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1.
Int J Mol Sci ; 25(3)2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38339141

RESUMO

Chemotherapy is still one of the main therapeutic approaches in cancer therapy. Nevertheless, its poor selectivity causes severe toxic side effects that, together with the development of drug resistance in tumor cells, results in a limitation for its application. Tumor-targeted drug delivery is a possible choice to overcome these drawbacks. As well as monoclonal antibodies, peptides are promising targeting moieties for drug delivery. However, the development of peptide-drug conjugates (PDCs) is still a big challenge. The main reason is that the conjugates have to be stable in circulation, but the drug or its active metabolite should be released efficiently in the tumor cells. For this purpose, suitable linker systems are needed that connect the drug molecule with the homing peptide. The applied linker systems are commonly categorized as cleavable and non-cleavable linkers. Both the groups possess advantages and disadvantages that are summarized briefly in this manuscript. Moreover, in this review paper, we highlight the benefit of oxime-linked anthracycline-peptide conjugates in the development of PDCs. For instance, straightforward synthesis as well as a conjugation reaction proceed in excellent yields, and the autofluorescence of anthracyclines provides a good tool to select the appropriate homing peptides. Furthermore, we demonstrate that these conjugates can be used properly in in vivo studies. The results indicate that the oxime-linked PDCs are potential candidates for targeted tumor therapy.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Daunorrubicina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Oximas/uso terapêutico , Peptídeos/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/metabolismo
2.
Int J Mol Sci ; 25(2)2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38256168

RESUMO

Malignant melanoma is one of the most aggressive and resistant tumor types, with high metastatic properties. Because of the lack of suitable chemotherapeutic agents for treatment, the 5-year survival rate of melanoma patients with regional and distant metastases is lower than 10%. Targeted tumor therapy that provides several promising results might be a good option for the treatment of malignant melanomas. Our goal was to develop novel melanoma-specific peptide-drug conjugates for targeted tumor therapy. Melanocortin-1-receptor (MC1R) is a cell surface receptor responsible for melanogenesis and it is overexpressed on the surface of melanoma cells, providing a good target. Its native ligand, α-MSH (α-melanocyte-stimulating hormone) peptide, or its derivatives, might be potential homing devices for this purpose. Therefore, we prepared three α-MSH derivative-daunomycin (Dau) conjugates and their in vitro and in vivo antitumor activities were compared. Dau has an autofluorescence property; therefore, it is suitable for preparing conjugates for in vitro (e.g., cellular uptake) and in vivo experiments. Dau was attached to the peptides via a non-cleavable oxime linkage that was applied efficiently in our previous experiments, resulting in conjugates with high tumor growth inhibition activity. The results indicated that the most promising conjugate was the compound in which Dau was connected to the side chain of Lys (Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2). The highest cellular uptake by melanoma cells was demonstrated using the compound, with the highest tumor growth inhibition detected both on mouse (38.6% on B16) and human uveal melanoma (55% on OMC-1) cells. The effect of the compound was more pronounced than that of the free drug.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Melanoma/tratamento farmacológico , alfa-MSH/farmacologia , Receptor Tipo 1 de Melanocortina , Agressão
3.
Int J Mol Sci ; 24(4)2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36834815

RESUMO

Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide-drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation.


Assuntos
Bombesina , Neoplasias da Próstata , Masculino , Humanos , Receptores da Bombesina/metabolismo , Preparações Farmacêuticas , Peptídeos , Neoplasias da Próstata/metabolismo , Daunorrubicina
4.
Drug Deliv ; 30(1): 2174210, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36752075

RESUMO

Chemotherapy is still a leading therapeutic approach in various tumor types that is often accompanied by a poor prognosis because of metastases. PEGylated liposomes with CREKA targeting moiety are well-known therapeutic agents, especially in highly metastatic experimental models. CREKA specifically targets tumor-associated ECM, which is present at the primary, as well as metastatic tumor sites. To better understand the function of the targeting moieties, we decided to design various liposome formulations with different amounts of targeting moiety attached to their DSPE-PEG molecules. Moreover, a new tumor-homing pentapeptide (SREKA) was designed, and a novel conjugation strategy between SREKA and DSPE-PEGs. First, the in vitro proliferation inhibition of drug-loaded liposomes and the cellular uptake of their cargo were investigated. Afterward, liposome stability in murine blood and drug accumulation in different tissues were measured. Furthermore, in vivo tumor growth, and metastasis inhibition potencies of the different liposome formulations were examined. According to our comparative studies, SREKA-liposomes have a uniform phenotype after formulation and have similar characteristics and tumor-homing capabilities to CREKA-liposomes. However, the exchange of the N-terminal cysteine to serine during conjugation results in a higher production yield and better stability upon conjugation to DSPE-PEGs. We also showed that SREKA-liposomes have significant inhibition on primary tumor growth and metastasis incidence; furthermore, increase the survival rate of tumor-bearing mice. Besides, we provide evidence that the amount of targeting moiety attached to DSPE-PEGs is largely responsible for the stability of liposomes, therefore it plays an important role in toxicity and targeting.


Assuntos
Lipossomos , Neoplasias , Camundongos , Animais , Lipossomos/química , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular Tumoral , Polietilenoglicóis/química , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico
5.
J Extracell Vesicles ; 11(4): e12207, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35398993

RESUMO

Nanoparticles can acquire a plasma protein corona defining their biological identity. Corona functions were previously considered for cell-derived extracellular vesicles (EVs). Here we demonstrate that nano-sized EVs from therapy-grade human placental-expanded (PLX) stromal cells are surrounded by an imageable and functional protein corona when enriched with permissive technology. Scalable EV separation from cell-secreted soluble factors via tangential flow-filtration (TFF) and subtractive tandem mass-tag (TMT) proteomics revealed significant enrichment of predominantly immunomodulatory and proangiogenic proteins. Western blot, calcein-based flow cytometry, super-resolution and electron microscopy verified EV identity. PLX-EVs partly protected corona proteins from protease digestion. EVs significantly ameliorated human skin regeneration and angiogenesis in vivo, induced differential signalling in immune cells, and dose-dependently inhibited T cell proliferation in vitro. Corona removal by size-exclusion or ultracentrifugation abrogated angiogenesis. Re-establishing an artificial corona by cloaking EVs with fluorescent albumin as a model protein or defined proangiogenic factors was depicted by super-resolution microscopy, electron microscopy and zeta-potential shift, and served as a proof-of-concept. Understanding EV corona formation will improve rational EV-inspired nano-therapy design.


Assuntos
Vesículas Extracelulares , Coroa de Proteína , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Imunomodulação , Placenta , Gravidez , Coroa de Proteína/metabolismo , Proteômica
6.
Cells ; 10(12)2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34943829

RESUMO

Acute myeloid leukemia (AML) cells can secrete trophic factors, including extracellular vesicles (EVs), instructing the stromal leukemic niche. Here, we introduce a scalable workflow for purification of immunomodulatory AML-EVs to compare their phenotype and function to the parental AML cells and their secreted soluble factors. AML cell lines HL-60, KG-1, OCI-AML3, and MOLM-14 released EVs with a peak diameter of approximately 80 nm in serum-free particle-reduced medium. We enriched EVs >100x using tangential flow filtration (TFF) and separated AML-derived soluble factors and cells in parallel. EVs were characterized by electron microscopy, immunoblotting, and flow cytometry, confirming the double-membrane morphology, purity and identity. AML-EVs showed significant enrichment of immune response and leukemia-related pathways in tandem mass-tag proteomics and a significant dose-dependent inhibition of T cell proliferation, which was not observed with AML cells or their soluble factors. Furthermore, AML-EVs dose-dependently reduced NK cell lysis of third-party K-562 leukemia targets. This emphasizes the peculiar role of AML-EVs in leukemia immune escape and indicates novel EV-based targets for therapeutic interventions.


Assuntos
Vesículas Extracelulares/metabolismo , Imunomodulação , Leucemia Mieloide Aguda/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Vesículas Extracelulares/ultraestrutura , Humanos , Terapia de Imunossupressão , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia
7.
Theranostics ; 11(17): 8430-8447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373751

RESUMO

Self-assembly of solid organs from single cells would greatly expand applicability of regenerative medicine. Stem/progenitor cells can self-organize into micro-sized organ units, termed organoids, partially modelling tissue function and regeneration. Here we demonstrated 3D self-assembly of adult and induced pluripotent stem cell (iPSC)-derived fibroblasts, keratinocytes and endothelial progenitors into both, planar human skin in vivo and a novel type of spheroid-shaped skin organoids in vitro, under the aegis of human platelet lysate. Methods: Primary endothelial colony forming cells (ECFCs), skin fibroblasts (FBs) and keratinocytes (KCs) were isolated from human tissues and polyclonally propagated under 2D xeno-free conditions. Human tissue-derived iPSCs were differentiated into endothelial cells (hiPSC-ECs), fibroblasts (hiPSC-FBs) and keratinocytes (hiPSC-KCs) according to efficiency-optimized protocols. Cell identity and purity were confirmed by flow cytometry and clonogenicity indicated their stem/progenitor potential. Triple cell type floating spheroids formation was promoted by human platelet-derived growth factors containing culture conditions, using nanoparticle cell labelling for monitoring the organization process. Planar human skin regeneration was assessed in full-thickness wounds of immune-deficient mice upon transplantation of hiPSC-derived single cell suspensions. Results: Organoids displayed a distinct architecture with surface-anchored keratinocytes surrounding a stromal core, and specific signaling patterns in response to inflammatory stimuli. FGF-7 mRNA transfection was required to accelerate keratinocyte long-term fitness. Stratified human skin also self-assembled within two weeks after either adult- or iPSC-derived skin cell-suspension liquid-transplantation, healing deep wounds of mice. Transplant vascularization significantly accelerated in the presence of co-transplanted endothelial progenitors. Mechanistically, extracellular vesicles mediated the multifactorial platelet-derived trophic effects. No tumorigenesis occurred upon xenografting. Conclusion: This illustrates the superordinate progenitor self-organization principle and permits novel rapid 3D skin-related pharmaceutical high-content testing opportunities with floating spheroid skin organoids. Multi-cell transplant self-organization facilitates development of iPSC-based organ regeneration strategies using cell suspension transplantation supported by human platelet factors.


Assuntos
Técnicas de Cultura de Células/métodos , Organoides/metabolismo , Fenômenos Fisiológicos da Pele/genética , Células-Tronco/metabolismo , Adulto , Animais , Diferenciação Celular/fisiologia , Células Endoteliais/citologia , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/fisiologia , Feminino , Fibroblastos/citologia , Fibroblastos/fisiologia , Voluntários Saudáveis , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Queratinócitos/citologia , Queratinócitos/fisiologia , Masculino , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Organoides/citologia , Regeneração/fisiologia , Medicina Regenerativa , Pele/metabolismo , Transfecção
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