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Conjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody-Trastuzumab: The New Approach of a Well-Known Strategy.

ABSTRACT: The strategy utilizing trastuzumab, a humanized monoclonal antibody against human epidermal growth receptor 2 (HER-2), as a therapeutic agent in HER-2 positive breast cancer therapy seems to have advantage over traditional chemotherapy, especially when given in combination with anticancer drugs. However, the effectiveness of single antibody or antibody conjugated with chemotherapeutics is still far from ideal. Antibody?dendrimer conjugates hold the potential to improve the targeting and release of active substance at the tumor site. In the present study, we developed and synthesized PAMAM dendrimer?trastuzumab conjugates carrying doxorubicin (dox) specifically to cells overexpressing HER-2. ¹HNMR, FTIR and RP-HPLC were used to characterize the products and analyze their purity. Toxicity of PAMAM?trastuzumab and PAMAM?dox?trastuzumab conjugates compared with free trastuzumab and doxorubicin towards HER-2 positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines was determined using MTT assay. Furthermore, the cellular uptake and cellular localization were studied by flow cytometry and confocal microscopy, respectively. A cytotoxicity profile of above mentioned compounds indicated that conjugate PAMAM?dox?trastuzumab was more effective when compared to free drug or the conjugate PAMAM?trastuzumab. Moreover, these results reveal that trastuzumab can be used as a targeting agent in PAMAM?dox?trastuzumab conjugate. Therefore PAMAM?dox?trastuzumab conjugate might be an interesting proposition which could lead to improvements in the effectiveness of drug delivery systems for tumors that overexpress HER-2.

SUBMITTER: Marcinkowska M

PROVIDER: S-EPMC6414888 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Conjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody-Trastuzumab: The New Approach of a Well-Known Strategy.

Marcinkowska Monika M Sobierajska Ewelina E Stanczyk Maciej M Janaszewska Anna A Chworos Arkadiusz A Klajnert-Maculewicz Barbara B

Polymers 20180214 2

The strategy utilizing trastuzumab, a humanized monoclonal antibody against human epidermal growth receptor 2 (HER-2), as a therapeutic agent in HER-2 positive breast cancer therapy seems to have advantage over traditional chemotherapy, especially when given in combination with anticancer drugs. However, the effectiveness of single antibody or antibody conjugated with chemotherapeutics is still far from ideal. Antibody⁻dendrimer conjugates hold the potential to improve the targeting and release ...[more]

PMID: 30966223

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Project description:Patents of some therapeutic monoclonal antibodies (mAb) used for cancer treatment are ending soon, allowing for the entry of similar analogs (biosimilars) onto the market. To have a biosimilar approved by health agencies, the manufacturer must typically demonstrate functional and physicochemical similarity between the biosimilar and the approved reference product. Functional similarity is often validated with cell-based assays, but the information gained is limited. In contrast, RNA-seq methods enable a sensitive transcriptomic analysis, providing detailed information on pathways and cellular responses. Trastuzumab inhibits signaling of the cell-surface receptor HER2, which is overexpressed in approximately 30% of all breast cancer patients. Here, we compare the functional effect of the mAb Trastuzumab and a corresponding biosimilar. The BT-474 breast cancer cell line was treated with the reference product, Trastuzumab (Herceptin®), or a proposed biosimilar (ApoTras), and the cellular transcriptomes were analyzed by RNA-seq. Functional similarity was assessed using two statistical contrasts. One contrast evaluated the mechanism of action by comparing treated samples (Her and ApoTras, n = 19) vs. untreated controls (n = 10), which identified 2623 differentially expressed genes (DEG) at a minimum fold change of 1.25. The other contrast directly compared ApoTras (n = 9) vs. Her (n = 10) to determine differences in expression between treatments and identified 24 DEG using a 1.25 fold- change threshold. This low DEG number reveals a very high similarity of effect of both mAb treatments on the cancer cells. A gene set overrepresentation analysis of DEG for mAb treatments revealed mechanisms of action, which were consistent with known trastuzumab effects. Supporting the small number of changes between both treatments, a post-hoc power analysis for the between-treatment comparison estimated power of 0.88 to detect a gene expression fold-changes of 2.0. To summarize these data, we introduce an overall similarity index (SI) to quantify treatment similarity based on changes in gene expression. Using statistical contrasts with RNA-seq analysis provides a powerful tool for the comparison of biological effects of biosimilar and originator compounds and can be broadly used for functional comparisons of drug treatments.

Dataset Information

Conjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody-Trastuzumab: The New Approach of a Well-Known Strategy.

Publications

Conjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody-Trastuzumab: The New Approach of a Well-Known Strategy.

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