Cancer-Targeted Delivery Systems Based on Peptides

Chatzisideri, Theodora; Leonidis, George; Sarli, Vasiliki

doi:10.4155/fmc-2018-0174

Cited by 38 publications

(38 citation statements)

References 207 publications

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“…Traditional chemotherapeutics (e.g., paclitaxel, doxorubicin) usually do not preferentially accumulate in tumors, but affect all tissues, which leads to detrimental side effects [1]. Thus, targeted therapy with antibody-drug conjugates (ADCs) and, more recently, small molecule-drug conjugates (SMDCs), has emerged as a viable alternative to enlarging the therapeutic window [2,3,4,5,6]. With the approvals of Adcetris ® (Seattle Genetics/Millennium), Kadcyla ® (Genentech/Roche), Besponsa ® (Wyeth/Pfizer), the re-approval of Mylotarg ® (Wyeth/Pfizer), and more than 80 ADCs in clinical trial pipelines, ADCs are to be considered as a new class of pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Octreotide Conjugates for Tumor Targeting and Imaging

et al. 2019

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Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.

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Section: Introductionmentioning

confidence: 99%

Octreotide Conjugates for Tumor Targeting and Imaging

et al. 2019

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“…Solutions to the short lifetime have been proposed based on two main approaches: (a) preparation of SST analogues attaching one or more groups to the peptide molecule, such as the N-methyl group, able to act as a shield for the in vivo hydrolysis [9]; (b) encapsulation of SST or its analogues in polymeric materials, such as poly(alkyl cyanoacrylate) nanocapsules [10], or in natural phospholipid vesicles, eventually coated with agents ensuring circulation in blood, such as polyethylene glycol (PEG), that protects liposomes from recognition and rapid removal from circulation by the phagocyte system [11]. SST, its analogue octreotide or other synthetic analogues are also studied in liposomal formulations combined with antitumoral drugs like daunorubicin or with radiopharmaceuticals, due to their ability to target SSTR-rich tumoral cells [12,13,14,15]. The biocompatibility and biodegradability of liposomes have an overwhelming importance thus motivating research to deepen the use of natural phospholipids as drug delivery components.…”

Section: Introductionmentioning

confidence: 99%

The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity

Larocca¹,

Toniolo

Tortorella

et al. 2019

Molecules

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The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1–2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to overcome the need for continuous infusion regimes. Multilamellar liposomes made of natural phosphatidylcholine were used for the incorporation of a mixture of somatostatin and sorbitol dissolved in citrate buffer at pH = 5. Lyophilization and reconstitution of the suspension were carried out, showing the flexibility of this preparation. Full characterization of this suspension was obtained as particle size, encapsulation efficiency and retarded release properties in aqueous medium and human plasma. Liposomal somatostatin incubated at 37 °C in the presence of Fe(II) and (III) salts were used as a biomimetic model of drug-cell membrane interaction, evidencing the free radical processes of peroxidation and isomerization that transform the unsaturated fatty acid moieties of the lipid vesicles. This study offers new insights into a liposomal delivery system and highlights molecular reactivity of sulfur-containing drugs with its carrier or biological membranes for pharmacological applications.

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“…Small molecule-drug conjugates represent a recent class of drugs with the potential to target tumor-specific or overexpressed antigens [11,12,22,23]. Since both RTK and some integrin subtypes such as α V β 3 are overexpressed in cancer cells, agents directed to both these targets appear to be extremely promising, also taking into account the tumor targeting properties of integrin ligands [18,19,24].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

Sartori

Corno

Cesare

et al. 2019

Cancers

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Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin αVβ3 covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and αVβ3 at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors.

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Cancer-Targeted Delivery Systems Based on Peptides

Cited by 38 publications

References 207 publications

Octreotide Conjugates for Tumor Targeting and Imaging

Octreotide Conjugates for Tumor Targeting and Imaging

The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

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