Conjugates of RGD peptides and porphyrin or (bacterio)chlorophyll photosynthesizers and their uses

A conjugate of at least one RGD-containing peptide or RGD-peptidomimetic and a water soluble photosensitizer of the formula II:

• wherein
• M represents 2H or an atom selected from the group consisting of Mg, Pd, Pt, Co, Ni, Sn, Sm, Cu, Zn, Mn, In, Eu, Fe, Au, Al, Gd, Dy, Er, Yb, Lu, Ga, Y, Rh, Ru, Si, Ge, Cr, Mo, P, Re, Tc, Tl and isotopes thereof;
• R1, is —NH—P, wherein P is a residue of an RGD-containing peptide or an RGD-peptidomimetic;
• R6 is —NR9R′9 or —N+R9R′9R″9A−, wherein R1 and R6 may together form a ring;
• R′2 is —O—R8;
• R4 is —CH═CR9R′9, —CH═CR9Hal, —CH═CH—CH2—NR9R′9, —CH═CH—CH2—N+R9R′9R″9A−, —CHO, —CH═NR9, —CH═N+R9R′9A−, —CH2—OR9, —CH2—SR9, —CH2—Hal, —CH2—R9, —CH2—NR9R′9, —CH2—N+R9R′9R″9A−, —CH2—CH2R9, —CH2—CH2Hal, —CH2—CH2OR9, —CH2—CH2SR9, —CH2—CH2—NR9R′9, —CH2—CH2—N+R9R′9R″9A−, —COCH3, C(CH3)═CR9R′9, —C(CH3)═CR9Hal, —C(CH3)═NR9, —CH(CH3)═N+R9R′9A−, —CH(CH3)—Hal, —CH(CH3)—OR9, —CH(CH3)—SR9, —CH(CH3)—NR9R′9, —CH(CH3)—N+R9R′9R″9A−, or —C≡CR9;
• R′4 is methyl or formyl;
• R8, R9, R′9 and R″9 each independently is:
• (a) H;
• (b) C1-C25 hydrocarbyl;
• (c) C1-C25 hydrocarbyl substituted by one or more functional groups selected from the group consisting of halogen, nitro, oxo, —OR, —SR, epoxy, epithio, —NRR′, —CONRR′, —CONR—NRR′, —NHCONRR′, —NHCONRNRR′, —COR, COOR, —OSO3R, —SO3R, —SO2R, —NHSO2R, —SO2NRR′, ═N—OR, —(CH2)n—CO—NRR′, —O—(CH2)n—OR, —O—(CH2), —O—(CH2), —R, —OPO3RR′, —PO2HR, and —PO3RR′, wherein R and R′ each independently is H, hydrocarbyl or heterocyclyl, R may further be a cation, R′ may further be a residue of an RGD peptide or RGD peptidomimetic, or R and R′ together with the N atom to which they are attached form a 5-7 membered saturated ring optionally containing a further heteroatom selected from O, S and N, wherein the further N atom may be substituted, and n is 1 to 6;
• (d) C1-C25 hydrocarbyl substituted by one or more functional groups selected from the group consisting of positively charged groups, negatively charged groups, basic groups that are converted to positively charged groups under physiological conditions, and acidic groups that are converted to negatively charged groups under physiological conditions;
• (e) C1-C25 hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties;
• (f) C1-C25 hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties and substituted by one or more functional groups as defined in (c) and (d) above;
• (g) C1-C25 hydrocarbyl substituted by a residue of an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, a polysaccharide, or a polydentate ligand and its chelating complexes with metals;
• or
• (h) a residue of an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, a polysaccharide;
• or a polydentate ligand and its chelating complexes with metals;
• A− is a physiologically acceptable anion;
• m is 0 or 1;
• the dotted line at positions 7-8 represents an optional double bond;
• and
• pharmaceutically acceptable salts and optical isomers thereof;
• wherein each said RGD-containing peptide or RGD-peptidomimetic is:
• (A) a cyclic RGD-containing peptide selected from the group consisting of:
• (i) the pentapeptide cycloRGDfK (SEQ ID NO:1), wherein f indicates D-Phe;
• (ii) the nonapeptide herein designated RGD-4C (SEQ ID NO:2);
• (iii) the tetrapeptide cycloRGDK (SEQ ID NO:4);
• (iv) the pentapeptide cycloRGDf-N(Me)K (SEQ ID NO:7), wherein f indicates D-Phe;
• and
• (v) the pentapeptide cycloRGDyK (SEQ ID NO:8), wherein y indicates D-Tyr;
• (B) a linear RGD-containing peptide selected from the group consisting of:
• (i) the hexapeptide GRGDSP (SEQ ID NO:3);
• (ii) the heptapeptide GRGDSPK (SEQ ID NO:5), and
• (iii) the peptide of sequence (GRGDSP)4K (SEQ ID NO:6);
• (C) an RGD-peptidomimetic selected from the group consisting of H2N—C(═NH)NH—(CH2)5—CO—NH—CH(CH2)—(CH2)2—COOH and H2N—C(═NH)NH—(CH2)2—CO—piperidine-CONH—CH[(CH2)4]—CH2—COOH, or
• (D) an RGD-containing peptide or RGD-peptidomimetic residue selected from the group consisting of —NH-RGD-CO—NH—(CH2)2—NH— and —NH-RGD-CO—NH—(CH2)3piperazino-(CH2)3—NH— comprised within a ring formed by R1 and R6.