Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors.
Therapies based on RNA interference, using agents such as siRNA, are limited by the absence of safe, efficient vehicles for targeted delivery in vivo. The barriers to siRNA delivery are well known and can be individually overcome by addition of functional modules, such as conjugation of moieties for cell penetration or targeting. But, so far, it has been impossible to engineer multiple modules into a single unit. Here, we describe the synthesis of degradable nanoparticles that carry eight synergistic functions: 1) polymer matrix for stabilization/controlled release; 2) siRNA for gene knockdown; 3) agent to enhance endosomal escape; 4) agent to enhance siRNA potency; 5) surface-bound PEG for enhancing circulatory time; and surface-bound peptides for 6) cell penetration; 7) endosomal escape; and 8) tumor targeting. Further, we demonstrate that this approach can provide prolonged knockdown of PLK1 and control of tumor growth in vivo. Importantly, all elements in these octa-functional nanoparticles are known to be safe for human use and each function can be individually controlled, giving this approach to synthetic RNA-loaded nanoparticles potential in a variety of clinical applications.
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
Jiangbing
J
Zhou
Toral R
TR
Patel
Michael
M
Fu
James P
JP
Bertram
W Mark
WM
Saltzman
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D011992:Endosomes / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry*
D011108:Polymers; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid