RESUMO
Nanotechnology has shown tremendous success in the drug delivery field for more effective and safer therapy, and has recently enabled the clinical approval of RNA medicine, a new class of therapeutics. Various nanoparticle strategies have been developed to improve the systemic delivery of therapeutics, among which surface modification of targeting ligands on nanoparticles has been widely explored for 'active' delivery to a specific organ or diseased tissue. Meanwhile, compelling evidence has recently been reported that organ-selective targeting may also be achievable by systemic administration of nanoparticles without surface ligand modification. In this Review, we highlight this unique set of 'passive' nanoparticles and their compositions and mechanisms for organ-selective delivery. In particular, the lipid-based, polymer-based, and biomimetic nanoparticles with tropism to different specific organs after intravenous administration are summarized. The underlying mechanisms (e.g., protein corona and size effect) of these nanosystems for organ selectivity are also extensively discussed. We further provide perspectives on the opportunities and challenges in this exciting area of organ-selective systemic nanoparticle delivery.
Assuntos
Nanopartículas , Nanopartículas/uso terapêutico , Sistemas de Liberação de Medicamentos , Nanotecnologia , Preparações Farmacêuticas , RNARESUMO
Current clinical applications of protein therapy are largely limited to systemically accessible targets in vascular or extracellular areas. Major obstacles to the widespread application of protein therapeutics in cancer treatment include low membrane permeability and endosomal entrapment. Herein, we report a multistage nanoparticle (NP) strategy for systemic and cytosolic protein delivery to tumor cells, by encapsulating a protein conjugate, tetra-guanidinium (TG)-modified saporin, into tumor microenvironment (TME) pH-responsive polymeric NPs. Upon reaching the tumor site after systemic circulation, the polymeric NPs respond rapidly to the acidic tumor microenvironment and release the TG-saporin conjugates, which penetrate the tumor tissue and enter into tumor cells via TG-mediated cytosolic transportation. The TG-saproin NPs showed potent inhibition of lung cancer cell growth in vitro and in vivo. We expect that this multistage NP delivery strategy with long blood circulation, deep tumor penetration, and efficient cytosolic transport may be applicable to various therapeutic proteins for effective cancer treatment.
Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Polímeros/uso terapêutico , Microambiente Tumoral/fisiologiaRESUMO
Nanotechnology has demonstrated great promise for the development of more effective and safer cancer therapies. We recently developed a highly selective inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML). However, the poor drug-like properties were hurdles to its further clinical development. Herein, we re-investigate it by conjugating an amphiphilic polymer and self-assembling into a nanoparticle (NP) with a high loading (~10.3%). The formulation greatly improved its solubility and drastically extended its circulation half-life from ~5.3 to ~117â¯h (>20-fold). In the 150â¯days long-term engraftment model experiment, long intravenous dosing intervals of the NPs (every 4 or 8â¯days) exhibited much better survival and negligible toxicities as compared to daily oral administration of the inhibitor. Moreover, the NPs showed excellent inhibition of tumor growth in the subcutaneous xenograft model. All results suggest that the ultra-long circulating pro-drug NP may provide an effective and safe therapeutic strategy for BCR-ABL-positive CML.
Assuntos
Genes abl/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nanopartículas/química , Inibidores de Proteínas Quinases/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Genes abl/genética , Humanos , Mesilato de Imatinib/química , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene-co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053.
RESUMO
Nanocrystals (NCs) enable the delivery of poorly water-soluble drugs with improved dissolution and bioavailability. However, their uncontrolled release and instability make targeted delivery challenging. Herein, a nano-in-nano delivery system composed of a drug nanocrystal core and liposome shell (NC@Lipo) is presented, which merges the advantages of drug nanocrystals (high drug loading) and liposomes (easy surface functionalization and high stability) for targeted delivery of hydrophobic drugs to tumors. CHMFL-ABL-053 (053), a hydrophobic drug candidate discovered by our group, was employed as a model drug to demonstrate the performance of NC@Lipo delivery system. Surface PEGylated (053-NC@PEG-Lipo) and folic acid-functionalized (053-NC@FA-Lipo) formulations were fabricated by wet ball milling combined with probe sonication. 053-NC@Lipo enabled high drug loading (up to 19.51%), considerably better colloidal stability, and longer circulation in vivo than 053-NC. Compared with free 053, 053-NC@PEG-Lipo and 053-NC@FA-Lipo exhibited higher tumor accumulation and considerably better in vivo antitumor efficacy in K562 xenograft mice with tumor growth inhibition rate (TGI) of up to 98%. Additionally, more effective tumor cell targeting in vitro and higher TGI in vivo were achieved with 053-NC@FA-Lipo. The NC@Lipo strategy may contribute to the targeted delivery of poorly water-soluble drugs with high drug loading, high stability, and tailorable surface, and has potential for the development of more efficient nanocrystal- and liposome-based formulations for commercial and clinical applications. It may also provide new opportunities for potential clinical application of candidate 053.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Animais , Sistemas de Liberação de Medicamentos , Lipossomos , Camundongos , ÁguaRESUMO
An efficient pH-responsive multifunctional polypeptide micelle for simultaneous imaging and in vitro photodynamic therapy (PDT) has been prepared. The goal here is to detect and treat cancer cells by near-infrared fluorescence (NIRF) imaging and PDT synchronously. A photosensitizer BODIPY-Br2 with efficient singlet oxygen generation was synthesized at first which owns both seductive abilities in fluorescence emission and reactive oxygen species (ROS) generation under light irradiation. Then, amphiphilic copolymer micelles pH-triggered disassembly were synthesized from N-carboxyanhydride (NCA) monomer via a ring-opening polymerization and click reaction for the loading of BODIPY-Br2 by hydrophobic interaction, and the driving force is the protonation of the diisopropylethylamine groups conjugated to the polypeptide side chains. In vitro tests performed on HepG2 cancer cells confirm that the cell suppression rate was improved by more than 40% in the presence of light in the presence of an extremely low energy density (12 J/cm(2)) with very low concentration of 5.4 µM photosensitizer. At the same time, the internalization of the nanoparticles by cells can also be traced by NIRF imaging, indicating that the NIR nanoparticles presented imaging guided photodynamic therapy properties. It provides the potential of using polypeptide as a biodegradable carrier for NIR image-guided photodynamic therapy.
Assuntos
Plásticos Biodegradáveis/uso terapêutico , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Anidridos/química , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Portadores de Fármacos/química , Fluorescência , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Nanopartículas/química , Peptídeos/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/química , Espécies Reativas de Oxigênio/química , Oxigênio Singlete/químicaRESUMO
Theranostic polymeric nanomaterials are of special important in cancer treatment. Here, novel galactose targeted pH-responsive amphiphilic multiblock copolymer conjugated with both drug and near-infrared fluorescence (NIR) probe has been designed and prepared by a four-steps process: (1) ring-opening polymerization (ROP) of N-carboxy anhydride (NCA) monomers using propargylamine as initiator; (2) reversible addition-fragmentation chain transfer (RAFT) polymerization of oligo(ethylene glycol) methacrylate (OEGMA) and gal monomer by an azido modified RAFT agent; (3) combing the obtained two polymeric segments by click reaction; (4) NIR copolymer prodrug was synthesized by chemical linkage of both cyanine dye and anticancer drug doxorubicin to the block copolymer via amide bond and hydrazone, respectively. The obtained NIRF copolymers were characterized by nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), and its was measured by means of micelles dynamic light scattering (DLS), field emission transmission electron microscopy (FETEM), and UV-vis and fluorescence spectrophotometry. The prodrug has strong fluorescence in the near-infrared region, and a pH sensitive drug release was confirmed at pH of 5.4 via an in vitro drug release experiment. Confocal laser scanning microscopy (CLSM) and flow cytometry experiments of the prodrug on both HepG2 and NIH3T3 cells reveal that the galactose targeted polymeric prodrug shows a fast and enhanced endocytosis due to the specific interaction for HepG2 cells, indicating the as-prepared polymer is a candidate for theranosis of liver cancer.