RESUMO
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.
Assuntos
Antineoplásicos , Neoplasias Encefálicas , Docetaxel , Membrana Eritrocítica , Glioma , Nanopartículas , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/química , Glioma/tratamento farmacológico , Animais , Nanopartículas/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/química , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Masculino , Sistemas de Liberação de Medicamentos , Avidina/administração & dosagem , Avidina/química , Humanos , Biotina/química , Biotina/administração & dosagem , Ratos Sprague-Dawley , Barreira Hematoencefálica/metabolismo , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
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.
Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Doxorrubicina , Sistemas de Liberação de Medicamentos , Chaperona BiP do Retículo Endoplasmático , Glioma , Camundongos Nus , Peptídeos , Animais , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Doxorrubicina/farmacocinética , Humanos , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Peptídeos/química , Peptídeos/administração & dosagem , Barreira Hematoencefálica/metabolismo , Proteínas de Choque Térmico/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Camundongos Endogâmicos BALB C , Receptores de Dopamina D2/metabolismo , Camundongos , MasculinoRESUMO
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.
Assuntos
Neoplasias Pulmonares , Nanopartículas , Humanos , Camundongos , Animais , Nanopartículas/uso terapêuticoRESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Nanopartículas , Coroa de Proteína , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Humanos , Lipossomos , Nanopartículas/química , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life, low targeting ability, and association with serious adverse reactions, such as bleeding complications. Inspired by the natural roles of platelets during thrombus formation, we fabricated a platelet-based delivery system (NO@uPA/PLTs) comprising urokinase (uPA) and arginine (Arg) for targeted thrombolysis and inhibition of re-embolism. The anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet functions. Nitric oxide (NO) generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel, thereby inhibiting re-embolism. NO@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic efficacy. In addition, the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery injury. The coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk, providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.
RESUMO
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.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Nanopartículas , Animais , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Ligantes , Lipídeos/uso terapêutico , Lipossomos/metabolismo , Camundongos , TaxoidesRESUMO
Glioblastoma, the most common malignant tumor of the central nervous system, readily relapses after surgery. Based on the CD47-SIRPα axis, we designed and implanted a thermo-sensitive hydrogel loaded with a gene complex into the postoperative cavity to inhibit the immune escape of residual tumor cells after surgery. A novel non-viral vector, G5-BGG, was synthesized and formed into a gene complex with shRNA plasmid. Our results showed that the G5-BGG/shRNA871 complex downregulated CD47 protein expression, leading to enhanced phagocytosis of U87MG cells by marrow-derived macrophages. G5-BGG/pDNA complex was loaded into a poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel. Studies confirmed that the G5-BGG/pDNA complex remained integrated in the hydrogel and was sustainably released for up to 7 days. In an in vivo orthotopic U87MG postoperative tumor model, G5-BGG/shRNA871-loaded hydrogel combined with temozolomide downregulated CD47 protein expression, increased macrophage infiltration into residual tumors, and significantly prolonged the survival time of mice, indicating potential applications for glioblastoma treatment.