Gold nanoparticle delivery to solid tumors: a multiparametric study on particle size and the tumor microenvironment.

Nanoparticle (NP) delivery to solid tumors remains an actively studied field, where several recent studies have shed new insights into the underlying mechanisms and the still overall poor efficacy. In the present study, Au NPs of different sizes were used as model systems to address this topic, where delivery of the systemically administered NPs to the tumor as a whole or to tumor cells specifically was examined in view of a broad range of tumor-associated parameters. Using non-invasive imaging combined with histology, immunohistochemistry, single-cell spatial RNA expression and image-based single cell cytometry revealed a size-dependent complex interaction of multiple parameters that promoted tumor and tumor-cell specific NP delivery. Interestingly, the data show that most NPs are sequestered by tumor-associated macrophages and cancer-associated fibroblasts, while only few NPs reach the actual tumor cells. While perfusion is important, leaky blood vessels were found not to promote NP delivery, but rather that delivery efficacy correlated with the maturity level of tumor-associated blood vessels. In line with recent studies, we found that the presence of specialized endothelial cells, expressing high levels of CD276 and Plvap promoted both tumor delivery and tumor cell-specific delivery of NPs. This study identifies several parameters that can be used to determine the suitability of NP delivery to the tumor region or to tumor cells specifically, and enables personalized approaches for maximal delivery of nanoformulations to the targeted tumor.

Inorganic Nanoparticles Change Cancer-Cell-Derived Extracellular Vesicle Secretion Levels and Cargo Composition, Resulting in Secondary Biological Effects.

Over the past decades, the medical exploitation of nanotechnology has been largely increasing and finding its way into translational research and clinical applications. Despite their biomedical potential, uncertainties persist regarding the intricate role that nanomaterials may play on altering physiology in healthy and diseased tissues. Extracellular vesicles (EVs) are recognized as an important pathway for intercellular communication and known to be mediators of cellular stress. EVs are currently explored for targeted delivery of therapeutic agents, including nanoformulations, to treat and diagnose cancer or other diseases. Here, we aimed to investigate whether nanomaterials could have a possible impact on EV functionality, their safety, and whether EVs can play a role in nanomaterial toxicity profiles. To evaluate this, the impact of inorganic nanomaterial administration on EVs derived from murine melanoma and human breast cancer cells was tested. Cells were incubated with subtoxic concentrations of 4 different biomedically relevant inorganic nanoparticles (NPs): gold, silver, silicon dioxide, or iron oxide. The results displayed a clear NP and cell-type-dependent effect on increasing or decreasing EV secretion. Furthermore, the expression pattern of several EV-derived miRNAs was significantly changed upon NP exposure, compared to nontreated cells. Detailed pathway analysis and additional studies confirmed that EVs obtained from NP-exposed cells could influence immunological responses and cellular physiology. Together, these data reveal that NPs can have wide-ranging effects which can result in toxicity concerns or enhanced therapeutic potential as a secondary enhanced effect mediated and enhanced by EVs.

Nanomaterial-Mediated Delivery of MLKL Plasmids Sensitizes Tumors to Immunotherapy and Reduces Metastases.

Cancer immunotherapy has emerged as a promising approach for the induction of an antitumor response. While immunotherapy response rates are very high in some cancers, the efficacy against solid tumors remains limited caused by the presence of an immunosuppressive tumor microenvironment. Induction of immunogenic cell death (ICD) in the tumor can be used to boost immunotherapy response in solid cancers by eliciting the release of immune-stimulatory components. However, the delivery of components inducing ICD to tumor sites remains a challenge. Here, a novel delivery method is described for antitumor therapy based on MLKL (Mixed Lineage Kinase Domain-Like), a key mediator of necroptosis and inducer of ICD. A novel highly branched poly (ß-amino ester)s (HPAEs) system is designed to efficiently deliver MLKL plasmid DNA to the tumor with consequent enhancement of immune antigen presentation for T cell responses in vitro, and improved antitumor response and prolonged survival in tumor-bearing mice. Combination of the therapy with anti-PD-1 treatment revealed significant changes in the composition of the tumor microenvironment, including increased infiltration of CD8+ T cells and tumor-associated lymphocytes. Overall, the HPAEs delivery system can enhance MLKL-based cancer immunotherapy and promote antitumor immune responses, providing a potential treatment to boost cancer immunotherapies.

The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co-Administration Depends on Neuropilin-1 and Neutrophil Levels.

The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.