Intracellular responsive dual delivery by endosomolytic polyplexes carrying DNA anchored porous silicon nanoparticles.
Bioresponsive cytosolic nanobased multidelivery has been emerging as an enormously challenging novel concept due to the intrinsic protective barriers of the cells and hardly controllable performances of nanomaterials. Here, we present a new paradigm to advance nano-in-nano integration technology amenable to create multifunctional nanovehicles showing considerable promise to overcome restrictions of intracellular delivery, solve impediments of endosomal localization and aid effectual tracking of nanoparticles. A redox responsive intercalator chemistry comprised of cystine and 9-aminoacridine is designed as a cross-linker to cap carboxylated porous silicon nanoparticles with DNA. These intelligent nanocarriers are then encapsulated within novel one-pot electrostatically complexed nano-networks made of a zwitterionic amino acid (cysteine), an anionic bioadhesive polymer (poly(methyl vinyl ether-alt-maleic acid)) and a cationic endosomolytic polymer (polyethyleneimine). This combined nanocomposite is successfully tested for the co-delivery of hydrophobic (sorafenib) or hydrophilic (calcein) molecules loaded within the porous core, and an imaging agent covalently integrated into the polyplex shell by click chemistry. High loading capacity, low cyto- and hemo-toxicity, glutathione responsive on-command drug release, and superior cytosolic delivery are shown as achievable key features of the proposed formulation. Overall, formulating drug molecules, DNA and imaging agents, without any interference, in a physico-chemically optimized carrier may open a path towards broad applicability of these cost-effective multivalent nanocomposites for treating different diseases.
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland. Electronic address: mohs@nanotech.dtu.dk.
Mohammad-Ali
MA
Shahbazi
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Patrick Vingadas
PV
Almeida
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Alexandra
A
Correia
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Barbara
B
Herranz-Blanco
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Neha
N
Shrestha
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland; Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014, Finland.
Ermei
E
Mäkilä
Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014, Finland.
Jarno
J
Salonen
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland.
Jouni
J
Hirvonen
Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland. Electronic address: helder.santos@helsinki.fi.
Hélder A
HA
Santos
D000970:Antineoplastic Agents / Q000008:administration & dosage; D002460:Cell Line; D057930:Click Chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D065546:Drug Liberation; D005452:Fluoresceins / Q000008:administration & dosage; D005456:Fluorescent Dyes / Q000008:administration & dosage; D006801:Humans; D008299:Maleic Anhydrides / Q000737:chemistry*; D053761:Nanocomposites / Q000737:chemistry / Q000648:ultrastructure; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011094:Polyethyleneimine / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D016062:Porosity; D012825:Silicon / Q000737:chemistry*; D000077157:Sorafenib
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008299:Maleic Anhydrides; D010671:Phenylurea Compounds; D011145:Polyvinyls; C000619773:poly(methyl vinyl ether-alt-maleic acid); D009536:Niacinamide; D011094:Polyethyleneimine; D004247:DNA; D000077157:Sorafenib; C007740:fluorexon; D012825:Silicon
Bioresponsive; Click chemistry; Combination therapy; Combined delivery; Endosomal escape; Nanocomplexes