"Nanoantibiotics": a new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era.

Current medical imaging technologies allow visualization of tissue anatomy in the human body at resolutions ranging from 100 micrometers to 1 millimeter. These technologies are generally not sensitive enough to detect early-stage tissue abnormalities associated with diseases such as cancer and atherosclerosis, which require micrometer-scale resolution. Here, optical coherence tomography was adapted to allow high-speed visualization of tissue in a living animal with a catheter-endoscope 1 millimeter in diameter. This method, referred to as "optical biopsy," was used to obtain cross-sectional images of the rabbit gastrointestinal and respiratory tracts at 10-micrometer resolution.

In Vivo Endoscopic Optical Biopsy with Optical Coherence Tomography

Prior studies suggested that nanoparticle drug delivery might improve the therapeutic response to anticancer drugs and allow the simultaneous monitoring of drug uptake by tumors. We employed modified PAMAM dendritic polymers <5 nm in diameter as carriers. Acetylated dendrimers were conjugated to folic acid as a targeting agent and then coupled to either methotrexate or tritium and either fluorescein or 6-carboxytetramethylrhodamine. These conjugates were injected i.v. into immunodeficient mice bearing human KB tumors that overexpress the folic acid receptor. In contrast to nontargeted polymer, folate-conjugated nanoparticles concentrated in the tumor and liver tissue over 4 days after administration. The tumor tissue localization of the folate-targeted polymer could be attenuated by prior i.v. injection of free folic acid. Confocal microscopy confirmed the internalization of the drug conjugates into the tumor cells. Targeting methotrexate increased its antitumor activity and markedly decreased its toxicity, allowing therapeutic responses not possible with a free drug.

https://cancerres.aacrjournals.org/content/canres/65/12/5317.full.pdf

Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer

Interaction of poly(amidoamine) dendrimers with supported lipid bilayers and cells: hole formation and the relation to transport.

Nanotechnology uses the unique properties of objects that function as a unit within the overall size range of 1-1,000 nanometres. The engineering of nanostructure materials, including nanoparticles, nanoemulsions or nanotubules, holds great promise for the development of new immunomodulatory agents, as such nanostructures can be used to more effectively manipulate or deliver immunologically active components to target sites. Successful applications of nanotechnology in the field of immunology will enable new generations of vaccines, adjuvants and immunomodulatory drugs that aim to improve clinical outcomes in response to a range of infectious and non-infectious diseases.

/pdf/applications-of-nanotechnology-for-immunology-2o88hq2pjc.pdf

Applications of nanotechnology for immunology

Development of immune response that protects mice from viral pneumonitis after a single intranasal immunization with influenza A virus and nanoemulsion.

http://www.dmphotonics.com/Femtosecond_Imaging/Thomas_BiophysJ_04.pdf

Detection and analysis of tumor fluorescence using a two-photon optical fiber probe.

Our earlier studies have shown the in vitro and in vivo targeting of a generation 5 (G5) dendrimer-based multifunctional conjugate that contained folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeutic drug. To clinically apply the synthesized G5-FA-MTX nanotherapeutic, it is important that the anticancer conjugate elicits cytotoxicity specifically and consistently. Toward this objective, we evaluated the large-scale synthesis of a G5-FA-MTX conjugate (Lot # 123-34) for its cytotoxic potential and specificity in vitro and in vivo. The cytotoxicity and specificity were tested by using a coculture assay in which FA receptor-expressing and nonexpressing cells (KB and SK-BR-3 cells, respectively) were cultured together and preferential killing was examined. The in-vitro data were compared with the in-vivo data obtained from a heterogeneous xenograft tumor model. The animal model of the artificial heterogeneous xenograft tumor showed that the nanotherapeutic was preferentially cytotoxic to KB cells.

Targeting the efficacy of a dendrimer-based nanotherapeutic in heterogeneous xenograft tumors in vivo.

Rationale New anthrax vaccines involve immunization with rPA, an immunologic target of antibodies that neutralize anthrax toxin. We have evaluated a non-toxic nanoemulsion as an adjuvant for intramuscular (IM) and intranasal (IN) immunization with rPA. Methods Balb/c mice were immunized with three monthly administrations of 2.5 and 25 ug rPA. The protein was given alone, in a solution of 1% nanoemulsion or with the nanoemulsion and CpG-rich oligonucleotides. Results IM injections of rPA with nanoemulsion resulted in higher titers of anti-PA IgG than IM administration of antigen alone, particularly with low doses of rPA. In contrast, nanoemulsion was absolutely required for the development of immunity after IN administration since anti-PA specific IgA (in bronchial lavage) and IgG (in serum) were observed only in animals receiving in rPA with nanoemulsion, whether or not CpG was present. No animal immunized IM with rPA developed a mucosal antibody response. rPA specific splenocyte activation was demonstrated by proliferative responses in vitro and was accompanied by markedly increased production of INFγ and TNFα, indicating that TH1 responses were induced by the nanoemulsion. Nanoemulsion increased in vitro binding of rPA to dendritic cells but not lymphocytes, suggesting dendritic cells participate in the induction of rPA mucosal immunity after IN immunization. Conclusions Nanoemulsions may serve as useful adjuvants for recombinant anthrax vaccines.

https://www.jacionline.org/article/S0091-6749(04)00532-9/pdf

Enhanced systemic and mucosal immune responses in mice immunized with recombinant Bacillus anthracis protective antigen (rPA) using a novel nanoemulsion adjuvant

We demonstrate the capability of a two-photon optical fiber fluorescence (TPOFF) probe for quantitative, in vivo fluorescence measurements in mice tumors.

Peter Cao

Papers

Development of immune response that protects mice from viral pneumonitis after a single intranasal immunization with influenza A virus and nanoemulsion.

Detection and analysis of tumor fluorescence using a two-photon optical fiber probe.

Targeting the efficacy of a dendrimer-based nanotherapeutic in heterogeneous xenograft tumors in vivo.

Enhanced systemic and mucosal immune responses in mice immunized with recombinant Bacillus anthracis protective antigen (rPA) using a novel nanoemulsion adjuvant

Quantitative, in vivo fluorescence measurements with a two-photon fiber probe