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1.
Life Sci ; 350: 122765, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38830506

RESUMO

BACKGROUND: Malnutrition is a common problem in developing countries, and the impact of severe malnutrition on optimal treatment outcomes of chemotherapy in pediatric cancer patients is well documented. However, despite being a more prevalent and distinct entity, moderate malnutrition is until now unexplored for its effects on treatment outcomes. AIMS: In this study we aimed to investigate the molecular basis of altered pharmacokinetics and cardiotoxicity of doxorubicin observed in early-life chronic moderate protein deficiency malnutrition. MATERIALS AND METHODS: We developed an animal model of early-life moderate protein-deficiency malnutrition and validated it using clinical samples. This model was used to study pharmacokinetic and toxicity changes and was further utilized to study the molecular changes in liver and heart to get mechanistic insights. KEY FINDINGS: Here we show that moderate protein-deficiency malnutrition in weanling rats causes changes in drug disposition in the liver by modification of hepatic ABCC3 and MRP2 transporters through the TNFα signalling axis. Furthermore, malnourished rats in repeat-dose doxorubicin toxicity study showed higher toxicity and mortality. A higher accumulation of doxorubicin in the heart was observed which was associated with alterations in cardiac metabolic pathways and increased cardiotoxicity. SIGNIFICANCE: Our findings indicate that moderate malnutrition causes increased susceptibility towards toxic side effects of chemotherapy. These results may necessitate further investigations and new guidelines on the dosing of chemotherapy in moderately malnourished pediatric cancer patients.


Assuntos
Cardiotoxicidade , Doxorrubicina , Animais , Doxorrubicina/farmacocinética , Doxorrubicina/efeitos adversos , Ratos , Cardiotoxicidade/etiologia , Masculino , Desmame , Fígado/metabolismo , Desnutrição Proteico-Calórica/metabolismo , Humanos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/toxicidade , Feminino , Modelos Animais de Doenças , Ratos Wistar
2.
Biochem Biophys Res Commun ; 677: 98-104, 2023 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-37566923

RESUMO

Breast cancer is the second most cancer worldwide in females. The primary factor responsible for tumor recurrence is the presence of breast cancer stem cells (BCSCs), which escape the chemo-radiotherapy. In this study, we have investigated the role of Secretory phospholipase-A2 Group 2A (sPLA2-IIA) that is overexpressed in BCSCs of MCF7 and MDA-MB-231 breast cancer cell lines. Further, overexpression of sPLA2-IIA revealed an increased EGFR/JNK/c-JUN/c-FOS signaling in BCSCs, while sPLA2-IIA knockdown significantly reduced the percentage of BCSCs and decreased signaling in both the cell lines. Importantly, sPLA2-IIA knockdown showed differentiation of BCSCs. Strikingly, PET imaging showed a decreased metastatic potential of BCSCs. Our study revealed a novel role of sPLA2-IIA in regulating BCSCs, which play a crucial role in regulating the differentiation and metastatic potential of BCSCs.


Assuntos
Neoplasias da Mama , Fosfolipases A2 Secretórias , Feminino , Humanos , Fosfolipases A2 Secretórias/genética , Fosfolipases , Recidiva Local de Neoplasia , Diferenciação Celular , Células-Tronco Neoplásicas , Fosfolipases A2 do Grupo II/genética
3.
Bioorg Med Chem Lett ; 86: 129240, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36931350

RESUMO

Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new 99mTc-labeled radiotracer for the aforementioned application following the well-established 99mTc-'4+1' chemistry. Formation of the desired [99mTc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the 99mTc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application.


Assuntos
Ácido Fólico , Neoplasias , Humanos , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Compostos Radiofarmacêuticos , Proteínas de Transporte/metabolismo , Tecnécio/química
4.
Drug Deliv Transl Res ; 13(2): 608-626, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36245060

RESUMO

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood-brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, -43 ± 9 mV) to overcome the O6-methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (Cmax fivefold and AUC0-24 4.9 fold) with early tmax (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Nanopartículas , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Linhagem Celular Tumoral , Camundongos Endogâmicos NOD , Camundongos SCID , Sistemas de Liberação de Medicamentos , Paclitaxel , Neoplasias Encefálicas/tratamento farmacológico , Transferrina
5.
Nanoscale ; 14(35): 12773-12788, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36001382

RESUMO

Spatiotemporal targeting of anti-glioma drugs remains a pressing issue in glioblastoma (GBM) treatment. We challenge this issue by developing a minimally invasive in situ implantable hydrogel implant comprising transferrin-targeted temozolomide-miltefosine nanovesicles in the surgically resected GBM cavity (tumour bed). Injection of the "nanovesicle in hydrogel system" in orthotopic GBM-bearing mice improved drug penetration into the peri-cavitary region (∼4.5 mm in depth) with the potential to act as a bridge therapy in the immediate postoperative period, before the initiation of adjuvant radiotherapy. The controlled and sustained release of temozolomide over a month in the surgical cavity eradicated the microscopic GBM cells present within the tumour bed, thereby augmenting the efficacy of adjuvant therapy. The drug (temozolomide and miltefosine) combination was tolerable and efficiently inhibited tumour growth, causing significant prolongation of the survival of tumour-bearing mice compared to that with the free drug. Direct implantation at the target site in the brain resulted in spatiotemporal anti-glioma activity with minimal extracranial and systemic distribution. Nanovesicle in flexible hydrogel systems can be used as potential platforms for the post-surgical management of GBM before initiating adjuvant radiation therapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Nanopartículas , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada/uso terapêutico , Glioblastoma/patologia , Glioma/tratamento farmacológico , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Camundongos , Fosforilcolina/análogos & derivados , Polímeros/uso terapêutico , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Transferrina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Gene Ther ; 29(12): 1908-1917, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35869277

RESUMO

Mutations in ARID2 and TP53 genes are found to be implicated in the tobacco related tumorigeneses. However, the effect of loss of ARID2 in the TP53 mutated background in tobacco related cancer including oral cancer has not been investigated yet. Hence, in this study we knockdown ARID2 using shRNA mediated knockdown strategy in TP53 mutated oral squamous cell carcinoma (OSCC) cell line and studied its tumorigenic role. Our study revealed that suppression of ARID2 in TP53 mutated oral cancer cells increases cell motility and invasion, induces drastic morphological changes and leads to a marked increase in the expression levels of cytokeratins, and integrins, CK8, CK18 and ß4-Integrin, markers of cell migration/invasion in oral cancer. ARID2 suppression also showed early onset and increased tumorigenicity in-vivo. Interestingly, transcriptome profiling revealed differentially expressed genes associated with migration and invasion in oral cancer cells including AKR1C2, NCAM2, NOS1, ADAM23 and genes of S100A family in ARID2 knockdown TP53 mutated oral cancer cells. Pathway analysis of differentially regulated genes identified "cancer pathways" and "PI3K/AKT Pathway" to be significantly dysregulated upon suppression of ARID2 in TP53 mutated OSCC cells. Notably, decreased ARID2 expression and increased CK8, CK18 expression leads to poor prognosis in Head and Neck cancer (HNSC) patients as revealed by Pan-Cancer TCGA data analysis. To conclude, our study is the first to demonstrate tumor suppressor role of ARID2 in TP53 mutated background indicating their cooperative role in OSCC, and also highlights its prognostic implications suggesting ARID2 as an important therapeutic target in OSCC.


Assuntos
Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Carcinogênese/genética , Linhagem Celular Tumoral , Integrinas/metabolismo , Queratina-8/metabolismo , Neoplasias Bucais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Nicotiana/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Sci Data ; 9(1): 348, 2022 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-35717538

RESUMO

Surface modifications of titanium implant influences the quality of osseointegration and are associated with favourable treatment prognosis in orthopaedic and cranio-maxillofacial cases. Hence, unlike previous works, the peri-implant region details of our novel osteogenic nanofibrous coated implants placed in rabbits (n = 6 + 1) were recorded over a 12-week period using a micro-CT imaging system. In this unique contribution, we have created a computed tomography (CT) library of rabbit's tibiae anatomy with osteogenic nanofibrous coated/uncoated implants and are introductory useful assets for investigating the correlation between osteogenic nanofibers coated implants and its effect on improved osseointegration. Apart from using this CT dataset to conduct serial 2D image studies, three-dimensional (3D) reconstructions, assessing segmentation algorithms and developing adequate image quantitation tools, there may be positive applications of these in comparative investigations of similar or related preclinical as well as future clinical studies, further design planning, development etc. required for evolution of implants beyond the present state of art.


Assuntos
Nanofibras , Osseointegração , Titânio , Animais , Materiais Revestidos Biocompatíveis , Coelhos , Propriedades de Superfície , Microtomografia por Raio-X , Raios X
8.
Nanomedicine ; 41: 102529, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35104671

RESUMO

Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NP + Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18 ±â€¯1.0% ID/g, P < .0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, P < .0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos SCID , Polietilenoglicóis/uso terapêutico , Radioisótopos
9.
J Control Release ; 343: 288-302, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35101477

RESUMO

The therapeutic gain in loco-regionally advanced unresectable head and neck squamous cell carcinoma (HNSCC) is limited with the traditional use of concurrent chemoradiotherapy (CRT) owing to dose-limiting toxicities of systemic clinical radiosensitizers. Delivery through regional platforms is challenging due to limited drug permeation but allows spatio-temporal control of combinatorial regimens locally to overcome drug resistance. We address these challenges by developing biodegradable gellan- and lipid-based dual nanocarriers-in-ion-triggered porous mucoadhesive hydrogels for enhanced site-specific delivery of clinically relevant radiosensitizers i.e. cisplatin and paclitaxel. Interestingly, the nanoparticle-in-gel prolonged the tumor bioaccumulation of both the chemotherapeutic drugs with reduced systemic absorption, thereby improving in vivo efficacy which was confirmed by PET-CT imaging and safety as compared to systemic commercial formulations approved for HNSCC chemoradiotherapy. The nanoparticles facilitated intracellular radiosensitizer uptake and cell arrest to synergistically enhance radiation-induced DNA nicks and apoptosis. Our findings suggest the clinical potential of the present platform in the loco-regional management of HNSCC requiring curative CRT.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Nanopartículas , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/métodos , Cisplatino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
10.
Nanoscale ; 14(1): 108-126, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34897360

RESUMO

The blood-brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen. Despite several anti-glioma drug delivery strategies, the lack of adequate chemotherapeutic bioavailability in gliomas has led to a suboptimal therapeutic gain in terms of improvement in survival and increased systemic toxicities. This has paved the way for designing highly specific and non-invasive drug delivery approaches for treating GBM. The intranasal (IN) route is one such delivery strategy that has the potential to reach the brain parenchyma by circumventing the BBB. We recently showed that in situ hydrogel embedded with miltefosine (HePc, proapoptotic anti-tumor agent) and temozolomide (TMZ, DNA methylating agent) loaded targeted nanovesicles prevented tumor relapses in orthotopic GBM mouse models. In this study, we specifically investigated the potential of a non-invasive IN route of TMZ delivered from lipid nanovesicles (LNs) decorated with surface transferrin (Tf) and co-encapsulated with HePc to reach the brain by circumventing the BBB in glioma bearing mice. The targeted nanovesicles (228.3 ± 10 nm, -41.7 ± 4 mV) exhibited mucoadhesiveness with 2% w/v mucin suggesting their potential to increase brain drug bioavailability after IN administration. The optimized TLNs had controlled, tunable and significantly different release kinetics in simulated cerebrospinal fluid and simulated nasal fluid demonstrating efficient release of the payload upon reaching the brain. Drug synergy (combination index, 0.7) showed a 6.4-fold enhanced cytotoxicity against resistant U87MG cells compared to free drugs. In vivo gamma scintigraphy of 99mTc labeled LNs showed 500- and 280-fold increased brain concentration post 18 h of treatment. The efficacy of the TLNs increased by 1.8-fold in terms of survival of tumor-bearing mice compared to free drugs. These findings suggested that targeted drug synergy has the potential to intranasally deliver a high therapeutic dose of the chemotherapy agent (TMZ) and could serve as a platform for future clinical application.


Assuntos
Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Administração Intranasal , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Camundongos , Nanopartículas , Temozolomida/administração & dosagem , Transferrina , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nanoscale ; 13(40): 17077-17092, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34622906

RESUMO

Advanced inoperable triple-negative breast cancer (TNBC) comprises aggressive tumors with a modest pathological response to neoadjuvant chemotherapy. The concomitant use of chemoradiotherapy improves the pathological response rates. However, the dose-dependent systemic toxicity of clinical radiosensitizers with poor circulation half-life and limited passive bioavailability limits their clinical utility. We address these challenges by rationally designing a stealth and tumor microenvironment responsive nano-conjugate platform for the ultrasound-mediated on-demand spatio-temporal delivery of plant flavonoid curcumin as a combinatorial regimen with clinically approved paclitaxel for the neoadjuvant chemoradiotherapy of locally advanced triple-negative breast cancer (TNBC). Interestingly, the focused application of ultrasound at the orthotopic TNBC xenograft of NOD-SCID mice facilitated the immediate infiltration of nano-conjugates at the tumor interstitium, and conferred in vivo safety over marketed paclitaxel formulation. In addition, curcumin significantly potentiated the in vivo chemoradiotherapeutic efficacy of paclitaxel upon loading into nano-conjugates. This gets further enhanced by the concurrent pulse of ultrasound, as confirmed by PET-CT imaging, along with a significant improvement in the mice survival. The quadrapeutic apoptotic effect by the combination of paclitaxel, curcumin, radiation, and ultrasound, along with a reduction in the tumor microvessel density and cell proliferation marker, confers the broad chemo-radiotherapeutic potential of this regimen for radio-responsive solid tumors, as well as metastatic niches.


Assuntos
Medicina de Precisão , Neoplasias de Mama Triplo Negativas , Animais , Apoptose , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente Tumoral
12.
J Cell Sci ; 134(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085695

RESUMO

Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.


Assuntos
Neoplasias , Príons , Amiloide/metabolismo , Animais , Transformação Celular Neoplásica/genética , Camundongos , Mutação , Príons/genética , Príons/metabolismo , Proteína Supressora de Tumor p53/genética
13.
Cells ; 11(1)2021 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-35011685

RESUMO

BACKGROUND: To elucidate the role of iPLA2/PLA2G6 in gingivobuccal squamous cell carcinoma (GB-SCC) and to ascertain the synthetic lethality-based chemoprevention role of aspirin in arachidonic acid metabolism (AAM) pathway down-regulated GB-SCC. METHODS: The in vitro efficacy of aspirin on GB-SCC cells (ITOC-03 and ITOC-04) was assessed by cell proliferation, colony formation, apoptosis, cell migration, cell cycle assay and RNA-seq, while inhibition of PLA2G6 and AAM pathway components was affirmed by qPCR, Western blot and immunofluorescence staining. The in vivo effect of aspirin was evaluated using NOD-SCID mice xenografts and immunohistochemical analysis. RESULTS: We found that aspirin, which has been reported to act through the COX pathway, is inhibiting PLA2G6, and thereby the COX and LOX components of the AAM pathway. The findings were validated using PLA2G6 siRNA and immunohistochemical marker panel. Moreover, a pronounced effect in ITOC-04 cells and xenografts implied aspirin-induced synthetic lethality in the AAM pathway down-regulated GB-SCC. CONCLUSIONS: This study reveals that aspirin induces the anti-tumor effect by a previously unrecognized mechanism of PLA2G6 inhibition. In addition, the effect of aspirin is influenced by the baseline AAM pathway status and could guide precision prevention clinical trials of AAM pathway inhibitors.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Gengivais/tratamento farmacológico , Fosfolipases A2 do Grupo VI/efeitos dos fármacos , Mutações Sintéticas Letais/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Camundongos , Camundongos SCID , Prognóstico , Transfecção
14.
Nucl Med Biol ; 93: 1-10, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33212346

RESUMO

INTRODUCTION: Strategic design and synthesis of nanoparticle based preparations could improve diagnostic screening of several cancer types, thereby facilitating better clinical management of the disease. Towards this, the present work aims to develop and evaluate a radioactive technetium-99m (99mTc) labeled gold nanoparticle (NP) preparation modified with folic acid, so as to diagnose folate receptor positive cancers viz. ovarian, breast, etc. METHODS: 11-Bromoundecanoic acid (UA) was synthetically modified both with folic acid and Hydrazinonicotinic acid (HYNIC) chelate at the carboxylic acid end and subsequently converted to thiol functionality at the bromo terminal to yield folic acid-UA-SH and HYNIC-UA-SH ligands respectively. Gold NPs modified with folic acid and HYNIC chelator were obtained on direct addition of folic acid-UA-SH and HYNIC-UA-SH to chloroauric acid in polysorbate 80 solution under reducing conditions. These NPs were then radiolabeled with 99mTc following HYNIC labeling approach. Both the inactive and 99mTc-labeled gold NPs were then tested for their biological efficacy in folate receptor (FR) positive KB cancer cell lines. Also, biodistribution studies of 99mTc-labeled gold NPs were carried in KB tumor xenografts to ascertain the efficacy towards FR in in vivo system. RESULTS: Polysorbate 80 could stabilize the gold NP preparation with average size <10 nm as determined by TEM. Inhibition of [3H]folic acid with functionalized gold nanoparticle revealed affinity towards FR positive KB cell lines with an IC50 ~ 9 µM. Biodistribution studies of 99mTc-labeled gold NP preparation in SCID mice bearing KB tumor showed an uptake of 1.39 ± 0.18%ID/g in tumor and 5.48 ± 0.72%ID/g in kidneys at 3 h post-injection. In vivo distribution in folic acid pre-treated animals could not establish the specificity towards folate receptors. CONCLUSIONS: Biological evaluation of functionalized gold NP showed affinity towards FR positive cancer cell lines. 99mTc-labeled NP exhibited target uptake in both in vitro and in vivo models, but folic acid inhibition could not establish the target specificity. Nevertheless, in vivo pharmacokinetics envisaged in the present design was achieved using the present gold functionalized NP preparation.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Ouro/química , Imagem Molecular/métodos , Nanoestruturas/química , Tecnécio/química , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Marcação por Isótopo , Camundongos , Tecnécio/farmacocinética , Distribuição Tecidual
15.
Bioorg Chem ; 105: 104447, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33207276

RESUMO

A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.


Assuntos
Antineoplásicos/síntese química , Benzofenonas/química , Chalcona/síntese química , Indóis/química , Neoplasias Bucais/tratamento farmacológico , Moduladores de Tubulina/síntese química , Animais , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/farmacologia , Colchicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Experimentais , Tomografia por Emissão de Pósitrons , Ligação Proteica , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
16.
Drug Deliv Transl Res ; 10(1): 159-167, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31468307

RESUMO

Buparvaquone (BPQ)-loaded asymmetric solid lipid nanoparticles (SLN) prepared by a modified nanoprecipitation method were evaluated for splenotropic drug delivery. BPQ SLN exhibited an average particle size of 650.28 ± 6.75 nm with polydispersity index ≤ 0.3, entrapment efficiency of 96.57 ± 0.190%, and drug loading of 24.63 ± 0.042%. Scanning electron microscopy (SEM) revealed elongated particles with flattened and rounded edges. Aspect ratio, an important determinant of asymmetricity of the BPQ SLN, measured as the ratio of average length (1143 ± 0.083 nm) to width (419 ± 0.031 nm) was found to be 2.727 ± 0.19. The hemolytic potential of 10.86 ± 0.04% and good serum stability suggested feasibility for intravenous administration. 99mTc-labeled BPQ SLN revealed high radiolabeling efficiency (> 95%) and good stability. Intravenous administration in mice revealed > 75% accumulation in the reticuloendothelial system organs. The percent radioactivity per gram of organ was in the order spleen > kidney > lungs > liver > lymph nodes, with high splenic accumulation and significantly lower concentration in the liver. An astoundingly high spleen/liver ratio with a maximum of 11.94 ± 1.37 at 3 h, which confirmed high splenic uptake is attributed to Kupffer cell bypass. Other factors contributing to splenotropy are the rigidity and the low molecular weight of the lipid in the BPQ SLN which enabled translocation of the particles into the splenic pulp. Our study proposes asymmetric BPQ SLN as a promising splenotropic delivery system for improved efficacy in theileriosis, a spleen resident infection.


Assuntos
Lipídeos/química , Naftoquinonas/administração & dosagem , Baço/química , Administração Intravenosa , Animais , Precipitação Química , Sistemas de Liberação de Medicamentos , Feminino , Camundongos , Microscopia Eletrônica de Varredura , Nanopartículas , Naftoquinonas/química , Naftoquinonas/farmacocinética , Tamanho da Partícula
17.
Sci Rep ; 9(1): 17638, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819073

RESUMO

Anchoring of endosseous implant through osseointegration continues to be an important clinical need. Here, we describe the development of superior endosseous implant demonstrating enhance osseointegration, achieved through surface modification via coating of osteogenic nanofibres. The randomized bio-composite osteogenic nanofibres incorporating polycaprolactone, gelatin, hydroxyapatite, dexamethasone, beta-glycerophosphate and ascorbic acid were electrospun on titanium implants mimicking bone extracellular matrix and subsequently induced osteogenesis by targeting undifferentiated mesenchymal stem cells present in the peri-implant niche to regenerate osseous tissue. In proof-of-concept experiment on rabbit study models (n = 6), micro-computed tomography (Micro-CT), histomorphometric analysis and biomechanical testing in relation to our novel osteogenic nanofibrous coated implants showed improved results when compared to uncoated controls. Further, no pathological changes were detected during gross examination and necropsy on peri-implant osseous tissues regenerated in response to such coated implants. The findings of the present study confirm that osteogenic nanofibrous coating significantly increases the magnitude of osteogenesis in the peri-implant zone and favours the dynamics of osseointegration.


Assuntos
Prótese Ancorada no Osso , Nanofibras , Osseointegração , Titânio , Animais , Parafusos Ósseos , Prótese Ancorada no Osso/ultraestrutura , Materiais Revestidos Biocompatíveis , Masculino , Transplante de Células-Tronco Mesenquimais , Microscopia Eletrônica de Varredura , Nanofibras/ultraestrutura , Coelhos , Tíbia/cirurgia , Microtomografia por Raio-X
18.
Biomed Pharmacother ; 114: 108770, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30913494

RESUMO

Low dose Methotrexate (MTX) therapy is considered a gold standard for Rheumatoid Arthritis (RA). Transdermal drug delivery is hypothesized as an alternative to conventional therapies to alleviate its adverse effects. In our study, MTX was entrapped in deformable liposomes and loaded in a hydroxyethyl cellulose gel. This system was evaluated by the Box Behnken statistical design for optimization. The effect of formulation variables on particle size, entrapment and ex vivo skin permeation was studied. The MTX nanogel was evaluated for its dermal toxicity (acute and repeat dose safety), in vivo biodistribution (using 125I radio-labelled MTX) and therapeutic efficacy (collagen induced arthritis [CIA] model). The optimized formulation demonstrated appreciable nanosize (110 ± 20 nm), drug entrapment (42 ± 1.9%) and high ex vivo transdermal flux (17.37 ± 1.5 µg/cm2/hr). In the dermal toxicity studies, nanogel formulation did not show any signs of irritation or toxicity, whereas in the biodistribution study, the MTX nanogel formulation depicted sustained systemic delivery up to 48 h with low accumulation in its organs of toxicity such as the liver, kidneys and gut. In the CIA model, the MTX nanogel significantly ameliorated hind paw swelling, reduced arthritic score, joint damage (histological, radiological examination) and attenuated the rise in serum cytokines such as TNF-ɑ and IL-6. In conclusion, the optimized MTX nanogel formulation displayed skin biocompatibility, sustained systemic delivery, safety as well as therapeutic efficacy.


Assuntos
Portadores de Fármacos/química , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Administração Cutânea , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Química Farmacêutica/métodos , Feminino , Lipossomos/química , Masculino , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoimina/farmacologia , Psoríase/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Distribuição Tecidual/fisiologia
19.
Int J Cancer ; 144(8): 2008-2019, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30304546

RESUMO

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Vesícula Biliar/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética , Adulto , Afatinib/farmacologia , Afatinib/uso terapêutico , Idoso , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento , Sequenciamento do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Drug Deliv Transl Res ; 8(3): 797-805, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29380155

RESUMO

The present investigation deals with preparation and characterization of anti-migraine zolmitriptan (ZMT) nanostructured polymeric carriers for nose to brain drug targeting. The drug-loaded colloidal nanocarriers of ZMT were prepared by modified ionic gelation of cationic chitosan with anionic sodium tripolyphosphate and characterized for particle size, zeta potential, and entrapment efficiency. Further, in order to investigate nose to brain drug targeting, biodistribution, and brain kinetics studies were performed using 99mtechnetium radiolabeled nanocarriers (99mTc-ZMTNP) in Swiss albino mice. The results were compared with intranasal pure drug solution (99mTc-ZMT) and intravenous nanocarriers (99mTc-ZMTNP). A single photon emission computerized tomography (SPECT) radioimaging studies were also carried out to visualize and confirm brain uptake of nanocarriers. The optimized nanocarriers showed particle size of 161 nm, entrapment efficiency of 80.6%, and zeta potential of + 23.7 mV. The pharmacokinetic parameters, Cmax, and AUC0-∞ values for ZMT concentration in the brain expressed as percent radioactivity per gram of brain in intranasal and intravenous route of administration were calculated. The brain Cmax and AUC0-∞ values found in three groups, intranasal 99mTc-ZMTNP, intranasal 99mTc-ZMT, and intravenous 99mTc-ZMTNP were (0.427 and 1.889), (0.272 and 0.7157), and (0.204 and 0.9333), respectively. The higher Cmax values of intranasal 99mTc-ZMTNP suggests better brain uptake as compared to other routes of administration. The significant higher values of nose to brain targeting parameters namely, drug targeting index (5.57), drug targeting efficiency (557.08%), and nose to brain drug direct transport (82.05%) confirmed drug targeting to brain via nasal route. The coupled bimodal SPECT-CT scintigrams confirm the brain uptake of intranasal 99mTc-ZMTNP demonstrating major radioactivity accumulation in brain. This study conclusively demonstrated the greater uptake of ZMT-loaded nanocarriers by nose to brain drug targeting, which proves promising drug delivery system.


Assuntos
Encéfalo/metabolismo , Portadores de Fármacos/administração & dosagem , Nanoestruturas/administração & dosagem , Oxazolidinonas/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Administração Intranasal , Administração Intravenosa , Animais , Encéfalo/diagnóstico por imagem , Quitosana/administração & dosagem , Quitosana/química , Quitosana/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Cinética , Masculino , Camundongos , Nanoestruturas/química , Oxazolidinonas/química , Oxazolidinonas/farmacocinética , Polifosfatos/administração & dosagem , Polifosfatos/química , Polifosfatos/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Tecnécio , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Triptaminas/química , Triptaminas/farmacocinética
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