Abstract
Despite aggressive surgical resections and combinatorial chemoradiations, certain highly malignant
populations of tumor cells resurrect and metastasize. Mixed-grade cancer cells fail to respond to
standard-of-care therapies by developing intrinsic chemoresistance and subsequently result in tumor
relapse. Macroautophagy is a membrane trafficking process that underlies drug resistance and
tumorigenesis in most breast cancers. Manipulating cellular homeostasis by a combinatorial
nanotherapeutic model, one can evaluate the crosstalk between type I and type II cell death and
decipher the fate of cancer therapy. Here, we present a multi-strategic approach in cancer targeting to
mitigate the autophagic flux with subcellular toxicity via lysosome permeation, accompanied by
mitochondrial perturbation and apoptosis. In this way, a nanoformulation is developed with a unique
blend of a lysosomotropic agent, an immunomodulating sulfated-polysaccharide, an adjuvant
chemotherapeutic agent, and a monoclonal antibody as a broad-spectrum complex for combinatorial
nanotherapy of all breast cancers. To the best of our knowledge, this manuscript illustrates for the first
time the applications of advanced microscopic techniques such as electron tomography, threedimensional rendering and segmentation of subcellular interactions, and fate of the multifunctional
therapeutic gold nanocages specifically targeted toward breast cancer cells
populations of tumor cells resurrect and metastasize. Mixed-grade cancer cells fail to respond to
standard-of-care therapies by developing intrinsic chemoresistance and subsequently result in tumor
relapse. Macroautophagy is a membrane trafficking process that underlies drug resistance and
tumorigenesis in most breast cancers. Manipulating cellular homeostasis by a combinatorial
nanotherapeutic model, one can evaluate the crosstalk between type I and type II cell death and
decipher the fate of cancer therapy. Here, we present a multi-strategic approach in cancer targeting to
mitigate the autophagic flux with subcellular toxicity via lysosome permeation, accompanied by
mitochondrial perturbation and apoptosis. In this way, a nanoformulation is developed with a unique
blend of a lysosomotropic agent, an immunomodulating sulfated-polysaccharide, an adjuvant
chemotherapeutic agent, and a monoclonal antibody as a broad-spectrum complex for combinatorial
nanotherapy of all breast cancers. To the best of our knowledge, this manuscript illustrates for the first
time the applications of advanced microscopic techniques such as electron tomography, threedimensional rendering and segmentation of subcellular interactions, and fate of the multifunctional
therapeutic gold nanocages specifically targeted toward breast cancer cells
| Original language | English |
|---|---|
| Pages (from-to) | 989-1001 |
| Journal | Nanoscale Advances |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Mar 2019 |