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2.
Asian J Pharm Sci ; 18(4): 100832, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37583708

RESUMO

Currently, the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy, owing to its precise structure, high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract, blood circulation and tumor tissues compared to other oral nanomedicines. Herein, this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes, which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters. The precise nano-prodrugs exhibit extraordinarily high drug loading (68.16%), electric neutrality, strong hydrophobicity, and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH. These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

3.
Front Pharmacol ; 14: 1190127, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37274109

RESUMO

Trans-δ-viniferin (TVN), as a natural extract, is a resveratrol dimer with attractive biological activities, particularly its anti-tumor character. However, the mechanism of TVN interfering with cancerous proliferation has not been fully understood. Herein in this study, we found that TVN could trigger cancerous mitochondrial membrane potential (ΔΨm) reduction, with intracellular reactive oxidative species (ROS) level increasing, leading to apoptosis, which makes TVN a promising candidate for lung cancer cells A549 treatment. Therefore, this study provides TVN as an option to meet the demand for higher antitumor availability with lower biotoxicity and other clinical applications.

4.
J Colloid Interface Sci ; 628(Pt B): 271-285, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-35998453

RESUMO

This study was conducted to construct a multifunctional nanodrug delivery system (NDDS) to deplete glutathione (GSH) in tumor cells and amplify oxidative stress, enhancing the synergistic effect of chemotherapy and photodynamic therapy (PDT). l-Buthionine-sulfoximine (BSO) and chlorin e6 (Ce6) were loaded into mesoporous silicon nanoparticles (MSN), and then MSN were modified with oxidized hyaluronic acid (OHA) as a pore-blocking agent. Cisplatin (Pt(II)) was further loaded by a coordination reaction with carboxyl groups in OHA to yield a multifunctional NDDS (denoted as MSN@OHA-Ce6/BSO/Pt). The physicochemical properties and antitumor activity of the prepared nanoparticles were characterized in detail. In vitro and in vivo experiments demonstrated that OHA was shed from MSN@OHA-Ce6/BSO/Pt under acidic conditions in tumors, resulting in the release of free BSO, Ce6, and Pt(II). The released BSO could reduce intracellular GSH expression by 48.8 %, effectively enhancing the PDT effect of Ce6 and the chemotherapy effect of Pt(II). Finally, the tumor inhibitory rate (vs saline) reached 73.8 % ± 2.5 % for MSN@OHA-Ce6/BSO/Pt in A549/DDP tumor-bearing nude mice. Therefore, the multifunctional NDDS significantly enhanced the synergistic effect of PDT and chemotherapy.


Assuntos
Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Camundongos , Animais , Fotoquimioterapia/métodos , Silício , Sistemas de Liberação de Fármacos por Nanopartículas , Cisplatino , Camundongos Nus , Ácido Hialurônico , Porfirinas/farmacologia , Porfirinas/química , Nanopartículas/química , Butionina Sulfoximina , Glutationa/química , Fármacos Fotossensibilizantes/química , Linhagem Celular Tumoral
5.
J Biomater Appl ; 37(4): 634-645, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35689328

RESUMO

Herein, we combined a derivative of cisplatin (CP) and the chemosensitizer lonidamine (LND) to design an amphiphilic prodrug, in which the ratio of LND to cisplatin was fixed at 2:1. Diaminedichlorodihydroxyplatinum (DH-CP) is a hydrophilic cisplatin derivative. Due to its appropriate amphiphilicity, this prodrug could self-assemble into stable nanoparticles (denoted as LNP-NPs). Under the action of excessive glutathione (GSH) in tumor cells, DH-CP could be reduced to cytotoxic cisplatin. In addition, the released LND could inhibit the metabolic process of tumor cells, and improving the sensitivity of tumor cells to cisplatin. In vitro studies demonstrated that LNP-NPs displayed significantly cytotoxicity on breast cancer cells, and the cell viability after co-incubation for 48 h (CP 16 µg/mL) were 18.77% (MCF-7) and 20.01% (EMT6), respectively. LNP-NPs could also significantly inhibit the growth of MCF-7 tumor-like spheroids, which were realized through the high coordination and cooperation between CP and LND. Therefore, the carrier-free drug delivery system based on LND and DH-CP is expected to achieve a good synergistic anti-tumor effect.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanopartículas , Pró-Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Glutationa/uso terapêutico , Humanos , Indazóis , Pró-Fármacos/uso terapêutico
6.
Carbohydr Polym ; 291: 119671, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35698359

RESUMO

Currently, the polysaccharide-based nano-prodrug crosslinked by stimuli-responsive synergetic prodrug is of great demand, owing to its excellent stability, synergetic effect and tumor selectivity, and circumventing the dilemma of dose-limiting toxicity and immunogenicity induced by that crosslinked or grafted via a single drug. Herein, the dynamic carboxymethyl chitosan (CMCS)-based nano-prodrugs with precise structure were facilely fabricated, via crosslinking reaction between CMCS and water-soluble synergistic small molecule prodrug (cisplatin-demethylcantharidin conjugate) and further stabilization by glutaraldehyde. The pH/glutathione (GSH)-responsive double-crosslinked structure endowed the nano-prodrugs with long-term storge and circulation stability at physiological pH, and dynamic transitions at tumor sites including extracellular surface amino protonation and intracellular efficient drug release, which promoted selective tumor accumulation and synergistic cytotoxicity, therefore achieving robust tumor suppression while decreasing side effects. Thus, the dynamic precise CMCS-based nano-prodrugs crosslinked by water-soluble synergistic prodrug have great potential for highly selective robust chemotherapy attractive for clinical translation.


Assuntos
Antineoplásicos , Quitosana , Nanopartículas , Neoplasias , Pró-Fármacos , Antineoplásicos/química , Quitosana/química , Glutationa , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Água
7.
Asian J Pharm Sci ; 17(6): 880-891, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36600901

RESUMO

To achieve highly selective synergistic chemotherapy attractive for clinical translation, the precise polymeric nano-prodrugs (PPD-NPs) were successfully constructed via the facile crosslinking reaction between pH-sensitive poly(ortho ester)s and reduction-sensitive small molecule synergistic prodrug (Pt(IV)-1). PPD-NPs endowed the defined structure and high drug loading of cisplatin and demethylcantharidin (DMC). Moreover, PPD-NPs exhibited steady long-term storage and circulation via the crosslinked structure, suitable negative potentials and low critical micelle concentration (CMC), improved selective tumour accumulation and cellular internalization via dynamic size transition and surficial amino protonation at tumoural extracellular pH, promoted efficient disintegration and drug release at tumoural intracellular pH/glutathione, and enhanced cytotoxicity via the synergistic effect between cisplatin and DMC with the feed ratio of 1:2, achieving significant tumour suppression while decreasing the side effects. Thus, the dynamic crosslinked polymeric nano-prodrugs exhibit tremendous potential for clinically targeted synergistic cancer therapy.

8.
Acta Pharm Sin B ; 11(11): 3595-3607, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34900539

RESUMO

Traditional chemotherapy exhibits a certain therapeutic effect toward malignant cancer, but easily induce tumor multidrug resistance (MDR), thereby resulting in the progress of tumor recurrence or metastasis. In this work, we deigned ternary hybrid nanodrugs (PEI/DOX@CXB-NPs) to simultaneously combat against tumor MDR and metastasis. In vitro results demonstrate this hybrid nanodrugs could efficiently increase cellular uptake at pH 6.8 by the charge reversal, break lysosomal sequestration by the proton sponge effect and trigger drugs release by intracellular GSH, eventually leading to higher drugs accumulation and cell-killing in drug-sensitive/resistant cells. In vivo evaluation revealed that this nanodrugs could significantly inhibit MDR tumor growth and simultaneously prevent A549 tumor liver/lung metastasis owing to the specifically drugs accumulation. Mechanism studies further verified that hybrid nanodrugs were capable of down-regulating the expression of MDR or metastasis-associated proteins, lead to the enhanced anti-MDR and anti-metastasis effect. As a result, the multiple combination strategy provided an option for effective cancer treatment, which could be potentially extended to other therapeutic agents or further use in clinical test.

9.
ACS Appl Mater Interfaces ; 13(31): 37665-37679, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34342216

RESUMO

Nanoscale hydroxyapatite (nHA) is considered as a promising drug carrier or therapeutic agent against malignant tumors. But the strong agglomeration tendency and lack of active groups seriously hamper their usage in vivo. To address these issues, we fabricated an organic-inorganic hybrid nanosystem composed of poly(acrylic acid) (PAA), nHA, and indocyanine green (ICG), and further modified with glucose to give a targeting nanosystem (GA@HAP/ICG-NPs). These hybrid nanoparticles (∼90 nm) showed excellent storage and physiological stability assisted by PAA and had a sustained drug release in an acidic tumor environment. In vitro cell experiments confirmed that glucose-attached particles significantly promoted cellular uptake and increased intracellular ICG and Ca2+ concentrations by glucose transporter 1 (GLUT1)-mediated endocytosis. Subsequently, the excessive Ca2+ induced cell or organelle damage and ICG triggered photothermal and photodynamic effects (PTT/PDT) under laser irradiation, resulting in enhanced cell toxicity and apoptosis. In vivo tests revealed that the hybrid nanosystem possessed good hemocompatibility and biosafety, facilitating in vivo circulation and usage. NIR imaging further showed that tumor tissues had more drug accumulation, resulting in the highest tumor growth inhibition (87.89%). Overall, the glucose-targeted hybrid nanosystem was an effective platform for collaborative therapy and expected to be further used in clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Durapatita/uso terapêutico , Verde de Indocianina/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Resinas Acrílicas/química , Resinas Acrílicas/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Portadores de Fármacos/toxicidade , Durapatita/química , Durapatita/toxicidade , Glucose/química , Glucose/toxicidade , Células Hep G2 , Humanos , Verde de Indocianina/química , Verde de Indocianina/efeitos da radiação , Verde de Indocianina/toxicidade , Raios Infravermelhos , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/química , Nanopartículas/efeitos da radiação , Nanopartículas/toxicidade , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/toxicidade , Terapia Fototérmica
10.
Colloids Surf B Biointerfaces ; 207: 112052, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34416443

RESUMO

Chemotherapy fails to achieve an ideal gliomas therapy due to the limited delivery of chemotherapeutics across the blood brain barrier (BBB), difficult accumulation of drugs in the gliomas area, and off-target toxicity. Herein, the pH-triggered small molecule nano-prodrugs (Try-CA-NPs) emulsified from hydrophobic tryptamine (Try)-cinnamaldehyde (CA) twin drug were successfully prepared through a facile method. Try-CA-NPs exhibited long-term storage and circulation stability. Furthermore, liposoluble Try-CA-NPs could easily cross BBB and efficiently accumulate in brain, selectively target to gliomas cells via Try-mediated cellular uptake, and enhance cytotoxicity through intracellular pH-triggered endosomal escape and efficient drug release, and synergistic effect between CA and Try, therefore achieving the complete destruction of SH-SY5Y multicellular spheroids (MCs). Thus, the pH-triggered small molecule nano-prodrugs emulsified from Try-CA twin drug have the great potential for clinically targeted synergistic glioma therapy.


Assuntos
Glioma , Nanopartículas , Pró-Fármacos , Acroleína/análogos & derivados , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Humanos , Concentração de Íons de Hidrogênio , Triptaminas
11.
Int J Biol Macromol ; 188: 11-23, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364934

RESUMO

Low intracellular drugs concentration is one of the main representations of multidrug resistance (MDR), which often results in a weak or failed chemotherapy on cancer treatment. Herein, an acid-sensitive and pluronic L61-linked hyaluronic acid nanogels (HA-L61OE/NGs) were developed for solving this problem. The nanogels could well hold more drugs under neutral condition, while triggering efficiently drugs release (61.42% within 24 h) in acidic environment. In vitro cells experiments demonstrated that the nanogels greatly increased intracellular drugs concentration by CD44-mediated endocytosis and L61-mediated anti-MDR effect, resulting in the enhanced cell-killing in MDR cells. In vivo studies verified HA-L61OE/NGs could avoid drugs leakage in blood and reduce systemic toxicity. Subsequently, the specific accumulation and penetration of nanogels at tumor regions lead to the highest tumor growth inhibition (TGI, 77.42%). Overall, HA-L61OE/NGs were effective on MDR tumor therapy and expected to be further used in clinical trials.


Assuntos
Ácido Hialurônico/farmacologia , Nanogéis/química , Neoplasias/tratamento farmacológico , Poloxâmero/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Poloxâmero/química
12.
Colloids Surf B Biointerfaces ; 207: 112024, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34384973

RESUMO

In this study, we aim to develop the pH-sensitive and tumor-targeting nanogels based on the co-polymerization of three terminal allyl-functionalized components, including ortho ester-conjugated mPEG (mPEG-MOE), ortho ester crosslinker (OEAM) and phenylboronic acid (APBA). The hybrid nanogels displayed a typical spherical structure with a diameter around 200 nm observed by dynamic light scattering (DLS) and scanning electron microscopy (SEM). The prepared nanogels possessed a good stability in neutral conditions, while displayed pH-triggered drug release profiles. Furthermore, in vitro study of cellular uptake and cytotoxicity indicated that the nanogels possessed the highest drug accumulation and cytotoxicity against EMT6 cells. In vivo antitumor examination suggested that these nanogels brought out excellent efficacy in enhancing drug concentration, restraining tumor growth, and prolonged the survival time of tumor-bearing mice. Thus, the prepared multi-functional nanogels possess great potentials for drug delivery in tumor treatment.


Assuntos
Doxorrubicina , Ésteres , Animais , Doxorrubicina/farmacologia , Portadores de Fármacos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Camundongos , Nanogéis , Polietilenoglicóis
13.
Asian J Pharm Sci ; 16(3): 363-373, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34276824

RESUMO

TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance (MDR) and as an anticancer agent for synergistic antitumor effects. However, the comparatively high critical micelle concentration (CMC), low drug loading (DL) and poor tumor target limit its further clinical application. To overcome these drawbacks, the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials, ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material. The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin (DOX)-loaded micelles at neutral aqueous solutions. The micelles exhibited the lower CMC (8.2 × 10-5 mg/ml), higher DL (10.8%) and long-term storage and circulation stability, and showed enhanced cellular uptake, apoptosis, cytotoxicity, and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH (5.0), MDR reversal of TPGS, and synergistic effect of DOX and TPGS. Therefore, the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.

14.
Int J Biol Macromol ; 186: 206-217, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34246671

RESUMO

Phycocyanin (PC) is considered to be an effective natural photosensitizer, but it has not been well utilized as its inefficient biostability and intracellular accumulation. To overcome these limitations, the nano-sized PC particles (LAPC/DOX) were developed by grafting with lactobionic acid (LA) and loading with doxorubicin (DOX). Compared to the PC solution, the storage-stability and photostability of PC particles were remarkably increased, and the formation of nanoparticles further improved its biostability. Besides, CLSM images confirmed that LA could also enhance cellular uptake, resulting in more intracellular PC and DOX accumulation. MTT assay revealed that LAPC/DOX caused the highest cytotoxicity by combined chemo-photodynamic therapy. Finally, LAPC/DOX could efficiently accumulate and spread in tumoral multicellular spheroids, resulting in the enhanced growth inhibition. Overall, the LAPC/DOX is effective in cancer treatment, which provides new insights for the usage of functional proteins in vivo.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Dissacarídeos/farmacologia , Doxorrubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Ficocianina/farmacologia , Antibióticos Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Dissacarídeos/química , Doxorrubicina/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Nanotecnologia , Fármacos Fotossensibilizantes/química , Ficocianina/química , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares , Fatores de Tempo
15.
Nanoscale ; 13(24): 10816-10828, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34113940

RESUMO

Cancer is still a major threat to human health at present. Developing new types of integrated nanoplatforms for the accurate diagnosis and effective treatment of cancer is very significant. Herein, an intelligent dual-stage core-shell cancer theranostic nanoplatform (Fe3+@Au1Ag24@PbP) with NIR laser/tumor-microenvironment (TME) co-responsiveness and multi-modal imaging-therapy was successfully prepared, which was composed of the precisely structured oil-soluble Au1Ag24 nanoclusters (NCs) and Fe3+ ions easily assembled within the oil and aqueous phases of the polyethylene glycol (PEG) block grafted polyketal (PK) copolymer (PK-b-PEG, PbP) vesicles, respectively. In this system, we were delighted to find that the prepared Au1Ag24 NCs possess multi-photoresponsive properties, endowing the nanoplatform with photoacoustic (PA)/photothermal (PT) imaging and synergetic photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer under near-infrared (NIR) laser irradiation. On the other hand, Fe3+ ions exhibit multi-TME response and regulation behaviors, including as catalysts for the decomposition of endogenous hydrogen peroxide (H2O2) in the solid tumor to produce O2 and as the oxidizing agent for the consumption of the intracellular GSH to avoid the reduction of the generated 1O2; therefore, the synchronously formed Fe2+ ions from the redox of Fe3+ with GSH could further react with H2O2 to produce hydroxyl radical (˙OH), which induced ferroptosis-based cancer treatment. The PbP shell possesses TME/pH sensitivity for controlled drug release and passive targeting, causing a large increase in Au1Ag24/Fe3+ accumulation within the weakly acidic tumor region and reducing the side effects on normal tissues. Both in vitro and in vivo experiments demonstrate that the Fe3+@Au1Ag24@PbP nanoplatform presented excellent PA/PT imaging-guided synergetic PTT/PDT/ferroptosis effects toward tumor cells and tumors. This integrating multi-responsive and multi-modal theranostic nanoplatform paves a new way for effective cancer therapy.


Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Lasers , Imagem Multimodal , Fototerapia , Medicina de Precisão , Nanomedicina Teranóstica
16.
Int J Biol Macromol ; 183: 1596-1606, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34022312

RESUMO

Tumor intrinsic or acquired multidrug resistance (MDR) is still one of the major obstacles to the success of nanomedicine. To address this, the pH-sensitive nanoparticles (L61-OE-CS) with MDR-reversal ability were prepared by the crosslinking between acid-labile ortho-ester-modified pluronic (L61-OE) and chitosan (CS) for efficient doxorubicin (DOX) delivery. The size and micromorphology of the prepared nanoparticles were observed by dynamic light scanning and scanning electron microscopy and the nanoparticles displayed a uniform spherical shape with a diameter around 200 nm. The pH-triggered morphology change of the nanoparticles was also observed by scanning electron microscope. Drug release profiles under different pH values showed that DOX release amount within 72 h reached 16% (pH 7.4) and 76.5% (pH 5.0), respectively. In vitro cellular uptake and MTT assay demonstrated that the ortho ester and pluronic-based nanoparticles had higher cytotoxicity than non-sensitive nanoparticles. In vivo antitumor experiments also proved the superiority of the dual-functional nanoparticles, and the tumor growth inhibition rate (TGI) on day 14 was higher than 80%. Therefore, L61-OE-CS nanoparticles have great potential to be used as drug carriers in anticancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Quitosana/química , Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Poloxâmero/química , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos , Difusão Dinâmica da Luz , Ésteres , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Nanopartículas , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Acta Biomater ; 129: 209-219, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34022467

RESUMO

To achieve an ideal drug delivery platform with precise composition and high tumor selectivity, the PEGylated dual-drug backboned prodrug was synthesized via the copolymerization between diamine monomer of ortho ester and cisplatin- demethylcantharidin conjugate (Pt(IV)-1), and then terminated by mPEG550-active ester. The amphipathic prodrug could self-assemble into nano-prodrugs, which endowed the precise structure and high drug loading. Moreover, the nano-prodrugs exhibited physicochemical stability at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change for selective tumor accumulation and enhanced cellular internalization at tumoral extracellular pH (6.8), and efficient drug release for synergetic apoptosis and cytotoxicity at tumoral intracellular pH (5.0)/glutathione. Thus, the precise dual-drug backboned nano-prodrugs with detachable PEGylation, dynamic size change and efficient drug release could be potentially translated for clinically selective cancer treatment. STATEMENT OF SIGNIFICANCE: Few nanomedicines have been clinically used for cancer treatment and little progress has been made in the last decades due to the unprecise composition and unsatisfactory tumor selectivity. Herein, the PEGylated dual-drug backboned nano-prodrugs were successfully constructed by rational design and endowed the defined structure, precise drug ratio, extraordinary high drug loading and reduction/pH dual sensitivity. The nano-prodrugs further exhibited the stable storage and blood circulation through PEGylation and low critical micelle concentration, enhanced tumor accumulation and cellular uptake via extracellular DePEGylation and dynamic size translation, and synergetic cytotoxicity via intracellular efficient drug release, respectively. This study can open a new avenue for easy industrial manufacture and quality control, and highly selective chemotherapy appealing for clinical translation. .


Assuntos
Antineoplásicos , Pró-Fármacos , Antineoplásicos/farmacologia , Cisplatino , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Micelas
18.
J Colloid Interface Sci ; 601: 85-97, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34058555

RESUMO

Chemotherapy efficiency of platinum(II) (Pt(II)) is often attenuated owing to the low intracellular drugs concentration and glutathione (GSH)-mediated detoxification. To address these problems, we fabricated a step-by-step responsive nanogel (~160 nm) by copolymerization between four functional monomers. Hydrophilic methoxypolyethylene glycols (mPEG) distributedrandomly on the surface of particles endowed the nanogel with "stealth" property in blood circulation, while the chemical crosslinking inside particles by platinum(IV) (Pt(IV)) linker remarkably increased the stability of nanogel in vivo. These advantages of nanogels leaded to higher accumulation at tumor region (6.4% ID/g), followed by triggering the dePEGylation effect by the cleavage of ortho ester at tumoral extracellular pH. Meanwhile, the exposed phenylboric acid (PBA) could significantly increase cellular uptake and intracellular drugs levels by targteing sialic acid residues on the cells membrane. More importantly, this nanogels could further deplete intracellular glutathione (GSH) by the dual-regulation of platinum(IV) and arylboronic ester, resulting in enhanced platinum(II) toxicity both in vitro and in vivo, eventually achieving superior inhibition rate (79.14%) in A549/DDP tumor. Thus, the sequentially responsive nanogel could be considered as an effective strategy for cancer treatment.


Assuntos
Antineoplásicos , Platina , Antineoplásicos/farmacologia , Glutationa , Humanos , Nanogéis , Polietilenoglicóis , Polietilenoimina
19.
Eur J Pharm Biopharm ; 163: 188-197, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33864903

RESUMO

The main objective of this paper is to develop a self-delivered prodrug system with nanoscale characteristics to enhance the efficacy of tumor therapy. The pH-sensitive prodrug was composed of ortho ester-linked dasatinib (DAS-OE), which was further self-assembled with or without doxorubicin (DOX) to obtain two carrier-free nanoparticles (DOX/DAS-OE NPs or DAS-OE NPs). The prodrug-based nanoparticles united the superiorities of small molecules and nano-assemblies together and displayed well-defined structure, uniform spherical shape, high drug loading ratio and on-demand drug release behavior. The drug loading content of DAS and DOX was 61.6% and 21.9%, respectively, and more than 80.2% of DAS and 60.2% DOX were released from DOX/DAS-OE NPs within 20 h at pH 5.0. Both in vitro and in vivo studies demonstrated that the pH-sensitive ortho ester bonds in the prodrug underwent hydrolysis to release DAS and DOX simultaneously after cellular internalization, resulting in remarkable antitumor effect. Tumor growth inhibition rate was 19.9% (free DAS), 35.5% (free DOX), 66.3% (DAS-OE NPs) and 82.8% (DOX/DAS-OE NPs), respectively. Thus, the ortho ester-linked prodrug system shows great potentials in cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dasatinibe/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Dasatinibe/química , Dasatinibe/farmacocinética , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Ésteres/química , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Neoplasias/patologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacocinética
20.
Colloids Surf B Biointerfaces ; 201: 111619, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33607325

RESUMO

To promote the highly selective synergistic chemotherapy, the pH-ultra-sensitive dynamic methotrexate nano-prodrugs with detachable PEGylation were successfully prepared via facile method, and the synergistic nanodrugs could be further constructed through encapsulating Doxorubicin (DOX) following the self-assembly process. The nano-prodrugs exhibited the low critical micelle concentration (CMC), negative zeta potential and stability for 5 days in PBS and FBS at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change at tumoral extracellular pH (6.8) for improved tumor accumulation and cellular internalization, and efficiently synergistic drug release at tumoral intracellular pH (5.0) for enhanced tumor apoptosis and cytotoxicity. Moreover, in vivo experiment suggested that the synergistic nanodrugs could significantly improve tumor accumulation and restrain tumor growth while decreasing adverse effects. Therefore, the dynamic methotrexate nano-prodrugs with detachable PEGylation are easy to clinically transform for highly selective synergistic chemotherapy.


Assuntos
Pró-Fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Concentração de Íons de Hidrogênio , Metotrexato , Micelas
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