Evaluation of the effect of a cell penetrating peptide (TAT) towards tailoring the targeting efficacy and tumor uptake of porphyrin

Guleria, Mohini; Suman, Shishu Kant; Kumar, Naveen; Sharma, Amit Kumar; Amirdhanayagam, Jeyachitra; Sarma, Haladhar Dev; Satpati, Drishty; Das, Tapas

doi:10.1039/d2md00097k

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…Although porphyrins have good tumor-targeting potential and optimal optical properties, their nonspecific uptake significantly weighs down their potential for clinical applications. To circumvent this, the use of various secondary targeting vectors, such as peptides and antibodies, has been reported in the literature. − , In the present work, a peptide, namely nuclear cell localization signal (NLS), was utilized with the aim of enhancing the target accumulation/uptake as well as maneuvering the pharmacokinetics of an in-house synthesized porphyrin derivative. As NLS [PKKKRKV] is a hydrophilic amino acid chain, a relatively lipophilic porphyrin derivative ( p -methoxyphenyl as a meso substituent) was chosen for the preparation peptide-porphyrin conjugate so as to strike a balance between lipophilicity and hydrophilicity to get the desirable in vivo outcome.…”

Section: Discussionmentioning

confidence: 99%

“…The development of small molecule-based agents which target neoplastic tissues through various pathways, including passive diffusion or tumor-microenvironment-specific routes, has seen occasional success in achieving the desired in vivo outcomes . Porphyrins fall into this category and find limited clinical applications due to suboptimal tumor uptake and undesirable accumulation in nontarget organs. − To address these biodistribution challenges, researchers have explored the conjugation of the porphyrins with other potential targeting molecules. − One such approach involves using a nuclear localization signal (NLS) peptide sequence, which is rich in positively charged amino acids. The cationic nature of NLS facilitates the transport of molecular cargo across the nuclear membrane, potentially aiding in the cellular import of linked porphyrin derivatives. − A seven amino acid sequence, namely PKKKRKV (Pro-Lys-Lys-Lys-Arg-Lys-Val), belongs to the family of NLS peptides, and like others in this family, it is well recognized by the nuclear pore complex.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation

Kumar,

Sharma,

Guleria

et al. 2024

Mol. Pharmaceutics

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The objective of the present work was to evaluate the potential of a nuclear localization signal (NLS) toward facilitating intracellular delivery and enhancement in the therapeutic efficacy of the molecular cargo. Toward this, an inhouse synthesized porphyrin derivative, namely, 5-carboxymethyelene-oxyphenyl-10,15,20-tris(4-methoxyphenyl) porphyrin (UTri-MA), was utilized for conjugation with the NLS sequence [PKKKRKV]. The three compounds synthesized during the course of the present work, namely DOTA-Lys-NLS, DOTA-UTriMA-Lys-NLS, and DOTA-Lys-UTriMA, were evaluated for cellular toxicity in cancer cell lines (HT1080), wherein all exhibited minimal dark toxicity. However, during photocytotoxicity studies with DOTA-Lys-UTriMA and DOTA-UTriMA-Lys-NLS conjugates in the same cell line, the latter exhibited significantly higher light-dependent toxicity compared to the former. Furthermore, the photocytotoxicity for DOTA-UTriMA-Lys-NLS in a healthy cell line (WI26VA4) was found to be significantly lower than that observed in the cancer cells. Fluorescence cell imaging studies carried out in HT1080 cancer cells revealed intracellular accumulation for the NLS-conjugated porphyrin (DOTA-UTriMA-Lys-NLS), whereas unconjugated porphyrin (DOTA-Lys-UTriMA) failed to do so. To evaluate the radiotherapeutic effects of the synthesized conjugates, all three compounds were radiolabeled with 177 Lu, a well-known therapeutic radionuclide with high radiochemical purity (>95%). During in vitro studies, the [ 177 Lu]Lu-DOTA-UTriMA-Lys-NLS complex exhibited the highest cell binding as well as internalization among the three radiolabeled complexes. Biological distribution studies for the radiolabeled compounds were performed in a fibrosarcoma-bearing small animal model, wherein significantly higher accumulation and prolonged retention of [ 177 Lu]Lu-DOTA-UTriMA-Lys-NLS (9.32 ± 1.27% IA/g at 24 h p.i.) in the tumorous lesion compared to [ 177 Lu]Lu-UTriMA-Lys-DOTA (2.3 ± 0.13% IA/g at 24 h p.i.) and [ 177 Lu]Lu-DOTA-Lys-NLS complexes (0.26 ± 0.17% IA/g at 24 h p.i.) were observed. The results of the biodistribution studies were further corroborated by recording serial SPECT-CT images of fibrosarcoma-bearing Swiss mice administered with [ 177 Lu]Lu-DOTA-UTriMA-Lys-NLS at different time points. Tumor regression studies performed with [ 177 Lu]Lu-DOTA-UTriMA-Lys-NLS in the same animal model with two different doses [250 μCi (9.25 MBq) and 500 μCi (18.5 MBq)] resulted in a significant reduction in tumor mass in the treated group of animals. The above results revealed a definite enhancement in the targeting ability of molecular cargo upon conjugation with NLS and hence indicated that this strategy may be helpful for the preparation of drug-NLS conjugates as multimodal agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation

Kumar,

Sharma,

Guleria

et al. 2024

Mol. Pharmaceutics

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“…Peptides are cheap and easy to synthesise; in addition, most peptides are capable of enduring harsh radiolabelling conditions 39 . Consequently, peptides have been used widely as radiopharmaceuticals 40–43 and as agents to modulate the pharmacokinetic properties radiopharmaceuticals 44–48 . The use of peptides in the development of CNS‐target radiopharmaceuticals is comparatively limited by comparison.…”

Section: Main Textmentioning

confidence: 99%

“… 39 Consequently, peptides have been used widely as radiopharmaceuticals 40 , 41 , 42 , 43 and as agents to modulate the pharmacokinetic properties radiopharmaceuticals. 44 , 45 , 46 , 47 , 48 The use of peptides in the development of CNS‐target radiopharmaceuticals is comparatively limited by comparison. In the following sections, we provide a brief overview of the use of peptides in nonradioactive therapeutic and diagnostic agents and discuss how these might be utilised in the development of novel CNS‐target radiopharmaceuticals.…”

Section: Main Textmentioning

confidence: 99%

Peptides for trans‐blood–brain barrier delivery

Blades

Ittner

Tietz

2023

Labelled Comp Radiopharmac

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Trans‐blood–brain barrier (BBB) delivery of therapeutic and diagnostic agents is a major challenge in the development of central nervous system (CNS) targeted radiopharmaceuticals. This review is an introduction to the use of peptides as delivery agents to transport cargos into the CNS. The most widely used BBB‐penetrating peptides are reviewed here, with a particular emphasis on the broad range of cargos delivered into the CNS using these. Cell‐penetrating peptides (CPPs) have been deployed as trans‐BBB delivery agents for some time; new developments in the CPP field offer exciting opportunities for the design of next generation trans‐BBB complexes. Many of the peptides highlighted here are ready to be combined with diagnostic and therapeutic radiopharmaceuticals to develop highly effective CNS‐targeted agents.

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“…Because their amphiphilicities are still maintained, they are capable of self-assembling in aqueous solution and acting as nanocarriers to deliver porphyrins and other active species in vivo . Even so, some porphyrins, such as Ce6, are inherently amphiphiles and can self-assemble to form nanoparticles without the addition of other hydrophilic tags. − Different types of hydrophilic tags can endow them and their self-assembles with unique advanced functionalities, for example, long circulation duration and resistance to protein adsorption in circulation in vivo from oligo (ethylene glycol), , cells and tumors targeting from peptides and glycosyls. − In addition, most of the self-assembled structures of porphyrin-hydrophilic tag amphiphiles are nanoaggregation without a bilayer membrane structure which often forms in the case of porphyrin-based lipids demonstrated by the reported documents. − …”

Section: Porphyrin-based Amphiphilesmentioning

confidence: 99%

Biomedical Application of Porphyrin-Based Amphiphiles and Their Self-Assembled Nanomaterials

Han,

Liu,

Peng

et al. 2023

Bioconjugate Chem.

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Porphyrins have been vastly explored and applied in many cutting-edge fields with plenty of encouraging achievements because of their excellent properties. As important derivatives of porphyrins, porphyrin-based amphiphiles (PBAs) not only maintain the advanced properties of porphyrins (catalysis, imaging, and energy transfer) but also possess self-assembly and encapsulation capability in aqueous solution. Accordingly, PBAs and their self-assembles have had important roles in diagnosing and treating tumors and inflammation lesions in vivo, but not limited to these. In this article, we introduce the research progress of PBAs, including their constitution, structure design strategies, and performances in tumor and inflammation lesion diagnosis and treatments. On that basis, the defects of synthesized PBAs during their application and the possible effective strategies to overcome the limitations are also proposed. Finally, perspectives on PBAs exploration are updated based on our knowledge. We hope this review will bring researchers from various domains insights about PBAs.

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Evaluation of the effect of a cell penetrating peptide (TAT) towards tailoring the targeting efficacy and tumor uptake of porphyrin

Abstract: Cell penetrating peptides (CPPs) are known to possess the unique capacity to penetrate biological membrane and translocate various molecules into the cells. Therefore, porphyrin-CPP conjugates could be envisaged to boost...

Cited by 6 publications

References 29 publications

Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation

Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation

Peptides for trans‐blood–brain barrier delivery

Biomedical Application of Porphyrin-Based Amphiphiles and Their Self-Assembled Nanomaterials

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