While biologic drugs such as proteins, peptides, or nucleic acids have shown promise in the treatment of neurodegenerative diseases, the blood−brain barrier (BBB) severely limits drug delivery to the central nervous system (CNS) after systemic administration. Consequently, drug delivery challenges preclude biological drug candidates from the clinical armamentarium. In order to target drug delivery and uptake into to the CNS, we used an in vivo phage display screen to identify peptides able to target drug-uptake by the vast array of neurons of the autonomic nervous system (ANS). Using next-generation sequencing, we identified 21 candidate targeted ANS-to-CNS uptake ligands (TACL) that enriched bacteriophage accumulation and delivered protein-cargo into the CNS after intraperitoneal (IP) administration. The series of TACL peptides were synthesized and tested for their ability to deliver a model enzyme (NeutrAvidin-horseradish peroxidase fusion) to the brain and spinal cord. Three TACL-peptides facilitated significant active enzyme delivery into the CNS, with limited accumulation in off-target organs. Peptide structure and serum stability is increased when internal cysteine residues are cyclized by perfluoroarylation with decafluorobiphenyl, which increased delivery to the CNS further. TACL-peptide was demonstrated to localize in parasympathetic ganglia neurons in addition to neuronal structures in the hindbrain and spinal cord. By targeting uptake into ANS neurons, we demonstrate the potential for TACL-peptides to bypass the blood− brain barrier and deliver a model drug into the brain and spinal cord.
The development of nanoscale drug delivery vehicles is an exciting field due to the ability of these vehicles to improve the pharmacokinetic and pharmacodynamic properties of existing therapeutics. These vehicles can improve drug effectiveness and safety by providing benefits such as increased blood circulation, targeted delivery, and controlled release. With regard to the building blocks, amphiphilic polypeptide and polypeptide hybrid (i.e., a macromolecule comprised of a polypeptide and another type of polymer) systems have been recently investigated for their abilities to self-assemble into vesicles. Advances in synthesis methodologies have allowed the development and characterization of many different amphiphilic polypeptide and polypeptide hybrid systems. In this review, we will discuss these vesicle-forming materials in terms of their synthesis, processing, and characterization. In addition, current efforts to use them for drug delivery purposes will be discussed.
With an increased prevalence and understanding of central nervous system (CNS) injuries and neurological disorders, nucleic acid therapies are gaining promise as a way to regenerate lost neurons or halt disease progression. While more viral vectors have been used clinically as tools for gene delivery, non-viral vectors are gaining interest due to lower safety concerns and the ability to deliver all types of nucleic acids. Nevertheless, there are still a number of barriers to nucleic acid delivery. In this focused review, we explore the in vivo challenges hindering non-viral nucleic acid delivery to the CNS and the strategies and vehicles used to overcome them. Advantages and disadvantages of different routes of administration including: systemic injection, cerebrospinal fluid injection, intraparenchymal injection and peripheral administration are discussed. Non-viral vehicles and treatment strategies that have overcome delivery barriers and demonstrated in vivo gene transfer to the CNS are presented. These approaches can be used as guidelines in developing synthetic gene delivery vectors for CNS applications and will ultimately bring non-viral vectors closer to clinical application.
The ease and versatility of dibromomaleimide chemistry has allowed the reversible attachment of biomolecules in a wide variety of applications such as polymer synthesis, cancer, and gene delivery."
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