The interface of bio-nano science and cancer medicine is an area experiencing much progress but also beset with controversy. Core concepts of the field-e.g., the enhanced permeability and retention (EPR) effect, tumor targeting and accumulation, and even the purpose of "nano" in cancer medicine-are hotly debated. In parallel, considerable advances in neighboring fields are occurring rapidly, including the recent progress of "immuno-oncology" and the fundamental impact it is having on our understanding and the clinical treatment of the group of diseases collectively known as cancer. Herein, we (i) revisit how cancer is commonly treated in the clinic and how this relates to nanomedicine; (ii) examine the ongoing debate on the relevance of the EPR effect and tumor targeting; (iii) highlight ways to improve the next-generation of nanomedicines; and (iv) discuss the emerging concept of working with (and not against) biology. While discussing these controversies, challenges, emerging concepts, and opportunities, we explore new directions for the field of cancer nanomedicine.

/pdf/bridging-bio-nano-science-and-cancer-nanomedicine-3qomlpmby8.pdf

Bridging Bio-Nano Science and Cancer Nanomedicine

Monoclonal antibodies to tumour-associated antigens have great theoretical potential for the specific targeting of radioactivity and anti-neoplastic agents to tumours. The clinical success of monoclonal antibody—based cancer diagnosis and therapy depends, however, on solving a number of pharmacokinetic delivery problems. These include: (i) slow elimination of monoclonal antibodies from the blood and poor vascular permeability; (ii) low and heterogeneous tumour uptake; (iii) cross-reactivity with normal tissues; (iv) metabolism of monoclonal antibody conjugates; and (v) immunogenicity of murine forms in humans.

Problems of delivery of monoclonal antibodies. Pharmaceutical and pharmacokinetic solutions.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Despite intergroup clinical trials conducted in Europe and North America, outcomes for high risk patients with this disease have not significantly improved in the last several decades, and survival of metastatic or relapsed disease remains extremely poor. Accrual into new clinical trials is slow and difficult, so in vitro cell line research and in vivo xenograft models present an attractive alternative for preclinical research for this cancer type. Currently, 30 commonly used human RMS cell lines exist, with differing origins, karyotypes, histologies, and methods of validation. Selecting an appropriate cell line for RMS research has important implications for outcomes. There are also potential pitfalls in using certain cell lines including contamination with murine stromal cells, cross-contamination between cell lines, discordance between the cell line and its associated original tumor, imposter cell lines, and nomenclature errors that result in the circulation of two or more presumed unique cell lines that are actually from the same origin. These pitfalls can be avoided by testing for species-specific isoenzymes, microarray analysis, assays for subtype-specific fusion products, and short tandem repeat analysis.

/pdf/human-rhabdomyosarcoma-cell-lines-for-rhabdomyosarcoma-3dhpuwpc57.pdf

Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: utility and pitfalls.

Alterations in the expression of normal cell surface components on 13 transplantable hepatocellular carcinomas were examined using a heteroantiserum [anti-Mr 105,000 glycoprotein (gp105)] reactive with a family of nine wheat germ agglutinin binding components from normal rat hepatocytes with an average molecular weight of 105,000. Analysis by two-dimensional polyacrylamide gel electrophoresis of components immunoprecipitated by anti-gp105 antiserum from detergent extracts of transplantable hepatocellular carcinoma cells surface labeled with 125I revealed qualitative and quantitative changes in the expression of anti-gp105-reactive components with the most consistent change being the apparent loss of a pair of acidic (pl 4.1 to 4.3) glycoproteins by all 13 transplantable hepatocellular carcinoma lines. One-dimensional peptide maps of fragments produced following digestion with V8 protease indicated that these acidic components were closely related in structure but differed significantly from other anti-gp105-reactive components. Immunodepletion analysis with monoclonal antibodies and heteroantisera reactive with individual components recognized by anti-gp105 antiserum showed that the two acidic glycoproteins were antigenically and structurally identical to cell-CAM 105, a Mr 105,000 glycoprotein involved in cell-cell adhesion of rat hepatocytes. Antibodies raised against purified cell-CAM 105 were specific in immunoprecipitation assays for the acidic components, strongly inhibited reaggregation of hepatocytes, and displayed no reactivity by indirect immunofluorescence or immunoprecipitation analysis with transplantable hepatocellular carcinoma cells. These results suggest that major alterations in the expression of cell-CAM 105 may be a consistent feature of the malignant phenotype.

Alterations in the Expression of a Hepatocyte Cell Adhesion Molecule by Transplantable Rat Hepatocellular Carcinomas

Biotechnology and pharmacy , Biotechnology and pharmacy , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

Biotechnology and Pharmacy

Hybridoma cells were derived from a mouse immunized with plasma membranes prepared from the fresh tumor tissues of a patient with malignant fibrous histiocytoma (MFH), a soft tissue sarcoma. Supernatants from the resultant hybridoma clones were screened for positive antibody binding to tumor membranes and negative binding to membrane preparations of normal tissues using a solid-phase radioimmunoassay. Two distinct monoclonal IgG1 (kappa) antibodies, 19-14 and 19-24, were identified that showed identical patterns of reactivity with a large panel of tissues. Both antibodies displayed high levels of binding to membranes prepared from a majority of MFH and osteogenic sarcoma tumors tested. Moderate levels of binding were obtained with melanoma, colorectal carcinoma, and first-trimester fetal membranes. Weak or no significant binding was observed with membranes from a variety of autologous and allogeneic normal adult tissues. Antibody reactivities could be specifically removed by absorption with MFH and osteosarcoma membranes but not with adult muscle membranes. An electrophoretic analysis of immunoprecipitated membrane antigens indicated that antibodies 19-14 and 19-24 reacted with the same protein, a monomer with an approximate molecular weight of 102,000. The antigen was detected in membrane preparations of MFH, osteosarcoma, and first trimester fetus, but was not present in normal adult spleen. However, a small amount of antigen of molecular weight 107,000 was precipitated from a normal adult liver preparation, which suggests that related antigens may be present in low levels in some normal tissues. Antibodies 19-14 and 19-24 also specifically bound to intact, cultured MFH cells, indicating that the relevant antigens were expressed on the outer cell surface.

https://cancerres.aacrjournals.org/content/canres/43/5/2113.full.pdf

Detection of a Human Sarcoma-associated Antigen with Monoclonal Antibodies

A murine monoclonal antibody (MoAb 19-24) directed against a human sarcoma antigen was prepared and labeled with 111In by use of the linker 1-(p-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (SCN-Bz-DTPA). Imaging and biodistribution of this radioimmunocomplex were evaluated. MoAb P3 was similarly labeled as a negative control. Of 24 athymic mice bearing s.c. human fibrosarcoma, 12 received 10 microCi of [111In]MoAb 19-24 and 12 received 10 microCi of [111In]MoAb P3. The mice were imaged at 24, 48, 68, or 168 hr, after i.p. injection. Region of interest and biodistribution analysis showed maximum localization of MoAb 19-24 in the tumor at 72 hr with maximum liver localization of 24 hr. Analysis of MoAb P3 showed maximum tumor and liver activity at 24 hr. Tumor specificity studies were also conducted in three nude mice bearing a sarcoma in the left flank and a Burkitt's lymphoma in the right flank. Selective uptake was seen in the sarcoma but not in the lymphoma. The excellent uptake of [111In]SCN-Bz-DTPA-MoAb 19-24 in sarcoma without appreciable liver activity indicates that it may be a useful tumor imaging agent in man.

https://jnm.snmjournals.org/content/29/11/1810.full.pdf

Improved sarcoma imaging and reduced hepatic activity with indium-111-SCN-Bz-DTPA linked to MoAb 19-24.

125I-labeled monoclonal antibody 19-24 (mouse isotype IgG1) was evaluated for its potential usefulness in the clinical radioimmunodetection of sarcoma. The antibody reacts with a cell surface antigen preferentially expressed in many human soft tissue and bone sarcomas. Chromatographic and electrophoretic analyses indicated that the labeled preparation was relatively pure. Binding studies in vitro demonstrated that specificity for antigen was retained after iodination and indicated that the labeled antibody possessed an immunoreactivity in excess of 90% and a binding constant of 8.1 X 10(9) M-1. When administered to athymic NCr-nu/nu mice bearing 1-cm diameter human fibrosarcoma HT-1080 xenografts, the labeled antibody preferentially localized in tumor deposits. Maximum tumor-to-blood radioactivity ratios (2.2-3.4) were obtained 7 days after antibody injection. Specificity of the localization was confirmed with a control mouse IgG1 antibody and by using a nonreactive xenograft. Distinct tumor images were obtained by gamma camera without the use of subtraction techniques, demonstrating the possible clinical utility of the labeled antibody.

Localization of Radiolabeled Monoclonal Antibody in a Human Soft Tissue Sarcoma Xenograft

The early localization of recurrent or metastatic sarcoma remains a challenging clinical problem. 125I-labeled monoclonal antibody (Mab) 19–24, produced in our laboratories against a human malignant fibrous histiocytoma, has been evaluated for detection of locally recurrent or metastatic disease in selected sarcoma patients. In vitro testing indicated various degrees of positive Mab reactivity with most sarcoma types, and low but significant reactivity with some nonsarcoma tumors and several normal tissues, including liver. The iodine-labeled Mab had an immunoreactivity of 90% and a high binding constant (8.1×109M−1). Biodistribution studies of radioisotope in sarcoma patients showed rapid clearance of radiolabeled from the blood and uptake in tumor deposits, liver, and spleen. A differential in radioactivity kinetics between liver and tumor was also found. Serial patient scanning determined optimal imaging time to be between 24 and 48 h after i.v. infusion of the radiolabeled Mab. Analysis of tissues obtained during surgery (including a dual antibody-label study using a nonspecific Mab) showed selective localization of the Mab into the sarcoma deposits. Radiolabeled Mab shows potential as a clinically useful tool for localization of sarcoma deposits.

Localization of human sarcoma with radiolabeled monoclonal antibody. A preliminary study.

A murine IgGl (k) monoclonal antibody, termed 33-11, was produced against purified bovine estrogen sulfotransferase. After the enzyme was separated into its four isoenzyme forms by native polyacrylamide gel electrophoresis, a Western blotting analysis indicated that the antibody reacted to a similar extent with each of the isoenzymes. An immunoprecipitation and SDS-poly acrylamide gel electrophoresis analysis was performed with an I-125-labeled enzyme preparation. Antibody 33-11 precipitated protein in the molecular weight range 70,000-74,000, the size of native estrogen sulfotransferase, plus additional bands with molecular weights of 29,000, 54,000, and 61,000. The lower molecular weight polypeptides may represent fragments, bearing a common epitope, produced by limited endogenous proteolysis of the intact enzyme. Solid-phase radioimmunoassay testing demonstrated strong and specific binding of the antibody to the bovine enzyme. No cross-reactivity was observed with a panel of nine other purified bovine proteins. An immunohistochemical analysis with the antibody was performed on two bovine tissues with high levels of enzyme activity. Placenta showed strong, specific staining of fetal giant cells of chorionic villi, while adrenal had weak but widespread staining which tended to be more concentrated in the inner cortex. Monoclonal antibody 33-11 has potential utility in the purification, detection, and quantitation of bovine estrogen sulfotransferase.

Production and characterization of a monoclonal antibody to bovine estrogen sulfotransferase.

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