Optical and MRI-Guided Theranostic Application of Ultrasmall Superparamagnetic Iron Oxide Nanodrug Conjugate for PSMA-Positive Prostate Cancer Therapy

Article

Author: Nováková, Zora ; Hapuarachchige, Sudath ; Artemov, Dmitri ; Surasinghe, Sharmane ; Bařinka, Cyril ; Liatsou, Ioanna

Active targeting is more effective than conventional passive targeted drug delivery systems in increasing therapeutic efficacy and minimizing systemic toxicities. Importantly, the nanoparticle-based targeted drug delivery systems combine active and passive targeting properties and significantly enhance therapeutic efficacy. In this study, we utilized ultrasmall superparamagnetic iron oxide (uSPIO) nanoparticles conjugated with anti-prostate-specific membrane antigen (PSMA) 5D3 monoclonal antibody, mertansine (DM1) antitubulin agent, and fluorophore to develop a targeted uSPIO-5D3-DM1-AF488/CF750 nanotheranostic for PSMA(+) prostate cancer (PC) therapy. This agent enables multimodality in vivo imaging using near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI). uSPIO-5D3-DM1-AF488 is selectively internalized into PSMA-positive cells by receptor-mediated endocytosis, and uSPIO-5D3-DM1-CF750 exhibited 1.62 and 166.2 ng/mL IC₅₀ values in PSMA(+) and PSMA(-) cells, respectively. The image-guided therapeutic study was conducted in vivo in human PC xenograft mouse models bearing bilateral PSMA(±) tumors (n = 10, two 10 mg/kg doses on days 1 and 14). The therapeutic results exhibited a significant control of the growth of PSMA(+) tumors starting at day 5 (p = 0.05) and significantly improved efficacy after day 9 (p = 0.0005) during the treatment period (t = 21 days). We observed the PSMA-specific uptake of uSPIO-5D3-DM1-CF750 in tumors in NIR IVIS Xenogen images and T₁- and T₂-weighted MRI with 20.6% and 42% reduction of overall T₁ and T₂, respectively. Approximately 70% of mice with PSMA(+) tumors treated with uSPIO-5D3-DM1-CF750 survived or did not exceed the threshold level of the tumor size during the treatment. Ex vivo biodistribution study proved 50% and 45% higher uptake of uSPIO-5D3-DM1-CF750 by PSMA(+) tumors compared to untargeted uSPIO-DM1-CF750 by PSMA(+) tumors and uSPIO-5D3-DM1-CF750 by PSMA(-) tumors, respectively. ICP-MS analysis demonstrated a 73% increase in uSPIO-5D3-DM1-CF750 uptake by PSMA(+) tumors compared to PSMA(+) tumors treated with pure uSPIO. The toxicological results reveal the safe profile in systemic toxicities without life-threatening changes in the complete blood count and clinical chemistry profile of toxicology.

01 Jan 2025·Chromatographia

An UPLC Method for Determination of Structural Analogues of DM1: the Payload of Trastuzumab Emtansine (T-DM1)

Author: Zhu, Yang ; Yin, Daquan ; Yao, Junliang

Abstract: DM1, a derivative of maytansine, is the payload of trastuzumab emtansine (T-DM1).In this work, a new gradient reverse-phase ultra-performance chromatog. (RP-UPLC) method was proposed for anal. of five structural analogs (DM1-2, AP-3, DM1-4D, DM1-3D, and DM1-3L) of DM1.The chromatog. separation was accomplished by using a Waters BEH Ph column (50 x 2.1 mm, 1.7 μm), at the wavelength of 252 nm.Validation of the method was carried out according the ICH guidelines in terms of specificity, accuracy, precision, linearity and robustness.The developed method was proved to be convenient and reliable for quant. determination of the DM1 analog impurities.It can also be used for the related substances determination in DM1 bulk samples.

01 Dec 2024·Advanced Biology

Assessing Novel Antibody‐Based Therapies in Reconstructive 3D Cell Models of the Tumor Microenvironment

Article

Author: Brito, Catarina ; Freitas, Catarina ; Rebelo, Sofia P. ; Lopes, Nuno F. ; Domenici, Giacomo ; Trindade, Gonçalo ; Miret Minard, Joan ; Ramella Gal, Isabella ; Duarte, Nádia

AbstractTargeted, combinatorial, and immunomodulatory therapies, such as antibody‐drug conjugates (ADCs) and immunomodulatory antibodies (Abs), are powerful weapons against tumor cells and immune cells within the tumor microenvironment (TME). Therefore, the evaluation of such therapies should be conducted in pre‐clinical models able to recapitulate the complex cellular and molecular crosstalk of the TME. To build‐in critical hallmarks of the TME, a breast cancer heterotypic 3D cell model (3D‐3) is devised using a microencapsulation strategy with an inert biomaterial (alginate) and agitation‐based cultures. Both stromal and immune components are added to multicellular tumor spheroids, therefore fostering cancer‐associated fibroblasts (CAFs) and tumor‐associated macrophages (TAMs) immunomodulatory interactions. The potential of the methodology to assess Ab‐based therapies is then addressed by employing a series of anti‐HER2‐based ADCs. ADCs induced tumor‐cell specific cytotoxicity toward HER2+ breast cancer spheroids while sparing HER2‐negative CAFs. In addition, an immunomodulatory blocking Ab against colony‐stimulating factor 1 receptor (CSF1R) decreases the expression of immunosuppressive and anti‐inflammatory markers in TAMs, like what is previously observed upon in vivo α‐CSF1R administration. Collectively, the human TME‐based 3D‐3 cell model is a suitable tool to evaluate the anti‐tumor and immunomodulatory potential of novel antibody‐based therapies directed against TME targets, such as cancer cells and macrophages.

100 Deals associated with Cantuzumab mertansine

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KEGG	Wiki	ATC	Drug Bank
D03364	Cantuzumab mertansine	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	United States	-	-
Neoplasms	Phase 1	-	ImmunoGen, Inc.	-

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