RESUMO
The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Our in vitro and in vivo experiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics.
Assuntos
Adipócitos , Antineoplásicos , Carcinoma Hepatocelular , Docetaxel , Exossomos , Neoplasias Hepáticas , Nanopartículas , Exossomos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Humanos , Docetaxel/administração & dosagem , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Adipócitos/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Camundongos Nus , Fototerapia/métodos , Sistemas de Liberação de Medicamentos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos BALB CRESUMO
Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.
Assuntos
Isoflavonas , Pró-Fármacos , Animais , Ratos , Administração Oral , Aminoácidos/química , Disponibilidade Biológica , Carbamatos/química , Pró-Fármacos/química , Solubilidade , ÁguaRESUMO
Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.
Assuntos
Antineoplásicos , Curcumina , Nanopartículas , Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Docetaxel/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Glutationa , Antineoplásicos/uso terapêutico , Linhagem Celular TumoralRESUMO
Nanotechnology's potential in revolutionising cancer treatments is evident in targeted drug delivery systems (DDSs) engineered to optimise therapeutic efficacy and minimise toxicity. This study examines a novel nanocarrier constructed with carbon nano-onions (CNOs), engineered and evaluated for its ability to selectively target cancer cells overexpressing the hyaluronic acid receptor; CD44. Our results highlighted that the CNO-based nanocarrier coupled with hyaluronic acid as the targeting agent demonstrated effective uptake by CD44+ PANC-1 and MIA PaCa-2 cells, while avoiding CD44- Capan-1 cells. The CNO-based nanocarrier also exhibited excellent biocompatibility in all tested pancreatic ductal adenocarcinoma (PDAC) cells, as well as healthy cells. Notably, the CNO-based nanocarrier was successfully loaded with chemotherapeutic 4-(N)-acyl- sidechain-containing prodrugs derived from gemcitabine (GEM). These prodrugs alone exhibited remarkable efficacy in killing PDAC cells which are known to be GEM resistant, and their efficacy was amplified when combined with the CNO-based nanocarrier, particularly in targeting GEM-resistant CD44+ PDAC cells. These findings demonstrate the potential of CNOs as promising scaffolds in advancing targeted DDSs, signifying the translational potential of carbon nanoparticles for cancer therapy.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pró-Fármacos , Humanos , Gencitabina , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Cebolas , Ácido Hialurônico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Currently, cisplatin resistance has been recognized as a multistep cascade process for its clinical chemotherapy failure. Hitherto, it remains challenging to develop a feasible and promising strategy to overcome the cascade drug resistance (CDR) issue for achieving fundamentally improved chemotherapeutic efficacy. Herein, a novel self-assembled nanoagent is proposed, which is constructed by Pt(IV) prodrug, cyanine dye (cypate), and gadolinium ion (Gd3+), for systematically conquering the cisplatin resistance by employing near-infrared (NIR) light activated mild-temperature hyperthermia in tumor targets. The proposed nanoagents exhibit high photostability, GSH/H+-responsive dissociation, preferable photothermal conversion, and enhanced cellular uptake performance. In particular, upon 785-nm NIR light irradiation, the generated mild temperature of ≈ 43 °C overtly improves the cell membrane permeability and drug uptake, accelerates the disruption of intracellular redox balance, and apparently enhances the formation of Pt-DNA adducts, thereby effectively overcoming the CDR issue and achieves highly improved therapeutic efficacy for cisplatin-resistant tumor ablation.
Assuntos
Cisplatino , Resistencia a Medicamentos Antineoplásicos , Hipertermia Induzida , Indóis , Propionatos , Cisplatino/farmacologia , Cisplatino/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Animais , Hipertermia Induzida/métodos , Camundongos , Linhagem Celular Tumoral , Raios Infravermelhos , Gadolínio/química , Gadolínio/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Camundongos Endogâmicos BALB C , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos Nus , Carbocianinas/química , Carbocianinas/farmacologiaRESUMO
Non-tuberculosis mycobacteria (NTM) can cause severe respiratory infection in patients with underlying pulmonary conditions, and these infections are extremely difficult to treat. In this report, we evaluate a nitric oxide (NO)-releasing prodrug [methyl tris diazeniumdiolate (MD3)] against a panel of NTM clinical isolates and as a treatment for acute and chronic NTM infections in vivo. Its efficacy in inhibiting growth or killing mycobacteria was explored in vitro alongside evaluation of the impact to primary human airway epithelial tissue. Airway epithelial tissues remained viable after exposure at concentrations of MD3 needed to kill mycobacteria, with no inherent toxic effect from drug scaffold after NO liberation. Resistance studies conducted via serial passage with representative Mycobacterium abscessus isolates demonstrated no resistance to MD3. When administered directly into the lung via intra-tracheal administration in mice, MD3 demonstrated significant reduction in M. abscessus bacterial load in both acute and chronic models of M. abscessus lung infection. In summary, MD3 is a promising treatment for complex NTM pulmonary infection, specifically those caused by M. abscessus, and warrants further exploration as a therapeutic.
Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Pró-Fármacos , Humanos , Animais , Camundongos , Óxido Nítrico , Antibacterianos/farmacologia , Pró-Fármacos/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas , Testes de Sensibilidade MicrobianaRESUMO
Synergistic photothermal immunotherapy has attracted widespread attention due to the mutually reinforcing therapeutic effects on primary and metastatic tumors. However, the lack of clinical approval nanomedicines for spatial, temporal, and dosage control of drug co-administration underscores the challenges facing this field. Here, a photothermal agent (Cy7-TCF) and an immune checkpoint blocker (NLG919) are conjugated via disulfide bond to construct a tumor-specific small molecule prodrug (Cy7-TCF-SS-NLG), which self-assembles into prodrug-like nano-assemblies (PNAs) that are self-delivering and self-formulating. In tumor cells, over-produced GSH cleaves disulfide bonds to release Cy7-TCF-OH, which re-assembles into nanoparticles to enhance photothermal conversion while generate reactive oxygen species (ROSs) upon laser irradiation, and then binds to endogenous albumin to activate near-infrared fluorescence, enabling multimodal imaging-guided phototherapy for primary tumor ablation and subsequent release of tumor-associated antigens (TAAs). These TAAs, in combination with the co-released NLG919, effectively activated effector T cells and suppressed Tregs, thereby boosting antitumor immunity to prevent tumor metastasis. This work provides a simple yet effective strategy that integrates the supramolecular dynamics and reversibility with stimuli-responsive covalent bonding to design a simple small molecule with synergistic multimodal imaging-guided phototherapy and immunotherapy cascades for cancer treatment with high clinical value.
Assuntos
Nanopartículas , Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/uso terapêutico , Nanomedicina Teranóstica , Neoplasias/terapia , Fototerapia , Nanopartículas/química , Antígenos de Neoplasias , Imunoterapia , Dissulfetos , Linhagem Celular TumoralRESUMO
Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.
Assuntos
Anti-Infecciosos , Neoplasias Colorretais , Pró-Fármacos , Humanos , Espécies Reativas de Oxigênio , Ácido Oleico , Platina , Fusobacterium nucleatum , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Polímeros , Nanopartículas Magnéticas de Óxido de Ferro , Antibacterianos/farmacologia , Peroxidases , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Stimuli-responsive cross-linked micelles (SCMs) are ideal nanocarriers for anti-cancer drugs. Compared with non-cross-linked micelles, SCMs exhibit superior structural stability. At the same time, the introduction of an environmentally sensitive crosslinker into a drug delivery system allows SCMs to respond to single or multiple stimuli in the tumor microenvironment, which can minimize drug leakage during the blood circulation process. In this study, curcumin (CUR) was modified as the hydrophobic core crosslinker by utilizing the bisphenol structure, and redox sensitive disulfide bonds were introduced to prepare the glutathione (GSH) stimulated responsive core crosslinker (abbreviated as N3-ss-CUR-ss-N3). In addition, amphiphilic polymer APEG-b-PBYP was prepared through the ring opening reaction, and reacted with the crosslinker through the "click" reaction. After being dispersed in the aqueous phase, core cross-linked nanoparticles (CCL NPs) were obtained. Finally, monoclonal antibody CD326 (mAb-CD326) was reduced and coupled to the hydrophilic chain ends to obtain the nanoparticles with surface modified antibodies (R-mAb-CD326@CCL NPs) for further enhancing targeted drug delivery. The structures of the polymer and crosslinker were characterized by 1H NMR, UV-Vis, FT-IR, and GPC. The morphology, size and stability of CCL NPs and R-mAb-CD326@CCL NPs were investigated by DLS and TEM. The in vitro drug release behavior of CCL NPs was also studied. The results showed that the CCL NPs exhibited reduction-responsiveness and were able to release the original drug CUR under 10 mM GSH conditions. Additionally, the CCL NPs exhibited excellent stability in both the simulated body fluid environment and organic solvents. Especially, R-mAb-CD326@CCL NPs can actively target tumor cells and showed better therapeutic efficacy in in vivo experiments with a tumor suppression rate of 78.7%. This work provides a new idea for the design of nano-drugs targeting breast cancer.
Assuntos
Curcumina , Neoplasias , Pró-Fármacos , Pró-Fármacos/química , Curcumina/química , Micelas , Anticorpos Monoclonais/uso terapêutico , Espectroscopia de Infravermelho com Transformada de Fourier , Polímeros/química , Neoplasias/tratamento farmacológicoRESUMO
ABBV-167, a phosphate prodrug of BCL-2 inhibitor venetoclax, was recently progressed into the clinic as an alternative means of reducing pill burden for patients in high-dose indications. The dramatically enhanced aqueous solubility of ABBV-167 allowed for high drug loading within a crystalline tablet and, when administered in phase I clinical study, conferred venetoclax exposure commensurate with the equivalent dose administered as an amorphous solid dispersion. In enabling the progression into the clinic, we performed a comprehensive evaluation of the CMC development aspects of this beyond the rule of five (bRo5) prodrug. Adding a phosphate moiety resulted in excessively complex chemical speciation and solid form landscapes with significant physical-chemical stability liabilities. A combination of experimental and computational methods including microelectron diffraction (MicroED), total scattering, tablet colorimetry, finite element, and molecular dynamics modeling were used to understand CMC developability across drug substance and product manufacture and storage. The prodrug's chemical structural characteristics and loose crystal packing were found to be responsible for the loss of crystallinity during its manufacturing, which in turn led to high solid-state chemical reactivity and poor shelf life stability. The ABBV-167 case exemplifies key CMC development challenges for complex chemical matter such as bRo5 phosphate prodrugs with significant ramifications during drug substance and drug product manufacturing and storage.
Assuntos
Pró-Fármacos , Humanos , Pró-Fármacos/química , Fosfatos , Desenvolvimento de Medicamentos , Solubilidade , ComprimidosRESUMO
COVID-19 has been shown to induce inflammatory disorders and CNS manifestations. Swift and efficient treatment strategies are urgently warranted for the management of COVID, inflammatory and neurological disorders. Hydrogen sulfide (H2S) has been associated with several clinical disorders due to its potential to influence a broad range of biological signalling pathways. According to recent clinical studies, COVID patients with lower physiological H2S had higher fatality rates. These findings clearly demonstrate an inverse correlation between H2S levels and the severity of COVID-19. H2S has been proposed as a protective molecule because of its antioxidant, anti-inflammatory, and antiviral properties. Various H2S-releasing prodrugs, hybrids and natural compounds have been tested for their therapeutic efficacy in viral infections and inflammatory disorders. In this review, I am highlighting the rationale for using H2S-based interventions for the management of COVID-19 and post-infection inflammatory disorders including neuroinflammation. I am also proposing therepurposing of existing H2S-releasing prodrugs, developing new NO-H2S-hybrids, targeting H2S metabolic pathways, and using H2S-producing dietary supplements as viable defensive strategies against SARS-CoV-2 infection and COVID-19 pathologies.
Assuntos
COVID-19 , Sulfeto de Hidrogênio , Pró-Fármacos , Humanos , Sulfeto de Hidrogênio/metabolismo , SARS-CoV-2 , Anti-Inflamatórios/farmacologiaRESUMO
The clinical application of growth factors such as recombinant human bone morphogenetic protein-2 (rh-BMP-2), for functional bone regeneration remains challenging due to limited in vivo efficacy and adverse effects of previous modalities. To overcome the instability and short half-life of rh-BMP-2 in vivo, we developed a novel osteogenic supplement by fusing a protein transduction domain (PTD) with BMP-2, effectively creating a prodrug of BMP-2. In this study, we first created an improved PTD-BMP-2 formulation using lipid nanoparticle (LNP) micellization, resulting in downsizing from micrometer to nanometer scale and achieving a more even distribution. The micellized PTD-BMP-2 (mPTD-BMP-2) demonstrated improved distribution and aggregation profiles. As a prodrug of BMP-2, mPTD-BMP-2 successfully activated Smad1/5/8 and induced mineralization with osteogenic gene induction in vitro. In vivo pharmacokinetic analysis revealed that mPTD-BMP-2 had a much more stable pharmacokinetic profile than rh-BMP-2, with a 7.5-fold longer half-life. The in vivo BMP-responsive element (BRE) reporter system was also successfully activated by mPTD-BMP-2. In the in vivo rat tibia distraction osteogenesis (DO) model, micro-computed tomography (micro-CT) scan findings indicated that mPTD-BMP-2 significantly increased bone volume, bone surface, axis moment of inertia (MOI), and polar MOI. Furthermore, it increased the expression of osteogenesis-related genes, and induced bone maturation histologically. Based on these findings, mPTD-BMP-2 could be a promising candidate for the next-generation osteogenesis drug to promote new bone formation in DO surgery. STATEMENT OF SIGNIFICANCE: This study introduces micellized bone morphogenetic protein-2 (mPTD-BMP-2), a next-generation osteogenic supplement that combines protein transduction domain (PTD) and nano-sized micelle formulation technique to improve transduction efficiency and stability. The use of PTD represents a novel approach, and our results demonstrate the superiority of mPTD-BMP-2 over rh-BMP-2 in terms of in vivo pharmacokinetic profile and osteogenic potential, particularly in a rat tibial model of distraction osteogenesis. These findings have significant scientific impact and potential clinical applications in the treatment of bone defects that require distraction osteogenesis. By advancing the field of osteogenic supplements, our study has the potential to contribute to the development of more effective treatments for musculoskeletal disorders.
Assuntos
Osteogênese por Distração , Pró-Fármacos , Ratos , Humanos , Animais , Tíbia/metabolismo , Osteogênese por Distração/métodos , Pró-Fármacos/farmacologia , Microtomografia por Raio-X , Proteínas Morfogenéticas Ósseas , Proteína Morfogenética Óssea 2/farmacologia , Osteogênese , Proteína Morfogenética Óssea 7/farmacologiaRESUMO
Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (N-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. In vivo studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.
Assuntos
Neoplasias , Pró-Fármacos , Selênio , Ratos , Animais , Camundongos , Ratos Sprague-Dawley , Pró-Fármacos/uso terapêutico , Ácido N-Acetilneuramínico , Bortezomib/farmacologia , Bortezomib/uso terapêutico , ÉsteresRESUMO
Photothermal therapy, combined with chemotherapy, holds promising prospects for the therapeutic outcome of malignant tumors. However, the synergistic therapeutic effect suffers from low coloading capacity and inefficient synchronous tumor-targeting delivery of chemodrug and photothermal photosensitizers. Herein, we designed a versatile carrier-free nanoplatform to seek improvement for chemo-photothermal therapy. An NIR photosensitizer IR-808 was used for noninvasive cancer imaging, diagnosis, and imaging-guided photothermal therapy. A reduction-sensitive paclitaxel prodrug (PTX-SS-PEG2k) was rationally synthesized by covalently linking paclitaxel with polyethylene glycol 2000 via a disulfide bond. Then, the carrier-free nanoassemblies were constructed with an inner core of IR-808 and an amphiphilic paclitaxel prodrug shell. PTX-SS-PEG2k served as a stabilizer and chemodrug and could facilitate the self-assembly of IR-808 nanoparticles with high coloading efficiency and reduction-sensitive drug release. The versatile nanoplatform exhibited multiple advantages, including high drug payload, reduction-sensitive drug release, tumor-targeting drug delivery, and potent synergistic antitumor effect. We provide a versatile theranostic nanoplatform, which improves the effectiveness of synergetic chemo-photothermal therapy and reduces the off-target toxicity.
Assuntos
Hipertermia Induzida , Nanopartículas , Pró-Fármacos , Pró-Fármacos/química , Terapia Fototérmica , Fototerapia/métodos , Linhagem Celular Tumoral , Paclitaxel , Nanopartículas/química , Liberação Controlada de Fármacos , Doxorrubicina/química , Hipertermia Induzida/métodosRESUMO
Preventing islet ß-cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self-care, but drugs focused on reducing islets ß-cell death are lacking. Given that ß-cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in ß-cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long-term and stable elimination of ROS in ß-cells without eliciting toxic side-effects. Here, it is proposed to restore the endogenous antioxidant capacity of ß-cells to efficiently prevent ß-cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also "send" selenium precisely to ß-cells with ROS response to greatly enhance the antioxidant capacity of ß-cells by increasing GPX1 expression. Therefore, SENDs greatly rescue ß-cells by restoring mitophagy and alleviating endoplasmic reticulum stress (ERS), and demonstrate much stronger efficacy than the first-line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment.
Assuntos
Diabetes Mellitus Tipo 2 , Pró-Fármacos , Selênio , Humanos , Antioxidantes/farmacologia , Selênio/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Mitofagia , Estresse Oxidativo , Glutationa Peroxidase GPX1 , Estresse do Retículo EndoplasmáticoRESUMO
Head and neck cancer is a major cancer type, with high motility rates that reduce the quality of life of patients. Herein, we investigated the effectiveness and mechanism of a combination therapy involving TLR9 activator (CpG-2722) and phosphatidylserine (PS)-targeting prodrug of SN38 (BPRDP056) in a syngeneic orthotopic head and neck cancer animal model. The results showed a cooperative antitumor effect of CpG-2722 and BPRDP056 owing to their distinct and complementary antitumor functions. CpG-2722 induced antitumor immune responses, including dendritic cell maturation, cytokine production, and immune cell accumulation in tumors, whereas BPRDP056 directly exerted cytotoxicity toward cancer cells. We also discovered a novel function and mechanism of TLR9 activation, which increased PS exposure on cancer cells, thereby attracting more BPRDP056 to the tumor site for cancer cell killing. Killed cells expose more PS in tumor for BPRDP056 targeting. Tumor antigens released from the dead cells were taken up by antigen-presenting cells, which enhanced the CpG-272-promoted T cell-mediated tumor-killing effect. These form a positive feed-forward antitumor effect between the actions of CpG-2722 and BPRDP056. Thus, the study findings suggest a novel strategy of utilizing the PS-inducing function of TLR9 agonists to develop combinational cancer treatments using PS-targeting drugs.
Assuntos
Neoplasias , Pró-Fármacos , Animais , Receptor Toll-Like 9 , Fosfatidilserinas , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Qualidade de Vida , ImunidadeRESUMO
Indocyanine green (ICG) has been employed in medical diagnostics due to its superior photophysical characteristics. However, these advantages are offset by its quick body clearance and inferior photo-stability. In this work, programmable prodrug carriers for chemotherapy/PDT/PTT against nasopharyngeal carcinoma (NPC) were created in order to increase photo-stability and get around biochemical hurdles. The programmable prodrug carriers (PEG-PLA@DIT-PAMAM) that proactively penetrated deeply into NPC tumors and produced the deep phototherapy and selective drug release under laser irradiation was created by dendrimer-DOX/ICG/TPP (DIT-PAMAM) and PEGylated poly (α-lipoic acid) (PLA) copolymer. Long circulation times and minimal toxicity to mammalian cells are two benefits of PEG-coated carriers. The overexpressed GSH on the tumor cell or vascular endothelial cell of the NPC disintegrated the PEG-g-PLA chains and released the DIT-PAMAM nanoparticles after the carriers had reached the NPC tumor periphery. Small, positively charged DIT-PAMAM nanoparticles may penetrate tumors effectively and remain inside tumor for an extended period of time. In addition, the induced ROS cleaved the thioketal linkers for both DOX and nanoparticles and product hyperthermia (PTT) to kill cancer cells under laser irradiation, facilitating faster diffusion of nanoparticles and more effective tumor penetration with a programmable publication of DOX. The programmable prodrug carries showed high photo-stability high photo-stability, which enabled very effective PDT, PTT, and tumor-specific DOX release. With the goal of combining the effects of chemotherapy, PDT, and PTT against NPC, this research showed the great efficacy of programmable prodrug carriers.
Assuntos
Hipertermia Induzida , Neoplasias Nasofaríngeas , Pró-Fármacos , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Poliésteres , MamíferosRESUMO
Dexamethasone (DXM) is a potent glucocorticoid with an anti-inflammatory and anti-angiogenic activity which is widely clinically used. Systemic side effects limit the long-term use of DXM in patients requiring formulations which deliver and selectively release the drug to the diseased tissues. This in vitro study compares the suitability of DXM and commonly used prodrugs dexamethasone-21-phosphate (DXMP) and dexamethasone-21-palmitate (DP) as well as DXM complexed by 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) for the use in thermosensitive liposomes (TSL). DXM showed a poor retention and a low final drug:lipid ratio in a 1,2-dipalmitoyl-snglycero-3-phosphodiglycerol-based TSL (DPPG2-TSL) and a low-temperature sensitive liposome (LTSL). In contrast to DXM, DXMP and DP were stably retained at 37 °C in TSL in serum and could be encapsulated with high drug:lipid ratios in DPPG2-TSL and LTSL. DXMP showed a rapid release at mild hyperthermia (HT) from both TSL in serum, whereas DP remained incorporated in the TSL bilayer. According to release experiments with carboxyfluorescein (CF), HP-γ-CD and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) are suitable vehicles for the loading of DXM into DPPG2-TSL and LTSL. Complexation of DXM with HP-γ-CD increased the aqueous solubility of the drug leading to approx. ten times higher DXM:lipid ratio in DPPG2-TSL and LTSL in comparison to un-complexed DXM. Both DXM and HP-γ-CD showed increased release at HT in comparison to 37 °C in serum. In conclusion, DXMP and DXM complexed by HP-γ-CD represent promising candidates for TSL delivery.
Assuntos
Hipertermia Induzida , Pró-Fármacos , Humanos , Lipossomos , Temperatura Alta , Excipientes , Doxorrubicina/uso terapêutico , Lipídeos , DexametasonaRESUMO
Pd-catalyzed chemistry has played a significant role in the growing subfield of bioorthogonal catalysis. However, rationally designing Pd nanocatalysts that show outstanding catalytic activity and good biocompatibility poses a great challenge. Herein, we propose an innovative strategy through exploiting black phosphorous nanosheets (BPNSs) to enhance Pd-mediated bioorthogonal catalytic activity. Firstly, the electron-donor properties of BPNSs enable in situ growth of Pd nanoparticles (PdNPs) on it. Meanwhile, due to the superb capability of reducing PdII , BPNSs can act as hard nucleophiles to accelerate the transmetallation in the decaging reaction process. Secondly, the lone pair electrons of BPNSs can firmly anchor PdNPs on their surface via Pd-P bonds. This design endows Pd/BP with the capability to retard tumor growth by activating prodrugs. This work proposes new insights into the design of heterogeneous transition-metal catalysts (TMCs) for bioorthogonal catalysis.
Assuntos
Nanopartículas , Neoplasias , Pró-Fármacos , Humanos , Paládio/química , Fósforo , Neoplasias/patologia , CatáliseRESUMO
Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund's adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal. SIGNIFICANCE STATEMENT: The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.