Lichen Yin

Redox-Responsive, Core-Cross-Linked Micelles Capable of On-Demand, Concurrent Drug Release and Structure Disassembly

We developed camptothecin (CPT)-conjugated, core-cross-linked (CCL) micelles that are subject to redox-responsive cleavage of the built-in disulfide bonds, resulting in disruption of the micellar structure and rapid release of CPT. CCL micelles were prepared via coprecipitation of disulfide-containing CPT-poly(tyrosine(alkynyl)-OCA) conjugate and monomethoxy poly(ethylene glycol)-b-poly(tyrosine(alkynyl)-OCA), followed by cross-linking of the micellar core via azide-alkyne click chemistry. CCL micelles exhibited excellent stability under physiological conditions, while they underwent rapid dissociation in reduction circumstance, resulting in burst release of CPT. These redox-responsive CCL micelles showed enhanced cytotoxicity against human breast cancer cells in vitro.

Reactive and Bioactive Cationic α-Helical Polypeptide Template for Nonviral Gene Delivery†

Poly(γ-(4-vinylbenzyl)-l-glutamate) (PVBLG) served as a bioactive and reactive template for the generation of a library of cationic α-helical polypeptides for gene delivery. The top performing polymer outperformed 25-kDa polyethylenimine by 12-fold. Preliminary data indicates that helicity of these cationic polypeptides is essential for their improved performance, with enhanced membrane disruption a likely source of their transfection efficiency.

Light-responsive helical polypeptides capable of reducing toxicity and unpacking DNA: Toward nonviral gene delivery

Non-viral gene delivery using synthetic cationic polymeric vectors is widely recognized as an attractive alternative to viral gene delivery which suffers from inherent immunogenicity and various side effects.[1] The transfection efficiency and chemotoxicity of these polymeric vectors are often closely related to their cationic charge density.[2] Materials with low charge density usually show low toxicity but are often poor transfection agents. Polycations with high charge density could mediate effective gene transfer which is however often associated with significant, charge-induced toxicity. [3] When modified with various charge-reducing moieties, including saccharides,[4] hydrocarbons,[5] and poly(ethylene glycol) (PEG),[6] polycations often benefit from improved safety profiles while in the meantime suffer from significantly reduced gene delivery capabilities. In addition to the charge-induced toxicity, excessive positive charges on polycations would also enhance the electrostatic attraction with the nucleic acids to restrict intracellular gene release.[3g,7] Therefore, it would be of great interest to develop a highly charged polycation that possesses full transfection capacity and membrane activity during the course of gene transfer, but can be triggered to transform to a less charged or uncharged material with low membrane activity post-transfection, such that intracellular DNA unpackaging can be facilitated and toxicity can be reduced.[8]

Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs

Polymeric nanoparticles have been widely applied to oral delivery of protein drugs, however, few studies focused on the systematical elucidation of the size-dependent oral absorption mechanism with well-defined polymeric nanoparticles. Rhodamine B labeled carboxylated chitosan grafted nanoparticles (RhB-CCNP) with different particle sizes (300, 600, and 1000 nm) and similar Zeta potentials (-35 mV) were developed. FITC labeled bovine serum albumin (FITC-BSA) was encapsulated into RhB-CCNP to form drug loaded polymeric nanoparticles (RhB-CCNP-BSA). RhB-CCNP-BSA with uniform particle size and similar surface charge possessed desired structural stability in simulated physiological environment to substantially guarantee the validation of elucidation on size-dependent absorption mechanisms of polymeric nanoparticles using in vitro, in situ, and ex vivo models. RhB-CCNP-BSA with smaller sizes (300 nm) demonstrated elevated intestinal absorption, as mechanistically evidenced by higher mucoadhesion in rat ileum, release amount of the payload into the mucus layer, Caco-2 cell internalization, transport across Caco-2 cell monolayers and rat ileum, and systemic biodistribution after oral gavage. Peyers patches could play a role in the mucoadhesion of nanoparticles, resulting in their close association with the intestinal absorption of nanoparticles. These results provided guidelines for the rational design of oral nanocarriers for protein drugs in terms of particle size.

Preparation, characterization, and oral delivery of insulin loaded carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles.

To improve the efficiency of insulin via oral administration, pH-sensitive carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles (CCGN) were prepared. CCGN were characterized by (1)H NMR, dynamic light scattering, zeta potential, and transmission electron microscopy, and the hypoglycemic effect of insulin loaded CCGN via the oral route was evaluated in normal and diabetic rats. CCGN exhibited a homogeneous morphology and a spherical shape with core-shell structure. They were aggregated in simulated gastric fluid while separated in simulated intestinal fluid. Insulin was mainly located in the shell of the CCGN via hydrogen bonding, electrostatic interaction, and Van der Waals force. Insulin release from the CCGN exhibited a pH-sensitive property in that it had a slow release rate at pH 2.0 and a fast release rate at pH 6.8 and 7.4. The pharmacological bioavailability after oral administration of insulin loaded CCGN at a dose of 25 IU/kg was found to be 9.7%. Besides, CCGN showed desirable tissue and blood compatibility. Therefore, the CCGN would be a promising delivery carrier for protein drugs via the oral route.

Hyaluronic acid coated poly(butyl cyanoacrylate) nanoparticles as anticancer drug carriers.

The hyaluronic acid (HA) coated poly(butyl cyanoacrylate) (PBCA) nanoparticles were synthesized through radical polymerization of butyl cyanoarylate (BCA) initiated by cerium ions in the presence of HA. The chemical coupling between HA and PBCA was demonstrated by FTIR, (1)H NMR and X-ray diffraction. The sizes of the nanoparticles with different HA/BCA ratios were 291-325 nm at cerium concentration of 0.8 mmol/L and HA molecular weight of 18,000 Da. Paclitaxel (PTX), a model anticancer drug, was encapsulated in negatively charged nanoparticles with a maximal encapsulation efficiency of 90%. In vitro release demonstrated that HA modification could effectively reduce the initial burst release in the first 10h and provide a sustained release in the subsequent 188 h. As evidenced by the hemolysis assay and MTT assay, HA coating could significantly reduce the cytotoxicity. Cellular uptake indicated that uptake of HA-PBCA nanoparticles by Sarcoma-180 (S-180) cells was 9.5-fold higher than that of PBCA nanoparticles. PTX-loaded HA-PBCA nanoparticles were more potent in tumor growth suppression than PTX-loaded PBCA nanoparticles or PTX injection following intravenous administration to S-180 tumor bearing mice. Therefore, the HA-PBCA nanoparticles could be an effective and safe vehicle for systemic administration of hydrophobic anticancer drugs.

Non‐Viral Gene Delivery via Membrane‐Penetrating, Mannose‐Targeting Supramolecular Self‐Assembled Nanocomplexes

Supramolecular self-assembled nanocomplexes (SSANs) capable of mannose receptor-mediated endocytosis and permeable to cellular and endosomal membranes are developed via the assembly of multiple rationally designed, function-specific materials. As a unique non-viral gene delivery vector, SSANs outperform commercial transfection reagents, including LPF2000, PEI, and jetPEI, by up to 2 orders of magnitude.

Chain-Shattering Polymeric Therapeutics with On-Demand Drug-Release Capability†

Design of smart polymeric therapeutics We designed and synthesized trigger-responsive chain-shattering polymeric therapeutics (CSPTs) via condensation polymerization of a UV-or hydrogen peroxide-responsive domain and a bisfunctional drug as co-monomers. CSPTs have precisely controlled molecular composition and unique chain-shattering type of drug release mechanism. Drug release kinetics can be precisely controlled by means of the trigger treatment. Chemotherapeutic-containing CSPTs showed trigger-responsive in vitro and in vivo antitumor efficacy.

Helical poly(arginine) mimics with superior cell-penetrating and molecular transporting properties

Poly(arginine) mimics bearing long hydrophobic side chains adopt stable helical conformation and exhibit helix-related cell-penetrating properties. Elongating polypeptide backbone length and increasing side chain hydrophobicity further increase the helicities of poly(arginine) mimics. They show superior cell membrane permeability up to two orders of magnitude higher than that of HIV-TAT peptide and excellent DNA and siRNA delivery efficiencies in various mammalian cells.

Supramolecular self-assembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation.

Intervention of the inflammation cascade with tumor necrosis factor-α (TNF-α) monoclonal antibodies or receptors represents a major approach in clinical immunotherapy against inflammatory diseases, which however, often suffers from high cost, autoimmunity to antibodies, and various side effects.[1] siRNA-mediated RNA interference (RNAi) has recently emerged as a potent modality in regulating gene expression by suppressing mRNA translation;[2-13] its high efficiency and specificity has made it a promising treatment paradigm for TNF-α-mediated inflammatory disorders.[14-18] The therapeutic potential of siRNA was recently exemplified by a report of attenuating systemic inflammation by targeting orally delivered Map4k4 siRNA to gut-associated macrophages (GAMs).[19] Owing to the infiltration of GAMs to systemic reticuloendothelial tissues, Map4k4 siRNA-mediated TNF-α knockdown in GAMs extended to other tissues and thus induced systemic anti-inflammatory effects.[19]