Micellic assemblies
Inventors
Stayton, Patrick S. • Hoffman, Allan S. • Convertine, Anthony J. • Duvall, Craig L. • Benoit, Danielle • Overell, Robert W. • Johnson, Paul H. • Gall, Anna S. • Prieve, Mary G. • Paschal, Amber E.E. • Diab, Charbel • De, Priyadarsi
Assignees
Genevant Sciences GmbH • WASHINGTON, University of • University of Washington
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Publication Number
US-9339558-B2
Publication Date
2016-05-17
Expiration Date
Abstract
Provided herein are micellic assemblies comprising a plurality of copolymers. In certain instances, micellic assemblies provided herein are pH sensitive particles.
Core Innovation
A micellic assembly comprising a core and a shell is described, where the micellic assembly comprises a plurality of block copolymers of Formula I. The block copolymers include constitutional selections A0-A4 and linking groups Y0-Y4 and Y3, with optional fluorine substitution on selected alkyl, cycloalkyl, heteroaryl, and aryl groups. The composition further defines hydrophilic at physiologic pH residues (Q0, Q1), residues that are positively charged at physiologic pH (Q2), and residues that are negatively charged at physiologic pH but undergo protonation at lower pH (Q3), together with mole-fraction parameters m, n, p, q, r and molecular-weight ranges v and w.
The described micelle architecture uses a chargeable core block and a hydrophilic shell block, with an endosomal pH-triggered conformational transition. In this transition, protonation and charge neutralization are described as driving membrane destabilizing behavior. The micellic assembly includes pH-form stability, formation of micelle, pseudo-micelle, or micelle-like structure, and retention of serum/plasma activity.
The document also describes functional residues and side chains for conjugation and delivery of polynucleotides, including siRNA, oligonucleotides, and gene therapy vectors. It discusses conjugatable side chains with activated groups such as N-hydrosuccinimide ester functionalities and click chemistry, as well as pyridyl disulfide-thiol exchange for siRNA conjugation, in the context of therapeutic and diagnostic use cases with targeting moieties.
Claims Coverage
The independent claim is directed to a micellic assembly having a core and shell formed from block copolymers of Formula I with defined structural selections, residue types, mole-fraction parameters, and molecular-weight ranges. The dependent refinements include delivery by contacting cells with the micellar assembly, pH-dependent morphology, specific residue/component choices, and a physiological acceptable counterion.
Micellic assembly with core and shell from block copolymers of Formula I
A micellic assembly comprising a core and a shell, where the micellic assembly comprises a plurality of block copolymers of Formula I with selected A0-A4 groups, Y0-Y4 groups, and Y3; where residues Q0-Q3 define hydrophilic, functionalizable, positively charged, and negatively protonatable behaviors at physiologic and lower pH; and where mole fractions m, n, p, q, and r and molecular weights v and w are constrained within specified ranges.
Intracellular polynucleotide delivery by contacting cells with the micellic assembly
A method for delivering a polynucleotide into a cell by contacting the cell with the micellic assembly of claim 1.
pH-defined micelle-like morphology
The micellic assembly takes the form of a micelle, a pseudo-micelle, or a micelle-like structure over a pH range of about 6.2 to 7.5.
Specific residue composition with m=0
The micellic assembly is defined by m=0 and by having a polyethylene glycol residue (Q1), an amino residue (Q2), and a carboxyl residue (Q3).
Diblock-copolymer context and physiological acceptable counterion constraint
The micellar assembly is defined where the diblock copolymer is defined by chemical Formula IV2, further specifying mole fractions p, q, and r, molecular weight ranges v and w, and a physiological acceptable counterion Z-.
Overall, the claim set focuses on a core-shell micellic assembly built from Formula I block copolymers with specified residue functionalities, constrained mole fractions and block molecular weights, plus dependent refinements that specify cell-contact polynucleotide delivery, pH-dependent micelle-like morphology, specific residue selections with m=0, and a tighter formulation context with a physiological acceptable counterion.
Stated Advantages
Membrane destabilization via an endosomal pH-triggered conformational transition driven by protonation or charge neutralization.
Enables conjugation and functionalization using conjugatable side chains with activated groups and click chemistry.
Supports delivery of polynucleotides including siRNA, oligonucleotides, and gene therapy vectors.
Provides micelle formation and performance as supported by characterization results described in the document.
Retention of serum/plasma activity.
Documented Applications
Therapeutic and diagnostic use involving polynucleotides, including siRNA and gene therapy vectors.
siRNA conjugation via pyridyl disulfide-thiol exchange.
Intracellular polynucleotide delivery by contacting cells with the micellic assembly.
Targeting-related applications with targeting moieties such as transferrin receptor, folate, and RGD.
PCSK9 and LDL cholesterol/hypercholesterolemia with ApoB100, and GAPDH siRNA.
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