RESUMO
This review highlights a new paradigm in macromolecular nanomedicine - drug-free macromolecular therapeutics (DFMT). The effectiveness of the new system is based on biorecognition events without the participation of low molecular weight drugs. Apoptosis of cells can be initiated by the biorecognition of complementary peptide/oligonucleotide motifs at the cell surface resulting in the crosslinking of slowly internalizing receptors. B-cell CD20 receptors and Non-Hodgkin lymphoma (NHL) were chosen as the first target. Exposing cells to a conjugate of one motif with a targeting ligand decorates the cells with this motif. Further exposure of decorated cells to a macromolecule (synthetic polymer or human serum albumin) containing multiple copies of the complementary motif as grafts results in receptor crosslinking and apoptosis induction in vitro and in vivo. The review focuses on recent developments and explores the mechanism of action of DFMT. The altered molecular signaling pathways demonstrated the great potential of DFMT to overcome rituximab resistance resulting from either down-regulation of CD20 or endocytosis and trogocytosis of rituximab/CD20 complexes. The suitability of this approach for the treatment of blood borne cancers is confirmed. In addition, the widespread applicability of DFMT as a new concept in macromolecular therapeutics for numerous diseases is exposed.
Assuntos
Linfoma não Hodgkin/terapia , Nanomedicina/métodos , Polímeros/uso terapêutico , Animais , Antígenos CD20/metabolismo , Apoptose , Humanos , Ligantes , Linfoma não Hodgkin/metabolismo , Terapia de Alvo MolecularRESUMO
Lipid nanoparticles (LNs) are widely investigated for oral drug delivery, and for achieving significant advantages in colloidal stability, biocompatibility and scaled-up possibility. However, researchers face challenge of developing methods to improve the ability of LNs in overcoming multiple barriers (i.e., mucus and epithelium barrier) in gastrointestinal (GI) tract because of the contradictory requirement of nanoparticle (NP) surface properties in the two processes. Therefore, we designed novel LNs with adjustable surface properties by coating lipid core with hydrophobic substitutes grafting N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA). In the present study, different substitutes (i.e., monocyclic, polycyclic, and linear segments) were grafted on pHPMA backbone. Screening studies demonstrated that type and grafting degree of substitutes both influenced hydrophilic-hydrophobic properties of NP surface and improved penetration through mucus. When a hydrophilic-hydrophobic balance was achieved, NPs showed elevated mucus permeability compared with bare LNs; this phenomenon subsequently contributed to higher cellular uptake. Moreover, ß-sitosterol (SITO)-modified pHPMA-coated (grafting degree: 5%) LNs (5% SITO-LNs) exhibited the highest mucus permeability, transepithelial transport, and in situ absorption. Interestingly, even with the highest surface hydrophilicity, 5% SITO-LNs with Caco-2 cells did not show impaired membrane affinity, which was not observed in other groups. Further investigations of mechanism demonstrated that membrane affinity was significantly enhanced by ß-SITO-mediated interaction with Niemann-Pick C1-like 1 (NPC1L1) protein on cell membranes. These results proved that hydrophobic substitutes play a critical role in altering hydrophilic-hydrophobic property of particle surface and improving penetration through multiple barriers. ß-SITO-induced specific interaction can provide additional benefits to efficiency of oral delivery of LNs.
Assuntos
Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Lipídeos/administração & dosagem , Lipídeos/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Acrilamidas/administração & dosagem , Acrilamidas/química , Acrilamidas/farmacocinética , Administração Oral , Portadores de Fármacos/farmacocinética , Absorção Gastrointestinal , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/farmacocinética , Muco/metabolismo , Nanopartículas/metabolismo , Permeabilidade , Sitosteroides/administração & dosagem , Sitosteroides/química , Sitosteroides/farmacocinética , Propriedades de SuperfícieRESUMO
The conjugates of polymer with anticancer drug, due to their enhanced permeability and retention effect can accumulate in solid tumors at a much higher concentration than n normal tissues or organs, which results n higher targeting distribution and lower systemic toxicity. As a macromolecule carrier, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer has many advantages, such as biocompatibility and nonimmunogenicity, so HPMA copolymer-anticancer conjugates has become the focus of large-weight-molecule targeted therapies. Now six HPMA copolymer-anticancer drugs have been evaluated clinically, and many other conjugates are in the stage of preclinical tests. In this paper, research advances in HPMA copolymer-anticancer conjugates are reviewed.