Trastuzumab Labeled to High Specific Activity with 111In by Conjugation to G4 PAMAM Dendrimers Derivatized with Multiple DTPA Chelators Exhibits Increased Cytotoxic Potency on HER2-Positive Breast Cancer Cells

Chan, Conrad; Cai, Zhongli; Reilly, Raymond M.

doi:10.1007/s11095-013-1044-1

Cited by 26 publications

(15 citation statements)

References 30 publications

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“…In the current study, trastuzumab-AuNP- 111 In were not modified with NLS peptides, but HER2 nonetheless harbors a putative NLS [27] which may mediate routing of internalized AuNP to a peri-nuclear location in BC cells. We similarly found that 111 Inlabeled and trastuzumab-modified G4 dendrimers with or without NLS peptide modification were internalized and transported to the nucleus in SK-BR-3 cells [28].…”

Section: Discussionmentioning

confidence: 67%

111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection

Cai

Chattopadhyay

Yang

et al. 2016

Nuclear Medicine and Biology

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Section: Discussionmentioning

confidence: 67%

111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection

Cai

Chattopadhyay

Yang

et al. 2016

Nuclear Medicine and Biology

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“…At the SA usually achieved for labelling mAbs with 111 In (< 1 MBq/μg), there may be as few as 1 in 50 antibody molecules that are radiolabelled, which limits their effectiveness for killing cancer cells, especially cells that have low-moderate target receptor expression (Ngo Ndjock Mbong et al 2015). A strategy which we have explored to increase the SA of trastuzumab labelled with 111 In is conjugation of the antibodies to G4 polyamidoamine (PAMAM) dendrimers derivatised with multiple DTPA (Chan et al 2013). This approach increased the SA by 100-fold compared to conjugation directly with DTPA and increased the cytotoxicity in vitro of these radioimmunoconjugates (RICs) on HER2-positive breast cancer cells by up to 9-fold.…”

Section: Radiolabelling Approachesmentioning

confidence: 99%

Auger electrons for cancer therapy – a review

Facca

Cai

et al. 2019

EJNMMI radiopharm. chem.

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249

207

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Background: Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I and 123 I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment. Results: AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. 125 I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (125 I and 123 I) or radiometal chelation (111 In, 67 Ga, 99m Tc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using 111 In-DTPAoctreotide and 125 I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with 125 I-mAb 425, with minimal normal tissue toxicity. Conclusions: Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision.

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“…The specific binding of TZ to HER2 receptors has been explored to develop targeted systems for the imaging and delivery of anticancer drugs to HER2-positive breast cancer cells 11 12 . The presence of free functional groups (-NH 2 and -COOH) on the surface of TZ provides the opppurtinity for conjugation of TZ to various drug carriers.…”

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confidence: 99%

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

Kulhari

Pooja

Shrivastava³

et al. 2016

Sci Rep

145

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Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem.

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Trastuzumab Labeled to High Specific Activity with 111In by Conjugation to G4 PAMAM Dendrimers Derivatized with Multiple DTPA Chelators Exhibits Increased Cytotoxic Potency on HER2-Positive Breast Cancer Cells

Abstract: Conjugation of trastuzumab to G4 PAMAM dendrimers modified with 30 DTPA permitted high SA (111)In labeling which increased their cytotoxic potency for BC cells with high or low HER2 density.

Cited by 26 publications

References 30 publications

111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection

111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection

Auger electrons for cancer therapy – a review

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

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