Targeted killing of prostate cancer cells using antibody–drug conjugated carbon nanohorns

Lucío, María Isabel; Opri, Roberta; Pinto, Marcella; Scarsi, Alessia; Fierro, J. L. G.; Meneghetti, Moreno; Fracasso, Giulio; Prato, Maurizio; Vázquez, Éster; Herrero, M. Antonia

doi:10.1039/c7tb02464a

Cited by 23 publications

(21 citation statements)

References 58 publications

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“…Concerning the use of CNH as nanovectors in cancer therapy, the encapsulation of the well-known cisplatin ( cis -diaminedichloroplatinum(II)), named herein as cddp (see Figure A), into this carbon nanomaterial has been a widely studied strategy. − It occurs due to the strong antitumor activity of this drug and the possibility to reduce its severe side effects. , In this context, Lucío et al developed a selective CNH-based nanocarrier with cddp molecules as prodrug species for killing prostate cancer cells. The efficiency of this DDS in selectively targeting the tumor cells was achieved due to the attachment of the monoclonal antibody D2B, which presented a selectivity for prostate-specific membrane antigen (PSMA), onto the surface of these nanomaterials.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Releasing Processes of Pt(II)-Based Anticancer Drugs from Oxidized Carbon Nanohorn: An In Silico Study

2022

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About half of all cancer chemotherapies currently applied involve medication with the three worldwide approved Pt(II)-based drugs, cisplatin (cddp), carboplatin (cpx), and oxaliplatin (oxa), due to their notable antitumor activity for several cancers. However, this wide application is accompanied by severe side effects, such as nephrotoxicity, myelosuppression, and neurotoxicity, as a result of their low bioavailability and selectivity for cancer cells. To mitigate these drawbacks, the use of chemically functionalized carbon nanohorns (CNH) as nanocarriers represents a potential formulation since CNH has been noted for their biodegradability, biocompatibility, low toxicity, and cavities dimensionally compatible with small drugs. This work reports energetic and dynamic analyses of complexes formed by oxidized CNH (CNHox) and the cddp, cpx, and oxa drugs. Using unbiased molecular dynamics (MD) simulations, we show that the encapsulated formulations (cddp@CNHox, cpx@CNHox, and oxa@CNHox) were more stable by ∼11.0 kcal mol–1 than the adsorbed ones (cddp > CNHox, cpx > CNHox, and oxa > CNHox). This high stability, mainly governed by van der Waals interactions, was responsible for the drug confinement during the entire simulation time (200 ns). The biased MD simulations of the inclusion complexes confirmed the nonspontaneity of the drug release since the potentials of mean force (PMF) indicated the endergonic character of this process. Additionally, the releasing energy profiles pointed out that the free energy barrier (ΔΔG ≠) for the escape from CNHox cavity follows the order oxa > cpx ∼ cddp, with the value for the oxa complex (21–26 kcal mol–1) found to be about 36 and 30% larger than those for cpx and cddp, respectively. While the approximate residence time (t res) of the oxa drug inside the CNHox cavity was 5.45 × 108 s, the same measure for the cddp and cpx drugs was 5.3 × 105 and 1.60 × 103 s. Simulations also revealed that the escape of oxa with the oxalate group facing the nanowindow was the most unfavorable process, giving t res = 1.09 × 109 s. Besides reinforcing and extending the nanovectorization of cddp, cpx, and oxa in CNHox for cancer chemotherapies, all features considered may provide interpretations for experimental data and encourage new investigations aiming to propose less aggressive treatments for oncological diseases.

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Section: Introductionmentioning

confidence: 99%

Unveiling the Releasing Processes of Pt(II)-Based Anticancer Drugs from Oxidized Carbon Nanohorn: An In Silico Study

2022

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“…CNHs can also be modified with specific targeting molecules and applied in target chemical therapy. A cisplatin loaded CNH attached with a mAb D2B, selective for prostate specific membrane antigen (PSMA) + prostate cancer cells, showed superior efficacy and specificity to kill PSMA + prostate cancer cells compared to hybrids Ab-CNHs and cisplatin-CNHs [ 165 ].…”

Section: Nanomaterials Used For Cancer Treatmentmentioning

confidence: 99%

Nanomaterials for cancer therapy: current progress and perspectives

et al. 2021

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Cancer is a disease with complex pathological process. Current chemotherapy faces problems such as lack of specificity, cytotoxicity, induction of multi-drug resistance and stem-like cells growth. Nanomaterials are materials in the nanorange 1–100 nm which possess unique optical, magnetic, and electrical properties. Nanomaterials used in cancer therapy can be classified into several main categories. Targeting cancer cells, tumor microenvironment, and immune system, these nanomaterials have been modified for a wide range of cancer therapies to overcome toxicity and lack of specificity, enhance drug capacity as well as bioavailability. Although the number of studies has been increasing, the number of approved nano-drugs has not increased much over the years. To better improve clinical translation, further research is needed for targeted drug delivery by nano-carriers to reduce toxicity, enhance permeability and retention effects, and minimize the shielding effect of protein corona. This review summarizes novel nanomaterials fabricated in research and clinical use, discusses current limitations and obstacles that hinder the translation from research to clinical use, and provides suggestions for more efficient adoption of nanomaterials in cancer therapy.

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“…Different groups analyzed IgGD2B tumor-targeting capacity ( Table 1 , refs. [ 28 , 29 , 30 , 31 , 32 ] and compared it with those of F(Ab) 2 and FAb fragments [ 28 ].…”

Section: Psma-targeted Diagnosis/therapy With Monoclonal Antibodiesmentioning

confidence: 99%

Validity of Anti-PSMA ScFvD2B as a Theranostic Tool: A Narrative-Focused Review

et al. 2021

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Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in other normal tissues and highly overexpressed in PCa, represents a reliable marker ideal for imaging and therapy. The development of anti-PSMA antibodies, such as D2B, demonstrated slow clearance of intact antibodies compared with fragments resulting in low tumor-to-blood ratios; however, the modular structural and functional nature of antibodies allowed the generation of smaller fragments, such as scFvs. In this review of the anti-PSMA antibody fragment scFvD2B, we combined further characterization of its biomolecular and tissue cross-reactivity characteristics with a comprehensive summary of what has already been performed in preclinical models to evaluate imaging and therapeutic activities. A molecular dynamics study was performed, and ScFvD2B occupied a limited conformational space, characterized by low-energy conformational basins, confirming the high stability of the protein structure. In the cross-reactivity study, the weak/absent immunoreactivity in non-tumor tissues was comparable to the PSMA expression reported in the literature. Biodistribution studies and therapeutic treatments were conducted in different animal models obtained by subcutaneous or locoregional injection of PSMA-positive-versus-negative xenografts. The maximum tumor uptake was observed for 123I(SPECT), 124I(PET), and optical imaging, which avoids kidney accumulation (compared with radiometals) and leads to an optimal tumor-to-kidney and tumor-to-background ratios. Regarding its possible use in therapy, experimental data suggested a strong and specific antitumor activity, in vitro and in vivo, obtained using CAR-T or NK-92/CAR cells expressing scFvD2B. Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment.

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Targeted killing of prostate cancer cells using antibody–drug conjugated carbon nanohorns

Abstract: Stable antibody–drug–carbon nanohorns conjugates are able to selectively target and kill prostate cancer cells thanks to a PSMA specific antibody.

Cited by 23 publications

References 58 publications

Unveiling the Releasing Processes of Pt(II)-Based Anticancer Drugs from Oxidized Carbon Nanohorn: An In Silico Study

Unveiling the Releasing Processes of Pt(II)-Based Anticancer Drugs from Oxidized Carbon Nanohorn: An In Silico Study

Nanomaterials for cancer therapy: current progress and perspectives

Validity of Anti-PSMA ScFvD2B as a Theranostic Tool: A Narrative-Focused Review

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