Multifunctionalized biocatalytic P22 nanoreactor for combinatory treatment of ER+ breast cancer

Abstract

BackgroundTamoxifen is the standard endocrine therapy for breast cancers, which require metabolic activation by cytochrome P450 enzymes (CYP). However, the lower and variable concentrations of CYP activity at the tumor remain major bottlenecks for the efficient treatment, causing severe side-effects. Combination nanotherapy has gained much recent attention for cancer treatment as it reduces the drug-associated toxicity without affecting the therapeutic response.ResultsHere we show the modular design of P22 bacteriophage virus-like particles for nanoscale integration of virus-driven enzyme prodrug therapy and photodynamic therapy. These virus capsids carrying CYP activity at the core are decorated with photosensitizer and targeting moiety at the surface for effective combinatory treatment. The estradiol-functionalized nanoparticles are recognized and internalized into ER+ breast tumor cells increasing the intracellular CYP activity and showing the ability to produce reactive oxygen species (ROS) upon UV365 nm irradiation. The generated ROS in synergy with enzymatic activity drastically enhanced the tamoxifen sensitivity in vitro, strongly inhibiting tumor cells.ConclusionsThis work clearly demonstrated that the targeted combinatory treatment using multifunctional biocatalytic P22 represents the effective nanotherapeutics for ER+ breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0345-2) contains supplementary material, which is available to authorized users.

Virus‐Based Nanomotors for Cargo Delivery

“…VLPs have been utilized to encapsulate diverse materials, such as metallic nanoparticles, drugs,, DNA,, RNAs,, proteins and enzymes,,, to obtain new materials, nanoreactors and delivery systems.…”

“…The protein nature of VLPs makes them easily functionalized with different ligands for recognizing specific receptors on the cell surface ,,. Different cell penetrating peptides CPP, have been used to penetrate cells and deliver cargo into specific compartments and specific ligands for targeting specific cell or tissues .…”

“…Different cell penetrating peptides CPP, have been used to penetrate cells and deliver cargo into specific compartments and specific ligands for targeting specific cell or tissues . In addition, the presence of reactive groups in the capsid surface could be used to cover the virus nanomotors with polyethylene glycol or other polymer to render them invisible (or stealth) for macrophages to reducing their immunogenicity ,. Further modification of the JVNs can be made to improve the efficiency and selectivity of internalization of our nanoparticles.…”

“…The conventional tamoxifen dose, in its different forms, varies from 5 mg/day or 10 mg on alternate days or 20 mg per week, as recommended by the European Institute of Oncology (EIO) in the clinical guidelines for management of hormone‐responsive ductal carcinoma in situ of the breast (www.ieo.it/en/). The JVNs could be functionalized and specifically targeted to tumor tissue, reducing the dose needed and increasing the treatment efficiency, as has been demonstrated in VLPs ,…”

“…Importantly, VLPs can be functionalized with specific ligands to be targeted or conjugated with other molecules to form more complex nanoparticles . The VLPs as nanocarriers show several advantages such as the cargo protection avoiding the direct interaction with the environment, absorption improvement, specific targeting of its cargo, and a better‐controlled distribution of the carried substances ,,. In addition, as protein‐based nanoparticles, VLPs show a considerable potential for biomedical applications owing to their biocompatibility, versatility, safety, and ability to protect their cargo.…”