RESUMO
Dimeric prodrugs have been investigated intensely as carrier-free drug self-delivery systems (DSDSs) in recent decades, and their stimuli-responsive drug release has usually been controlled by the conjugations between the drug molecules, including the stimuli (pH or redox) and responsive sensitivity. Here, an acid-triggered dimeric prodrug of doxorubicin (DOX) was synthesized by conjugating two DOX molecules with an acid-labile ketal linker. It possessed high drug content near the pure drug, while the premature drug leakage in blood circulation was efficiently suppressed. Furthermore, its aggregation structures were controlled by fabricating nanomedicines via different approaches, such as fast precipitation and slow self-assembly, to regulate the drug release performance. Such findings are expected to enable better anti-tumor efficacy with the desired drug release rate, beyond the molecular structure of the dimeric prodrug.
Assuntos
Doxorrubicina , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Portadores de Fármacos/química , Estrutura MolecularRESUMO
The diselenide bond has attracted intense interest in redox-responsive drug delivery systems (DDSs) in tumor chemotherapy, due to its higher sensitivity than the most investigated bond, namely the disulfide bond. Here, a diselenide-bridged doxorubicin dimeric prodrug (D-DOXSeSe) was designed by coupling two doxorubicin molecules with a diselenodiacetic acid (DSeDAA) molecule via α-amidation, as a redox-triggered drug self-delivery system (DSDS) for tumor-specific chemotherapy. The drug release profiles indicated that the D-DOXSeSe could be cleaved to release the derivatives selenol (DOX-SeH) and seleninic acid (DOX-SeOOH) with the triggering of high GSH and H2O2, respectively, indicating the double-edged sword effect of the lower electronegativity of the selenide atom. The resultant solubility-controlled slow drug release performance makes it a promising candidate as a long-acting DSDS in future tumor chemotherapy. Moreover, the interaction between the conjugations in the design of self-immolation traceless linkers was also proposed for the first time as another key factor for a desired precise tumor-specific chemotherapy, besides the conjugations themselves.
Assuntos
Ácidos Carboxílicos , Doxorrubicina , Liberação Controlada de Fármacos , Oxirredução , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Sistemas de Liberação de Medicamentos , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Compostos de Selênio/química , Compostos de Selênio/síntese química , Peróxido de Hidrogênio/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese químicaRESUMO
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) often leads to the failure of antitumor chemotherapy, and codelivery of chemodrug with P-gp siRNA (siP-gp) represents a promising approach for treating chemoresistant tumors. To maximize the antitumor efficacy, it is desired that the chemodrug be latently released upon completion of siP-gp-mediated gene silencing, which however, largely remains an unmet demand. Herein, core-shell nanocomplexes (NCs) are developed to overcome MDR via staged liberation of siP-gp and chemodrug (doxorubicin, Dox) in hierarchical response to reactive oxygen species (ROS) concentration gradients. The NCs are constructed from mesoporous silica nanoparticles (MSNs) surface-decorated with cRGD-modified, PEGylated, ditellurium-crosslinked polyethylenimine (RPPT), wherein thioketal-linked dimeric doxorubicin (TK-Dox2) and photosensitizer are coencapsulated inside MSNs while siP-gp is embedded in the RPPT polymeric layer. RPPT with ultrahigh ROS-sensitivity can be efficiently degraded by the low-concentration ROS inside cancer cells to trigger siP-gp release. Upon siP-gp-mediated gene silencing and MDR reversal, light irradiation is performed to generate high-concentration, lethal amount of ROS, which cleaves thioketal with low ROS-sensitivity to liberate the monomeric Dox. Such a latent release profile greatly enhances Dox accumulation in Dox-resistant cancer cells (MCF-7/ADR) in vitro and in vivo, which cooperates with the generated ROS to efficiently eradicate MCF-7/ADR xenograft tumors.
Assuntos
Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Nanopartículas , RNA Interferente Pequeno , Espécies Reativas de Oxigênio , Humanos , Espécies Reativas de Oxigênio/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/química , RNA Interferente Pequeno/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Nanopartículas/química , Camundongos , Camundongos Nus , Feminino , Dióxido de Silício/química , Linhagem Celular Tumoral , Células MCF-7 , Camundongos Endogâmicos BALB C , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Antibody-drug conjugates (ADCs) are a rapidly expanding class of anticancer therapeutics, with 14 ADCs already approved worldwide. We developed unique linker technologies for the bioconjugation of drug molecules with controlled-release applications. We synthesized cathepsin-cleavable ADCs using a dimeric prodrug system based on a self-immolative dendritic scaffold, resulting in a high drug-antibody ratio (DAR) with the potential to reach 16 payloads due to its dendritic structure, increased stability in the circulation and efficient release profile of a highly cytotoxic payload at the targeted site. Using our novel cleavable linker technologies, we conjugated the anti-human epidermal growth factor receptor 2 (anti-HER2) antibody, trastuzumab, with topoisomerase I inhibitors, exatecan or belotecan. The newly synthesized ADCs were tested in vitro on mammary carcinoma cells overexpressing human HER2, demonstrating a substantial inhibitory effect on the proliferation of HER2-positive cells. Importantly, a single dose of our trastuzumab-based ADCs administered in vivo to mice bearing HER2-positive tumors, showed a dose-dependent inhibition of tumor growth and survival benefit, with the most potent antitumor effects observed at 10 mg/kg, which resulted in complete tumor regression and survival of 100% of the mice. Overall, our novel dendritic technologies using the protease-cleavable Val-Cit linker present an opportunity for the development of highly selective and potent controlled-released therapeutic payloads. This strategy could potentially lead to the development of novel and effective ADC technologies for patients diagnosed with HER2-positive cancers. Moreover, our proposed ADC linker technology can be implemented in additional medical conditions such as other malignancies as well as autoimmune diseases that overexpress targets, other than HER2.
Assuntos
Antineoplásicos , Imunoconjugados , Humanos , Camundongos , Animais , Inibidores da Topoisomerase I/uso terapêutico , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacologia , Linhagem Celular Tumoral , Trastuzumab/química , Antineoplásicos/química , Receptor ErbB-2/metabolismo , Imunoconjugados/uso terapêutico , Imunoconjugados/químicaRESUMO
Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therapy (PDT) and anti-angiogenic agents has emerged as a novel treatment paradigm. Herein, a novel and less-invasive approach is reported to achieve anti-angiogenic and photodynamic combination therapy of wAMD by intravenous administration of a photoactivatable nanosystem (Di-DAS-VER NPs). The nanosystem is self-assembled by reactive oxygen species (ROS)-sensitive dasatinib (DAS) prodrug and photosensitizer verteporfin (VER). After red-light irradiation to the diseased eyes, intraocular release of anti-angiogenic DAS is observed, together with selective neo-vessels occlusion by VER-generated ROS. Notably, Di-DAS-VER NPs demonstrates promising therapeutic efficacy against CNV with minimized systemic toxicity. The study enables an efficient intravenous wAMD therapy by integrating a photoactivation process with combinational therapeutics into one simple nanosystem.
Assuntos
Neovascularização de Coroide , Degeneração Macular , Fotoquimioterapia , Porfirinas , Humanos , Espécies Reativas de Oxigênio/uso terapêutico , Verteporfina/uso terapêutico , Degeneração Macular/tratamento farmacológico , Degeneração Macular/patologia , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologiaRESUMO
All trans-retinoic acid (atRA) has potent anti-inflammatory and antiplatelet activity, but its clinical translation as an antithrombotic drug has been hampered by its low therapeutic efficacy. Here, we describe a facile and elegant strategy that converts atRA into systemically injectable antithrombotic nanoparticles. The strategy involves the dimerization of two atRA molecules using a self-immolative boronate linker that is cleaved specifically by hydrogen peroxide (H2O2) to release anti-inflammatory hydroxybenzyl alcohol (HBA), followed by dimerization-induced self-assembly to generate colloidally stable nanoparticles. The boronated atRA dimeric prodrug (BRDP) could form injectable nanoparticles in the presence of fucoidan that serves as an emulsifier and a targeting ligand to P-selectin overexpressed on the damaged endothelium. In response to H2O2, fucoidan-decorated BRDP (f-BRDP) nanoassemblies dissociate to release both atRA and HBA, while scavenging H2O2. In a mouse model of ferric chloride (FeCl3)-induced carotid arterial thrombosis, f-BRDP nanoassemblies target the thrombosed vessel and significantly inhibit thrombus formation. The results demonstrate that dimerization of atRA molecules via a boronate linker enables the formation of stable nanoassemblies with several benefits: high drug loading, drug self-delivery, on-demand multiple antithrombotic actions, and simple fabrication of nanoparticles. Overall, this strategy provides a promising expedient and practical route for the development of translational self-deliverable antithrombotic nanomedicine.
Assuntos
Trombose das Artérias Carótidas , Nanopartículas , Pró-Fármacos , Trombose , Animais , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Nanomedicina , Peróxido de Hidrogênio , Polímeros/uso terapêutico , Trombose/tratamento farmacológico , Trombose das Artérias Carótidas/tratamento farmacológico , Anti-Inflamatórios/uso terapêuticoRESUMO
Biomimetic therapeutics offer great potential for drug delivery that avoids immune recognition. However, the coated cell membrane usually hinders the cellular uptake of nanoparticles; thus, structure-changeable formulations have attracted increasing attention. Herein, we report photolytic pyropheophorbide a (PA)-inserted red blood cell (RBC) membrane-camouflaged curcumin dimeric prodrug (CUR2-TK)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles [(CUR2-TK)-PLGA@RBC-PA] for enhanced cancer therapy. In these nanoparticles, the inner core was constructed using PLGA and loaded with our synthesized reactive oxygen species (ROS)-responsive cleavable curcumin dimeric prodrug (CUR2-TK). The nanoparticles generated ROS in response to the light irradiation attributed to the incorporated PA. The ROS further triggered the lysis of the cell membrane and exposed the nanoparticles for enhanced tumor cellular uptake, and the ROS also cleaved CUR2-TK for controlled CUR drug release. Moreover, the ROS performed photodynamic therapy (PDT). The chemotherapy and PDT produced a combined effect in the treatment of cancer cells, thus enhancing anticancer therapeutic efficacy.
Assuntos
Curcumina , Nanopartículas , Neoplasias , Fotoquimioterapia , Pró-Fármacos , Linhagem Celular Tumoral , Curcumina/farmacologia , Curcumina/uso terapêutico , Membrana Eritrocítica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chemotherapy is one of the commonly used therapies for the treatment of malignant tumors. Insufficient drug-loading capacity is the major challenge for polymeric micelle-based drug delivery systems of chemotherapy. Here, the redox-responsive star-shaped polymeric prodrug (PSSP) and the dimeric prodrug of paclitaxel (PTX) were prepared. Then the dimeric prodrug of PTX (diPTX, diP) was loaded into the core of the star-shaped polymeric prodrug micelles of PSSP by hydrophobic interaction forming the redox-responsive prodrug micelles of diPTX@PSSP for intracellular drug release in tumor cells. The hydrodynamic diameter of diPTX@PSSP nanoparticles was 114.3 nm ± 2.1 (PDI = 0.219 ± 0.016), and the micelles had long-term colloidal stability and the drug-loading content (DLC) of diPTX and PTX is 16.7 and 46.9%, respectively. The prepared micelles could broke under the reductive microenvironment within tumor cells, as a result, the dimeric prodrug of diP and polymeric prodrug micelles of PSSP were rapidly disassembled, leading to the rapid release of intracellular drugs. In vitro release studies showed that under the condition of reduced glutathione (GSH) (10 mM), the release of PTX was significantly accelerated with approximately 86.6% released within 21 h, and the released PTX in cytoplasm could promote the disintegration of microtubules and induce cell apoptosis. These results indicated that the new type of this reduction-sensitive nanodrug delivery system based on dimeric prodrug@polymeric prodrug micelles would be a promising technology in chemotherapy.
RESUMO
Although podophyllotoxin (POD) demonstrates high efficiency to inhibit various cancers, its clinic application is limited to poor bioavailability. Nanoparticles derived from homodimeric prodrugs with high drug loading potential are emerging as promising nanomedicines. However, complete intracellular drug release remains a major hindrance to the use of homodimeric prodrugs-based nanomedicine. We sought to develop a reactive oxygen species (ROS) responsive POD dimeric prodrug by incorporating vitamin K3 (VK3) and Pluronic F127 to synthesize a spheroid nanoparticle (PTV-NPs). PTV-NPs with high POD content could release drugs under the ROS enrichment microenvironment in cancer cells. The released VK3 could produce abundant ROS selectively in tumor cells catalyzed by the overexpressed NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme. In turn, the resultant high ROS concentration promoted the conversion of POD dimeric prodrug to POD monomer, thereby achieving the selective killing of cancer cells with weak system toxicity. In vitro and in vivo studies consistently confirmed that PTV-NPs exhibit high drug loading potential and upstanding bioavailability. They are also effectively internalized by tumor cells, induce abundant intracellular ROS generation, and have high tumor-specific cytotoxicity. This ROS-responsive dimeric prodrug nanoplatform characterized by selective self-amplification drug release may hold promise in the field of antitumor drug delivery.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/patologia , Podofilotoxina/administração & dosagem , Podofilotoxina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NAD(P)H Desidrogenase (Quinona)/metabolismo , NADP/metabolismo , Nanopartículas/química , Podofilotoxina/farmacocinética , Poloxâmero/química , Polímeros/química , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/fisiologia , Vitamina K 3/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.
Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Glicólise , Morte Celular Imunogênica , Terapia de Imunossupressão , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Pró-Fármacos/uso terapêuticoRESUMO
Gastric cancer (GC) remains a major public health problem. Ursolic acid (UA) is reported to be effective in inhibiting GC; however, its low solubility and poor biocompatibility have greatly hindered its clinical application. Herein, an innovative reactive oxygen species (ROS)-sensitive UA dimeric prodrug is developed by coupling two UA molecules via a ROS-cleavable linkage, which can self-assemble into stable nanoparticles in the presence of surfactant. This new UA-based delivery system comprises the following major components: (I) dimeric prodrug inner core that can achieve high drug-loading (55%, w/w) and undergo rapid and selective conversion into intact drug molecules in response to ROS; (II) a polyethylene glycol (PEG) shell to improve colloid stability and extend blood circulation, and (III) surface-modified internalizing RGD (iRGD) to increase tumor targeting. Enhancement of the antitumor effect of this delivery system was demonstrated against GC tumors in vitro and in vivo. This novel approach offers the potential for clinical applications of UA.
Assuntos
Nanopartículas/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Química Farmacêutica , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Distribuição Aleatória , Triterpenos/administração & dosagem , Triterpenos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto , Ácido UrsólicoRESUMO
With the rapid development of conjugation chemistry and biomedical nanotechnology, prodrug-based nanosystems (PNS) have emerged as promising drug delivery nanoplatforms. Dimeric prodrug, as an emerging branch of prodrug, has been widely investigated by covalently conjugating two same or different drug molecules. In recent years, great progress has been made in dimeric prodrug-based nanosystems (DPNS) for cancer therapy. Many advantages offered by DPNS have significantly facilitated the delivery efficiency of anticancer drugs, such as high drug loading capacity, favorable pharmacokinetics, tumor stimuli-sensitive drug release and facile combination theranostics. Given the rapid developments in this field, we here outline the latest updates of DPNS in cancer treatment, focusing on dimeric prodrug-encapsulated nanosystems, dimeric prodrug-nanoassemblies and tumor stimuli-responsive DPNS. Moreover, the design principle, advantages and challenges of DPNS for clinical cancer therapy are also highlighted.
Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanomedicina , Neoplasias/tratamento farmacológicoRESUMO
In the present study, we have developed the robust nanoparticles (MGC-GNP/PTX), which are TAMs and tumor cells-dual recognizable, for targeting cancer therapy. Of great importance, the developed nano-platforms are glutathione (GSH)-activable, which means it remains structure intact under normal physiological condition and can be disrupted when exposed to certain concentration of GSH. As demonstrated by the drug release assay in vitro, MGC-GNP/PTX exhibited an excellent structure stability under the normal condition with only 10% of cumulative drug release at 72â¯h. However, after increasing the concentration of GSH to 1â¯mM or 10â¯mM, the release of PTX from the nanoparticles was significantly accelerated and approximately 35% or 95% of drugs was released. Cellular experiments and in vivo tumor targeting assay displayed that the developed nanoparticles have a super capacity of tumor cells and TAMs-dual targeting drug delivery, which resulted in much stronger cytotoxicity when compared to the unmodified ones. Finally, the pharmacodynamic evaluation indicated that the mice treated with MGC-GNP/PTX displayed the strongest tumor suppression ability versus other groups. More importantly, the treatment of MGC-GNP/PTX did not significantly influence the body weight and pathological of the mice, indicated that the prepared nanoparticle system had a satisfactory bio-safety for targeting tumor drug delivery.