[0001] The present invention relates to improvements in drug delivery.
[0002] More particularly it relates to the use of Cell Penetrating Agents (CPA’s), and more particularly still to the use of Cell Penetrating Peptides (CPP’s) which have been stabilized 5 by, for example: i) stapling two amino acids to form Stapled CPP’s (StaP’s) or ii) stitching three or more amino acids to form stitched CPP’s (StiP’s).
[0003] These stabilized CPP’s are conjugated to a drug or Biologically Active Compound (BAC) directly or via a Bi-Functional Linker (BFL) so that the BAC can be carried though a cell membrane by the CPP. The resulting molecules are referred to as Drug Carrying Cell 10 Penetrating Molecules (DCCPM’s).
[0004] The preferred BAC’s delivered in this manner are oligonucleotides (ON’s), more preferably still electrically low charge carrying oligonucleotides (charge -3 to +3 at pH 7.5) and most preferably electrically neutral oligonucleotides (charge -1 to +1 at pH 7.5), such as, but not limited to, polynucleic acids (PNAs), phosphorodiamidate morpholino oligonucleotides (PMO’s) 15 or modified derivatives thereof.
[0005] The preferred BFL may be PEGylated, comprising poly ethylene glycol (PEG) groups including modifications such as an amine group, or incorporate a spacer, such as -Ala. These modifications can improve solubilisation or provide appropriate spacing between functional moieties. 20
[0006] The invention also relates to a method of facilitating the uptake of a BAC into a cell, the use of a DCCPM in the treatment of a disease requiring alteration of an endogenous or exogenous gene, a method of improving the bioavailability of a drug or BAC, a method of introducing a drug or BAC to a site which is refractory to the drug or BAC in its native state, a method of treating a subject comprising administering the DCCPM’s of the invention and to a 25 pharmaceutical composition comprising the DCCPM and one or more pharmaceutically acceptable excipients.
[0007] Still further aspects will be apparent from the detailed description
