Method for transporting a compound across the blood-brain barrier
Inventors
Béliveau, Richard • Demeule, Michel
Assignees
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Publication Number
US-9221867-B2
Publication Date
2015-12-29
Expiration Date
Abstract
The present invention relates to improvements in the field of drug delivery. More particularly, the invention relates to a non-invasive and flexible method and carrier for transporting a compound or drug across the blood-brain barrier of an individual. In particular the present invention relates to a carrier for transporting an agent attached thereto across a blood-brain barrier, wherein the carrier is able to cross the blood-brain barrier after attachment to the agent and thereby transport the agent across the blood-brain barrier. The present invention relates to improvements in the field of drug delivery. More particularly, the invention relates to a non-invasive and flexible method and carrier for transporting a compound or drug across the blood-brain barrier of an individual. In particular the present invention relates to a carrier for transporting an agent attached thereto across a blood-brain barrier, wherein the carrier is able to cross the blood-brain barrier after attachment to the agent and thereby transport the agent across the blood-brain barrier.
Core Innovation
The disclosure addresses non-invasive transport across the blood-brain barrier (BBB) by using a carrier that increases brain penetration or transcytosis across the BBB to a level greater than that of aprotinin. In particular, the carrier is based on AngioPep-1 (SEQ ID NO:4) or on a polypeptide consisting of the amino acid sequence RGKRNNFKTEEY (residues 8-19 of SEQ ID NO:4).
A central aspect of the disclosed innovation is that the increased transcytosis is presented as receptor-associated and sensitive to conditions affecting receptor involvement. The disclosure reports that an LLR antagonist receptor-associated protein (RAP) inhibits aprotinin transcytosis, and it is used in the context of receptor involvement for transport across the BBB.
The disclosure further presents that BBB integrity is preserved during carrier-mediated transcytosis, including sucrose permeability being unchanged. It also reports that the integrity of the carrier is retained after transcytosis, and it characterizes conjugates using an agent attached to the carrier. AngioPep-1-based design is supported by measured permeability/transcytosis data and by additional evaluation approaches, including in vitro BBB co-culture and in situ mouse brain perfusion.
Claims Coverage
The independent claims cover 2 inventive features: an isolated carrier with enhanced brain penetration/transcytosis relative to aprotinin, and a conjugate that includes such a carrier with an agent attached, where the conjugate can cross the blood brain barrier. Across these independent claims, the main inventive features are defined by specific AngioPep-1 (SEQ ID NO:4) or the RGKRNNFKTEEY (residues 8-19) polypeptide segment, the comparative performance versus aprotinin, and the requirement that the conjugate cross the BBB.
A carrier with greater brain penetration or transcytosis than aprotinin
An isolated carrier, wherein the brain penetration or transcytosis across the blood-brain barrier of said carrier is greater than that of aprotinin; the carrier comprises AngioPep-1 (SEQ ID NO:4) or consists of a polypeptide having the amino acid sequence RGKRNNFKTEEY (residues 8-19 of SEQ ID NO:4).
An AngioPep-1- or RGKRNNFKTEEY-based carrier conjugate that can cross the BBB
A conjugate comprising a carrier comprising AngioPep-1 (SEQ ID NO:4) or consisting of a polypeptide having the amino acid sequence RGKRNNFKTEEY (residues 8-19 or SEQ ID NO:4), wherein the brain penetration or transcytosis across the blood-brain barrier of said carrier is greater than that of aprotinin, and an agent attached to said carrier, wherein said conjugate is able to cross the blood brain barrier.
Overall, the claim coverage is anchored on carrier designs that yield brain penetration/transcytosis across the BBB greater than aprotinin, using AngioPep-1 (SEQ ID NO:4) or the RGKRNNFKTEEY (residues 8-19) polypeptide segment, and extending this concept to a conjugate by attaching an agent so the conjugate is able to cross the BBB.
Stated Advantages
Improved brain penetration or transcytosis across the blood-brain barrier compared to aprotinin.
Conjugates including the carrier and an attached agent are able to cross the blood brain barrier.
Preservation of blood-brain barrier integrity, including sucrose permeability unchanged.
Documented Applications
Transport or delivery across the blood-brain barrier in connection with conjugates comprising a carrier and an attached agent, including evaluation by BBB in vitro co-culture and in situ mouse brain perfusion.
Use of an agent attached to the carrier as a conjugate able to cross the blood brain barrier, supported by example conjugation using an aprotinin-biotin conjugate.
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