Nanotechnology and nano-sized tools: Newer approaches to circumvent oncolytic adenovirus limitations.

Oncolytic adenoviruses (OAds), engineered Ads preferentially infect and lyse tumor cells, have attracted remarkable attention as immunotherapy weapons for the treatment of various malignancies. Despite hopeful successes in preclinical investigations and translation into clinical phases, they face some challenges that thwart their therapeutic effectiveness, including low infectivity of cancer cells, liver sequestration, pre-existing neutralizing antibodies, physical barriers to the spread of Ads, and immunosuppressive TME. Nanotechnology and nano-sized tools provide several advantages to overcome these limitations of OAds. Nano-sized tools could improve the therapeutic efficacy of OAds by enhancing infectivity and cellular uptake, targeting and protecting from pre-existing immune responses, masking and preventing liver tropism, and co-delivery with other therapeutic agents. Herein, we reviewed the constructs of various OAds and their application in clinical trials, as well as the limitations they have faced. Furthermore, we emphasized the potential applications of nanotechnology to solve the constraints of OAds to improve their anti-tumor activities.

Heterologous administration of HPV16 E7 epitope-loaded nanocomplexes inhibits tumor growth in mouse model.

The nanostructured complexes can result in enhanced vaccine efficacy by facilitating the distribution and uptake of antigens by antigen-presenting cells (APCs), thereby stimulating immune responses. Here, we hypothesized that either directly coating of nanoadjuvants including aluminum phosphate (AlPO4) and adenovirus (Ad) with a modified HPV16 E7 MHC-I specific epitope, RAHYNIVTF49-57, or mixing the CpG oligodeoxynucleotide (CpG-ODN) with the cationic epitope to form nanocomlexes, and their combinational therapy would enhance their anti-tumor effects in a TC-1 mouse model. The positively-charged HPV16 E7 epitope was attracted to the oppositely-charged adjuvants by electrostatic interaction to generate epitope/adjuvant nanocomplexes. We showed that coating the nanosized adjuvants with the cationic epitope increased the particles' surface charge without significant change in their size. We then tested the cellular immunogenicity and therapeutic efficacy of nanocomplexes by measuring IL-10 and IFN-γ production, the expression of CD107a as a marker of CTL response, and tumor growth inhibition. The nanocomplexes were administered either in homologous or heterologous prime-boost regimens, and heterologous immunizations including Ad/Pep-CpG/Pep, CpG/Pep-Ad/Pep, Ad/Pep-Alum/Pep, and Alum/Pep-Ad/Pep induced significantly higher levels of IL-10, IFN-γ, and CD107a-expressing CD8 T cells compared with homologous administrations. Furthermore, the tumor growth was significantly suppressed in mice receiving nanostructured complexes in the heterologous immunizations. Our study highlights the potential of the heterologous prime-boost administration of the epitope-coated nanostructures as an effective immunization strategy.