Nanoparticle Interactions with the Tumor Microenvironment.

Compared to normal tissues, the tumor microenvironment (TME) has a number of aberrant characteristics including hypoxia, acidosis, and vascular abnormalities. Many researchers have sought to exploit these anomalous features of the TME to develop anticancer therapies, and several nanoparticle-based cancer therapeutics have resulted. In this Review, we discuss the composition and pathophysiology of the TME, introduce nanoparticles (NPs) used in cancer therapy, and address the interaction between the TME and NPs. Finally, we outline both the potential problems that affect TME-based nanotherapy and potential strategies to overcome these challenges.

Gold Nanoparticles sensitize pancreatic cancer cells to gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid cancers with dismal prognosis. Several mechanisms that are mainly responsible for aggressiveness and therapy resistance of PDAC cells include epithelial to mesenchymal transition (EMT), stemness and Mitogen Activated Protein Kinase (MAPK) signaling. Strategies that inhibit these mechanisms are critically important to improve therapeutic outcome in PDAC. In the current study, we wanted to investigate whether gold nanoparticles (AuNPs) could sensitize pancreatic cancer cells to the chemotherapeutic agent gemcitabine. We demonstrated that treatment with AuNPs of 20 nm diameter inhibited migration and colony forming ability of pancreatic cancer cells. Pre-treatment with AuNPs sensitized pancreatic cancer cells to gemcitabine in both viability and colony forming assays. Mechanistically, pre-treatment of pancreatic cancer cells with AuNPs decreased gemcitabine induced EMT, stemness and MAPK activation. Taken together, these findings suggest that AuNPs could be considered as a potential agent to sensitize pancreatic cancer cells to gemcitabine.

Gold Nanoparticles Disrupt Tumor Microenvironment - Endothelial Cell Cross Talk To Inhibit Angiogenic Phenotypes in Vitro.

It is currently recognized that perpetual cross talk among key players in tumor microenvironment such as cancer cells (CCs), cancer associated fibroblasts (CAFs), and endothelial cells (ECs) plays a critical role in tumor progression, metastasis, and therapy resistance. Disruption of the cross talk may be useful to improve the outcome of therapeutics for which limited options are available. In the current study we investigate the use of gold nanoparticles (AuNPs) as a therapeutic tool to disrupt the multicellular cross talk within the TME cells with an emphasis on inhibiting angiogenesis. We demonstrate here that AuNPs disrupt signal transduction from TME cells (CCs, CAFs, and ECs) to ECs and inhibit angiogenic phenotypes in vitro. We show that conditioned media (CM) from ovarian CCs, CAFs, or ECs themselves induce tube formation and migration of ECs in vitro. Migration of ECs is also induced when ECs are cocultured with CCs, CAFs, or ECs. In contrast, CM from the cells treated with AuNPs or cocultured cells pretreated with AuNPs demonstrate diminished effects on ECs tube formation and migration. Mechanistically, AuNPs deplete ∼95% VEGF165 from VEGF single-protein solution and remove up to ∼45% of VEGF165 from CM, which is reflected on reduced activation of VEGF-Receptor 2 (VEGFR2) as compared to control CM. These results demonstrate that AuNPs inhibit angiogenesis via blockade of VEGF-VEGFR2 signaling from TME cells to endothelial cells.

Evolutionary selection of personalized melanoma cell/tissue dual-homing peptides for guiding bionanofibers to malignant tumors.

Both melanoma cells and tissues were allowed to interact with an identical pool of billions of human-safe phage nanofiber clones with each genetically displaying a unique 12-mer peptide at the tips, respectively, resulting in the discovery of bionanofibers displaying a melanoma cell/tissue dual-homing peptide for personalized targeted melanoma therapy.

Tuning photothermal properties of gold nanodendrites for in vivo cancer therapy within a wide near infrared range by simply controlling their degree of branching.

Although dendritic nanoparticles have been prepared by many different methods, control over their degree of branching (DB) is still impossible, preventing us from understanding the effect of the DB on the properties of the nanodendrites as cancer therapeutics. Herein, we developed a novel seed-mediated method to prepare gold nanodendrites (AuNDs) in an organic solvent using long chain amines as a structural directing agent. We discovered that the DB could be tuned facilely by simply adjusting synthetic parameters, such as the solvent type, the type and concentration of the long chain amines. We found that DB tuning resulted in dramatic tunability in the optical properties in the near infrared (NIR) range, which led to significantly different performance in the photothermal cancer therapy. Our in vitro and in vivo studies revealed that AuNDs with a higher DB were more efficient in photothermal tumor destruction under a lower wavelength NIR irradiation. In contrast, those with a lower DB performed better in tumor destruction under a higher wavelength NIR irradiation, indicating that AuNDs of even lower DB should have even better photothermal cancer therapy efficiency within the second NIR window. Thus, the tunable optical properties of AuNDs in the NIR range allow us to selectively determine a suitable laser wavelength for the best cancer therapeutic performance.

Genetically Engineered Virus Nanofibers as an Efficient Vaccine for Preventing Fungal Infection.

Candida albicans (CA) is a kind of fungus that can cause high morbidity and mortality in immunocompromised patients. However, preventing CA infection in these patients is still a daunting challenge. Herein, inspired from the fact that immunization with secreted aspartyl proteinases 2 (Sap2) can prevent the infection, it is proposed to use filamentous phage, a human-safe virus nanofiber specifically infecting bacteria (≈900 nm long and 7 nm wide), to display an epitope peptide of Sap2 (EPS, with a sequence of Val-Lys-Tyr-Thr-Ser) on its side wall and thus serve as a vaccine for preventing CA infection. The engineered virus nanofibers and recombinant Sap2 (rSap2) are then separately used to immunize mice. The humoral and cellular immune responses in the immunized mice are evaluated. Surprisingly, the virus nanofibers significantly induce mice to produce strong immune response as rSap2 and generate antibodies that can bind Sap2 and CA to inhibit the CA infection. Consequently, immunization with the virus nanofibers in mice dramatically increases the survival rate of CA-infected mice. All these results, along with the fact that the virus nanofibers can be mass-produced by infecting bacteria cost-effectively, suggest that virus nanofibers displaying EPS can be a vaccine candidate against fungal infection.

Bacteriophage bionanowire as a carrier for both cancer-targeting peptides and photosensitizers and its use in selective cancer cell killing by photodynamic therapy.

A photosensitizer, pyropheophorbid-a (PPa), is conjugated to SKBR-3 breast cancer cell-specific biological nanowire phage, to form a novel PPa-phage complex, which is further successfully used in selectively killing SKBR-3 breast cancer cells by the mechanism of photodynamic therapy (PDT).