RESUMEN
The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel "Y"-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.
Asunto(s)
Barrera Hematoencefálica , Neoplasias Encefálicas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Chaperón BiP del Retículo Endoplásmico , Glioma , Ratones Desnudos , Péptidos , Animales , Glioma/tratamiento farmacológico , Glioma/metabolismo , Glioma/patología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Doxorrubicina/farmacocinética , Humanos , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Péptidos/química , Péptidos/administración & dosificación , Barrera Hematoencefálica/metabolismo , Proteínas de Choque Térmico/metabolismo , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapéutico , Ratones Endogámicos BALB C , Receptores de Dopamina D2/metabolismo , Ratones , MasculinoRESUMEN
Challenges for glioma treatment with nanomedicines include physio-anatomical barriers (the blood-brain barrier and blood-brain tumor barrier), low drug loading capacity, and limited circulation time. Here, a red blood cell membrane-coated docetaxel drug nanocrystal (pV-RBCm-NC(DTX)), modified with pHA-VAP (pV) for all-stage targeting of glioma, was designed. The NC(DTX) core exhibited a high drug loading capacity but low in vivo stability, and the RBCm coating significantly enhanced the stability and prolonged in vivo circulation. Moreover, the Y-shaped targeting ligand pV was modified by a mild avidin-biotin interaction, which endowed RBCm-NC(DTX) with superior barrier-crossing ability and therapeutic efficacy. The integration of nanocrystal technology, cell membrane coating, and the avidin-biotin insertion method into this active targeting biomimetic formulation represents a promising drug delivery strategy for glioma.
Asunto(s)
Antineoplásicos , Neoplasias Encefálicas , Docetaxel , Membrana Eritrocítica , Glioma , Nanopartículas , Docetaxel/administración & dosificación , Docetaxel/farmacocinética , Docetaxel/química , Glioma/tratamiento farmacológico , Animales , Nanopartículas/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Membrana Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/química , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Masculino , Sistemas de Liberación de Medicamentos , Avidina/administración & dosificación , Avidina/química , Humanos , Biotina/química , Biotina/administración & dosificación , Ratas Sprague-Dawley , Barrera Hematoencefálica/metabolismo , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.
RESUMEN
Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.
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Neoplasias Pulmonares , Nanopartículas , Humanos , Ratones , Animales , Nanopartículas/uso terapéuticoRESUMEN
Chemotherapy is still the mainstay treatment for metastatic triple-negative breast cancers (TNBC) currently in clinical practice. The unmet needs of chemotherapy for metastatic TNBC are mainly from the insufficient drug delivery and unavailable targeting strategy that thwart the whole progression of metastatic TNBC. The in vivo ligands-mediated active targeting efficiency is usually affected by protein corona. While, the protein corona-bridged natural targeting, in turn, provides a new way for specific drug delivery. Herein, we develop a novel metastatic progression-oriented in vivo self-assembled Cabazitaxel nanocrystals (CNC) delivery system (PC/CNC) through the CNC automatically absorbing functional plasma proteins (transferrin, apolipoprotein A-IV and apolipoprotein E) in vivo, aiming to achieve the simultaneously targeted delivery to primary tumors, circulating tumor cells and metastatic lesions. With the unique advantages of superhigh drug-loading and protein corona empowered active targeting properties to tumor cells, HUVECs, active-platelets and blood-brain barrier/blood-tumor barrier, the PC/CNC exhibits a significantly improved therapeutic effect in metastatic TNBC therapy compared with free drug and CNC-loaded liposomes.
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Nanopartículas , Corona de Proteínas , Neoplasias de la Mama Triple Negativas , Línea Celular Tumoral , Humanos , Liposomas , Nanopartículas/química , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Drug nanocrystals, which are comprised of active pharmaceutical ingredients and only a small amount of essential stabilizers, have the ability to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs; in turn, drug nanocrystal technology can be utilized to develop novel formulations of chemotherapeutic drugs. Compared with passive targeting strategy, active tumor-targeted drug delivery, typically enabled by specific targeting ligands or molecules modified onto the surface of nanomedicines, circumvents the weak and heterogeneous enhanced permeability and retention (EPR) effect in human tumors and overcomes the disadvantages of nonspecific drug distribution, high administration dosage and undesired side effects, thereby contributing to improving the efficacy and safety of conventional nanomedicines for chemotherapy. Continuous efforts have been made in the development of active tumor-targeted drug nanocrystals delivery systems in recent years, most of which are encouraging and also enlightening for further investigation and clinical translation.
RESUMEN
Glioblastoma (GBM) is the most aggressive brain tumor with poor prognosis and frequent recurrence. The blood-brain barrier (BBB), blood-brain tumor barrier (BBTB) hinder the entry of therapeutics into the glioma region. Vasculogenic mimicry (VM) formed by invasive glioma cells is also related to recurrence of GBM. VAP is a D-peptide ligand of GRP78 protein overexpressed on BBTB, VM, and glioma cells but not on normal tissues. Besides, p-hydroxybenzoic acid (pHA) can effectively traverse the BBB. Herein we developed an all-stage glioma-targeted cabazitaxel (CBZ) nanocrystal loaded liposome modified with a "Y" shaped targeting ligand composed of pHA and VAP (pV-Lip/cNC). The pure drug nanocrystal core provided high drug loading, while lipid membrane promoted the stability and circulation time. pV-Lip/cNC exhibited excellent glioma homing, barriers crossing, and tumor spheroid penetrating capability in vitro. Treatment of pV-Lip/cNC displayed enhanced CBZ accumulation in glioma and anti-glioma effect with a median survival time (53 days) significantly longer than that of cNC loaded liposomes modified with either single ligand (42 days for VAP and 45 days for pHA) in the murine orthotopic GBM model. These results indicated pV-Lip/cNC could traverse the BBB and BBTB, destruct VM, and finally kill glioma cells to realize all-stage glioma therapy.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Nanopartículas , Animales , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioma/tratamiento farmacológico , Glioma/metabolismo , Ligandos , Lípidos/uso terapéutico , Liposomas/metabolismo , Ratones , TaxoidesRESUMEN
Intravenous injection of thrombolytic drugs is the most effective strategy for the treatment of thrombotic diseases. However, the clinical application of most thrombolytic drugs is limited by hemorrhagic risks and narrow therapeutic index. The targeted drug delivery systems may help to address these problems. Inspired by the crucial role of platelets in the process of thrombus, Platelet membrane-coated PLGA cores loading lumbrokinase (PNPs/LBK) were designed for effective thrombolysis with reduced hemorrhagic risk. Using a mouse carotid thrombosis model, the affinity of platelet membrane-coated nanoparticles to the thrombus was confirmed. Also, the PNPs/LBK exhibited excellent thrombolytic efficacy at a low dose, compared with free LBK. More importantly, PNPs/LBK showed less adverse effect on the function of the coagulation system, and thus reduced hemorrhagic risk. These results indicated that a promising thrombus-targeted drug delivery system was achieved by coating PLGA nanoparticles with platelet membrane. Such rationally designed drug delivery system will provide a broad platform for thrombus treatment.
Asunto(s)
Nanopartículas , Trombosis , Plaquetas , Fibrinolíticos/uso terapéutico , Humanos , Terapia Trombolítica , Trombosis/tratamiento farmacológicoRESUMEN
Uncontrollable cell proliferation and irreversible neurological damage make glioma one of the most deadly diseases in clinic. Besides the multiple biological barriers, glioma stem cells (GSCs) that are responsible for the maintenance and recurrence of tumor tissues also hinder the therapeutic efficacy of chemotherapy. Therefore, all-stage precisional glioma targeted therapy regimens that could efficiently deliver drugs to glioma cells and GSCs after overcoming multiple barriers have received increasing scrutiny. Methods: A polymeric micelle-based drug delivery system was developed by modifying a "Y-shaped" well-designed ligand of both GRP78 protein and quorum sensing receptor to achieve all-stage precisional glioma targeting, then we evaluated the targeting ability and barrier penetration ability both in vitro and in vivo. In order to achieve all-stage precisional therapy, we need kill both GSCs and glioma related cells. Parthenolide (PTL) has been investigated for its selective toxicity to glioma stem cells while Paclitaxel (PTX) and Temozolomide (TMZ) are widely used in experimental and clinical therapy of glioma respectively. So the in vivo anti-glioma effect of combination therapy was evaluated by Kaplan-Meier survival analysis and immunohistochemical (IHC) examination of tumor tissues. Results: The "Y-shaped" well-designed peptide, termed DWVAP, exhibited excellent glioma (and GSCs) homing and barrier penetration ability. When modified on micelle surface, DWVAP peptide significantly enhanced accumulation of micelles in brain and glioma. In addition, DWVAP micelles showed no immunogenicity and cytotoxicity, which could guarantee their safety when used in vivo. Treatment of glioma-bearing mice with PTL loaded DWVAP modified PEG-PLA micelles plus PTX loaded DWVAP modified PEG-PLA micelles or PTL loaded DWVAP modified PEG-PLA micelles plus TMZ showed improved anti-tumor efficacy in comparison to PTL and PTX loaded unmodified micelles or PTL loaded unmodified micelles plus TMZ. Conclusion: Combination of all-stage targeting strategy and concomitant use of chemotherapeutics and stem cell inhibitors could achieve precise targeted therapy for glioma.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos/uso terapéutico , Glioma/tratamiento farmacológico , Paclitaxel/administración & dosificación , Temozolomida/administración & dosificación , Animales , Línea Celular Tumoral , Chaperón BiP del Retículo Endoplásmico , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Micelas , Péptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Ratas Sprague-Dawley , Sesquiterpenos/administración & dosificaciónRESUMEN
BACKGROUND: Local photothermal therapy (PTT) provides an easily applicable, noninvasive adjunctive therapy for colorectal cancer (CRC), especially when multidrug resistance (MDR) occurs. However, using PTT alone does not result in complete tumor ablation in many cases, thus resulting in tumor recurrence and metastasis. MATERIALS AND METHODS: In this study, we aim to develop a personalized local therapeutic platform combining PTT with long-acting chemotherapy for the treatment of MDR CRC. The platform consists of polyethylene glycol (PEG)-coated gold nanorods (PEG-GNRs) and D-alpha-tocopheryl PEG 1000 succinate (TPGS)-coated paclitaxel (PTX) nanocrystals (TPGS-PTX NC), followed by the incorporation into an in situ hydrogel (gel) system (GNRs-TPGS-PTX NC-gel) before injection. After administration, PEG-GNRs can exert quick and efficient local photothermal response under near-infrared laser irradiation to shrink tumor; TPGS-PTX NC then provides a long-acting chemotherapy due to the sustained release of PTX along with the P-glycoprotein inhibitor TPGS to reverse the drug resistance. RESULTS: The cytotoxicity studies showed that the IC50 of GNRs-TPGS-PTX NC-gel with laser irradiation decreased to ~178-folds compared with PTX alone in drug-resistant SW620 AD300 cells. In the in vivo efficacy test, after laser irradiation, the GNRs-TPGS-PTX NC-gel showed similar tumor volume inhibition compared with GNRs-gel at the beginning. However, after 14 days, the tumor volume of the mice treated with GNRs-gel quickly increased, while that of the mice treated with GNRs-TPGS-PTX NC-gel remained controllable due to the long-term chemotherapeutic effect of TPGS-PTX NC. The mice treated with GNRs-TPGS-PTX NC-gel also showed no weight loss and obvious organ damages and lesions during the treatment, indicating a low systemic side effect profile and a good biocompatibility. CONCLUSION: Overall, the nano-complex may serve as a promising local therapeutic patch against MDR CRC with one-time dosing to achieve a long-term tumor control. The doses of PEG-GNRs and TPGS-PTX NC can be easily adjusted before use according to patient-specific characteristics potentially making it a personalized therapeutic platform.