, nanoparticles delivery of anticancer drugs to tumor tissues can be achieved by the enhanced permeability and retention effect. However, this passive mode of drug delivery has intrinsic limitations, such as tumor heterogeneity, that diminish tumor targeting specificity. A new concept has emerged, that of nanotherapeutics which selectively target immune cells to mediate drug delivery into tumors. This work focuses on a novel strategy to increase the delivery of nanotherapeutics to tumors by using neutrophils loaded with chemotherapeutics-containing nanoparticles to target photoactivatable tumors, and by taking advantage of the acidic microenvironment of tumors for selective pH-dependent drug release. The novel strategy we studied combines photodynamic therapy to stimulate inflammation around tumors and attract neutrophils charged with acid-pH sensitive, drug-containing, protein-based nanoparticles. Photodynamic therapy usually consists of three components: a photosensitizer, light and tissue oxygen. We proposed a novel approach by combining monoclonal antibody-photosensitizer conjugates and the laser light to induce inflammation in a tumor. For the targeted release of chemotherapeutic drugs, we designed a novel model of drug-containing nanoparticles in which the release of the drug is selectively activated by the acid microenvironment of tumors. This model was studied and validated using DOX-cis-BSA nanoparticles as prototypes. In DOX-cis-BSA nanoparticles, doxorubicin (DOX), a widely used chemotherapeutic agent, is attached to bovine serum albumin (BSA) via a pH-sensitive linker, cis-aconitic anhydride (cis). This linker readily hydrolyzes in the acidic tumoral environment, thus providing tumor-selective release of DOX. In summary, this thesis is aimed at developing a new type of nanoparticles that can be internalized by neutrophils to mediate the delivery of an anticancer drug to tumors after photodynamic therapy. Our work demonstrates that 1) inflammation can be successfully induced by laser-light in tumors labeled with tumor-specific monoclonal antibody-photosensitizer conjugates, and 2) acid-pH sensitive DOX-cis-BSA nanoparticles can be successfully synthesized. Our data provide feasibility evidence for the development of a novel delivery platform for chemotherapeutic drugs and suggest potential effectiveness of our new approach in cancer treatment.

Nanoparticle targeting of neutrophil improves cancer therapy

Files and links (1)

Abstract

Metrics

Details