Alpha-v beta-6 integrin ligands and uses thereof

Abstract

Integrin ligands having serum stability and affinity for avß6 integrins are described. Compositions comprising avß6 integrin ligands having serum stability and having affinity for avß6 integrins and methods of using them are also described. 20 24 20 26 95 24 A pr 2 02 4 A B S T R A C T 2 0 2 4 2 0 2 6 9 5 2 4 2 0 2 4 A p r

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This is a divisional of Australian Patent Application No. 2017354041, the originally-filed specification of which is incorporated herein by reference in its entirety. 5 FIELD OF THE INVENTION Disclosed are peptide-based alpha-v beta-6 (av06) integrin ligands useful in targeting av06 integrin and / or targeting cells that express av06 integrin. The av06 integrin ligands can be conjugated to one or more cargo molecules to facilitate the delivery of the cargo molecules 10 to cells expressing av06 integrin, such as epithelial cells. BACKGROUND Integrin alpha-v beta-6 (av06), which is expressed in various epithelial cells, is a receptor for the latency-associated peptide (LAP) of TGF-0 and for the (ECM) proteins fibronectin, 15 vitronectin, and tenascin. Although barely detectable in normal healthy adult epithelia, av06 integrin is upregulated during wound healing and in different cancers (e.g., colon, ovarian, endometrial, and gastric cancer), and often associates with poor cancer prognosis. It has been shown that av06 20 integrin can promote cell invasion and migration in metastasis, and inhibit apoptosis. av06 integrin may also regulate expression of matrix metalloproteases (MMPs) and activate TGF-01. There is increasing evidence, primarily from in vitro studies, that suggest that av06 integrin may promote carcinoma progression. Thus, integrin av06 is attractive as a tumor biomarker and potential therapeutic target and for its role in expression of matrix 25 metalloproteases (MMPs) and activation of TGF-01. SUMMARY Described herein are novel, engineered, non-naturally occurring peptide-based av06 integrin ligands (also termed av06 ligands). The av06 integrin ligands disclosed herein are stable in 30 serum and have affinity for, and can bind specifically to, av06 integrins. Further described herein are compositions that include av06 integrin ligands, and methods of use for av06 integrin ligands and compositions described herein. 2024202695   24 Apr 2024 The avP6 integrin ligands described herein have improved stability compared to other known avP6 integrin-binding peptides, such as the natural peptide RGDLATLRQL (SEQ ID NO: 1). While having increased serum stability, the novel avP6 ligands described herein retain binding 5 to (affinity for) avP6 integrin. In a first aspect, this disclosure provides engineered, non-naturally occurring avP6 integrin ligands. In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG1DLXaa1Xaa2L (SEQ ID NO: 85) (Formula I), wherein Z is an amine-terminal cap (e.g., 10   any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L- glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or 15 known in the art); and Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art). 20 In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG1DLXaa1Xaa2L-J-R1 (SEQ ID NO: 86) (Formula II), wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an 25 L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino 30 acids described herein or known in the art); J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known 2024202695   24 Apr 2024 in the art), L-P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; and R1 is optional and, if present, includes polyethylene glycol (PEG) and / or a linking group. 5 In some embodiments, the avP6 integrin ligands disclosed herein can include a reactive group or a protected reactive group, and comprise the general formula: Z-RG1DLXaa1Xaa2L-J-R1-R2 (SEQ ID NO: 87) (Formula III), wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is 10 L-arginine; G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino 15 acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 20    5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L-P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; R1 is optional and, if 25 present, includes polyethylene glycol (PEG) and / or a linking group; and R2 includes a reactive group or a protected reactive group. In some embodiments, an avP6 integrin ligand can be conjugated to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; 30 or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30) cargo molecules (e.g., any of the cargo molecules described herein or known in the art), wherein the avP6 integrin ligand comprises the general formula: (Z-RG1DLXaa1Xaa2L-J-R1)n-R3 (SEQ ID NO: 88) (Formula IV), wherein Z is an amine- 2024202695   24 Apr 2024 terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in 5 the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); J is optional and, if present, 10 includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L-P amino acids (e.g., any of the L-P amino acids described herein 15 or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; R1 is optional and, if present, includes polyethylene glycol (PEG) and / or a linking group; n is an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 20 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and R3 includes the one or more cargo molecule. In some embodiments, R3 includes one cargo molecule. In some embodiments, R3 includes more than one cargo molecule. 25 In some embodiments, an avP6 integrin ligand can be conjugated to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30) cargo molecules (e.g., any of the cargo molecules described herein or known in the art), 30 wherein the avP6 integrin ligand comprises the general formula: (Z-RG1DLXaa1Xaa2L-J-R1)n-R4-(R3)p (SEQ ID NO: 89) (Formula V), wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or 2024202695   24 Apr 2024 known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P 5 amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 10   25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L-P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; R1 is optional and, if present, includes polyethylene glycol (PEG) and / or a linking group; n is an 15    integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); R3 includes the one or more cargo molecule; p is an integer greater than 0 (e.g., 1,2,3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23, 20    24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and R4 is optional and, if present, comprises a scaffold and / or linking group that includes at least one attachment point for each ligand and at least one attachment point for each cargo molecule. In some embodiments, R3 includes one cargo 25 molecule. In some embodiments, R3 includes more than one cargo molecule. As used herein, an “amine-terminal cap” (shown as “Z” in formulae herein), comprises a chemical moiety that is capable of increasing and / or otherwise improving protease resistance and / or serum stability characteristics of an RGDLATL natural peptide. Such improvements 30 can be determined, for example, using methods generally known in the art, including but not limited to, for example, by determining half-life of the avP6 integrin ligand, avP6 integrin ligand-cargo molecule conjugate, or avP6 integrin ligand-containing composition in vivo and / or in vitro. In some embodiments, Z includes a protease resistant acylation, sulfonylation, or alkylation of the N-terminal amine of an avP6 integrin ligand disclosed herein. In some 2024202695   24 Apr 2024 embodiments, the amine-terminal cap Z can be alkyl-CO, ArCO, alkyl-S02, ArSO2, alkyl or aryl groups. In some embodiments, the alkyl group can be either linear or branched aliphatic alkyl groups and aryl groups can be either aromatic or heteroaromatic groups. In some embodiments, the amine-terminal cap Z can be but is not limited to, CHsCO, CH3CH2CO, 5 CH3(CH2)2CO, (CH3)2CHCO, CH3(CH2)3CO, (CH3)2CHCH2CO, CH3CH2CH(CH3)CO, (CH3)3CCO, CH3(CH2)4CO, CH3SO2, CH3CH2SO2, CH3(CH2)2SO2, (CH3)2CHSO2, CH3(CH2)3SO2, (CH3)2CHCH2SO2, CH3CH2CH(CH3)SO2, (CH3)3CSO2, PhCO, PhSO2, alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, methyl, ethyl, propyl, butyl, pentyl, NH2NH, PEG, guanidinyl, CH3OCH2CH2OCH2CH2CO, CH3O(CH2CH2O)2CH2CH2CO, 10 CH3O(CH2CH2O)3CH2CH2CO,                       CH3O(CH2CH2O)4CH2CH2CO, CH3O(CH2CH2O)5CH2CH2CO,   CH3OCH2CH2OCH2CO, CH3O(CH2CH2O)2CH2CO, CH3O(CH2CH2O)3CH2CO, CH3O(CH2CH2O)4CH2CO, CH3O(CH2CH2O)5CH2CO, CH3OCH2CH2OCO, CH3O(CH2CH2O)2CO, CH3O(CH2CH2O)3CO, CH3O(CH2CH2O)4CO, CH3O(CH2CH2O)5CO, HOCH2CH2OCH2CH2CO, HO(CH2CH2O)2CH2CH2CO, 15 HO(CH2CH2O)3CH2CH2CO, HO(CH2CH2O)4CH2CH2CO, HO(CH2CH2O)5CH2CH2CO, HOCH2CH2OCH2CO,       HO(CH2CH2O)2CH2CO,       HO(CH2CH2O)3CH2CO, HO(CH2CH2O)4CH2CO, HO(CH2CH2O)5CH2CO, HOCH2CH2OCO, HO(CH2CH2O)2CO, HO(CH2CH2O)3CO,           HO(CH2CH2O)4CO,           HO(CH2CH2O)5CO, CH3CH2OCH2CH2OCH2CH2CO,                 CH3CH2O(CH2CH2O)2CH2CH2CO, 20  CH3CH2O(CH2CH2O)3CH2CH2CO,                CH3CH2O(CH2CH2O)4CH2CH2CO, CH3CH2O(CH2CH2O)5CH2CH2CO,                    CH3CH2OCH2CH2OCH2CO, CH3CH2O(CH2CH2O)2CH2CO,                      CH3CH2O(CH2CH2O)3CH2CO, CH3CH2O(CH2CH2O)4CH2CO, CH3CH2O(CH2CH2O)5CH2CO, CH3CH2OCH2CH2OCO, CH3CH2O(CH2CH2O)2CO,    CH3CH2O(CH2CH2O)3CO,    CH3CH2O(CH2CH2O)4CO, 25  CH3CH2O(CH2CH2O)5CO, CH3OCH2CH2CO, HOCH2CH2CO, or CH3CH2OCH2CH2CO. In some embodiments, the amine-terminal cap Z is CH3CO. In some embodiments, the amine-terminal cap Z is CH3CH2CO. In some embodiments, the amine-terminal cap Z is CH3(CH2)2CO. In some embodiments, the amine-terminal cap Z is CH3(CH2)3CO. In some 30 embodiments, the amine-terminal cap Z is CH3(CH2)4CO. In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RGlDLAXaauL (SEQ ID NO: 90) (Formula Ic), wherein Z, R, G1, D, and L are each as defined for Formula I herein; A is L-alanine; and Xaau is a non-standard amino acid. 2024202695   24 Apr 2024 In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG'DLAAbuL (SEQ ID NO: 91) (Formula Id), wherein Z, R, G1, D, and L are each as defined for Formula I herein; A is L-alanine; and Abu is L-a-amino-butyric acid (25 Aminobutyric acid). In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 92) (Formula VI), wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is 10 L-arginine; G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino 15 acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino 20 acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); and R1 is optional and, if present, includes polyethylene glycol (PEG) and / or 25 a linking group. In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG1DLAXaauL-Xaa3Xaa4L-R1 (SEQ ID NO: 93) (Formula VIb), wherein Z, R, G1, D, L, and R1 are each as defined for Formula VI herein; A is L-alanine; Xaau is a non-standard amino 30 acid; Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); and Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids 2024202695   24 Apr 2024 described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art). In some embodiments, the avP6 integrin ligands comprise the general formula: 5   Z-RG1 DLAAbuL-Xaa3Xaa4L-R1 (SEQ ID NO: 94) (Formula Vic), wherein Z, R, G1, D, L, and R1 are each as defined for Formula VI herein; A is L-alanine; Abu is L-a-amino-butyric acid (2-Aminobutyric acid); Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-10 disubstituted amino acids described herein or known in the art); and Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art). 15 In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RGlDLAXaauL-XaauXaauL-Rl (SEQ ID NO: 95) (Formula Vid), wherein Z, R, G1, D, L, and R1 are each as defined for Formula VI herein; A is L-alanine; and Xaau is a non-standard amino acid. 20 In some embodiments, Z-R in any of the formulae or ligands herein is replaced with R', wherein R' is Dap(guanidino): 25 In some embodiments, the avP6 integrin ligands comprise the general formula: RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII), wherein R is L-arginine; G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an 2024202695   24 Apr 2024 a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino 5 acids described herein or known in the art); Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid 10   (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); R1 is optional and, if present, includes polyethylene glycol (PEG) and / or a linking group; and at least one of Xaa1, Xaa2, Xaa3, and Xaa4 is a non-standard amino acid. In some embodiments, the avP6 integrin ligands comprise the general formula: 15 RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII), wherein at least two of Xaa1, Xaa2, Xaa3, and Xaa4 are non-standard amino acids. In some embodiments, the avP6 integrin ligands comprise the general formula: RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII), wherein at least three of Xaa1, Xaa2, Xaa3, and Xaa4 are non-standard amino acids. 20 In some embodiments, the avP6 integrin ligands comprise the general formula: RG1 DLAAbuL-CitAibL-R1 (SEQ ID NO: 97) (Formula Villa), wherein R, G1, D, L and R1 are each as defined for Formula VIII herein; A is L-alanine; Abu is L-a-amino-butyric acid (2-Aminobutyric acid); Cit is citrulline, and Aib is a-amino-isobutyric acid (2-Aminoisobutyric 25 acid). In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 1. 30 In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 2. In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 3. 2024202695   24 Apr 2024 In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 4. 5 In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 5. In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 6. 10 In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 7. In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially 15 of, the structure of Figure 8. In some embodiments, the avP6 integrin ligand comprises, consists of, or consists essentially of, the structure of Figure 9. 20 In some embodiments, the avP6 integrin ligands comprises, consists of, or consists essentially of, the structure of Figure 10. In some embodiments, the avP6 integrin ligands comprises, consists of, or consists essentially of, the structure of Figure 11. 25 In some embodiments, any of the avP6 integrin ligands disclosed herein can be linked to a cargo molecule, a reactive group, and / or a protected reactive group. A reactive group can be used to facilitate conjugation of the avP6 integrin ligand to a molecule, such as one or more cargo molecules (e.g., any of the cargo molecules described herein or known in the art). The 30 avP6 integrin ligands disclosed herein can increase targeting of a cargo molecule to an avP6 integrin or a cell expressing an avP6 integrin. A cargo molecule can be, but is not limited to, a pharmaceutically active ingredient or compound, a drug product, a prodrug, or a therapeutically valuable substance. In some embodiments, a cargo molecule can be, but is not limited to, a small molecule, an antibody, an antibody fragment, an immunoglobulin, a monoclonal 2024202695   24 Apr 2024 antibody, a label or marker, a lipid, a natural or modified nucleic acid or polynucleotide (e.g., an oligomeric compound such as an antisense oligonucleotide or an RNAi agent), a peptide, an aptamer, a polymer, a polyamine, a protein, a toxin, a vitamin, a polyethylene glycol, a hapten, a digoxigenin, a biotin, a radioactive atom or molecule, or a fluorophore. In some 5 embodiments, a cargo molecule includes a pharmaceutically active ingredient, a drug product, or a prodrug. In some embodiments, a cargo molecule includes an oligomeric compound as a pharmaceutically active ingredient. In some embodiments, a cargo molecule includes an RNAi agent as a pharmaceutically active ingredient. 10 Described herein is the use of the described avP6 ligands to target a cargo molecule to an avP6 expressing cell. The cell may be in vitro, in situ, ex vivo, or in vivo. In another aspect, this disclosure provides compositions that include one or more of the engineered, non-naturally occurring avP6 ligands described herein. For example, in some 15 embodiments, compositions comprising one or more avP6 integrin ligands disclosed herein include one or more oligomeric compound(s), such as one or more RNAi agent(s), to be delivered to a cell in vivo. In some embodiments, described herein are compositions for delivering an RNAi agent to a cell in vivo, wherein the RNAi agent is conjugated to one or more avP6 ligands. 20 Compositions that include one or more avP6 ligands are described. In some embodiments, a composition comprises a pharmaceutically acceptable excipient. In some embodiments, a composition that includes one or more avP6 ligands comprises one or more other pharmaceutical substances or pharmaceutically active ingredients or compounds. 25 In other embodiments, the compositions comprise medicaments that include one or more avP6 ligands as described herein. In some embodiments, the medicament further comprises a pharmaceutically acceptable excipient. 30 Compositions that include one or more avP6 integrin ligands disclosed herein can be delivered in vivo or in vitro, for example, to type I and II alveolar epithelial cells, goblet cells, secretory epithelial cells, ciliated epithelial cells, comeal and conjunctival epithelial cells, dermal epithelial cells, cholangiocytes, enterocytes, ductal epithelial cells, glandular epithelial cells, renal tubules, and epithelial tumors (carcinomas). 2024202695   24 Apr 2024 In another aspect, the present disclosure provides methods comprising the use of one or more avP6 ligands and / or compositions as described herein and, if desired, bringing the disclosed avP6 ligands and / or compositions into a form suitable for administration as a pharmaceutical 5 product. In other embodiments, the disclosure provides methods for the manufacture of the ligands and compositions, e.g., medicaments, described herein. Compositions that include one or more avP6 integrin ligands can be administered to subjects in vivo using routes of administration known in the art to be suitable for such administration in 10 view of the cargo molecule sought to be administered, including, for example, intravenous, subcutaneous, intraperitoneal, intradermal, transdermal, oral, sublingual, topical, intratumoral, intranasal, or inhaled (aerosol or dry powder formulations) administration. In some embodiments, the compositions that include one or more avP6 integrin ligands may be administered for systemic delivery, for example, by intravenous or subcutaneous 15 administration. In some embodiments, the compositions that include one or more avP6 integrin ligands may be administered for localized delivery, for example, by inhaled delivery via dry powder inhaler or nebulizer. In some embodiments, the compositions that include one or more avP6 integrin ligands may be administered for localized delivery by topical administration. 20 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a type I alveolar epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods for delivering one or more desired cargo 25 molecule(s) to a type II alveolar epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a goblet cell in vivo, the methods comprising administering to the subject one 30 or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a secretory epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 2024202695   24 Apr 2024 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a ciliated epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 5 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a comeal epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 10 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a conjunctival epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods for delivering one or more desired cargo 15 molecule(s) to a dermal epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a cholangiocyte in vivo, the methods comprising administering to the subject 20 one or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to an enterocyte in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 25 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a ductal epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 30 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a glandular epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 2024202695   24 Apr 2024 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to a renal tubule in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. 5 In some embodiments, disclosed herein are methods for delivering one or more desired cargo molecule(s) to an epithelial tumor (carcinoma) in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more cargo molecule. In some embodiments, disclosed herein are methods of delivering an oligomeric compound to 10 a type I alveolar epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a type I alveolar epithelial cell in vivo, the methods comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, 15 disclosed herein are methods of inhibiting the expression of a target gene in a type I alveolar epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. In some embodiments, disclosed herein are methods of delivering an oligomeric compound to 20 a type II alveolar epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a type II alveolar epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein 25 are methods of inhibiting the expression of a target gene in a type II alveolar epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. In some embodiments, disclosed herein are methods of delivering an oligomeric compound to 30 a goblet cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a goblet cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene 2024202695   24 Apr 2024 in a goblet cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. In some embodiments, disclosed herein are methods of delivering an oligomeric compound to 5 a secretory epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a secretory epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the 10 expression of a target gene in a secretory epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. In some embodiments, disclosed herein are methods of delivering an oligomeric compound to 15 a ciliated epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a ciliated epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the 20 expression of a target gene in a ciliated epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. In some embodiments, disclosed herein are methods of delivering an oligomeric compound to 25 a comeal epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a comeal epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the 30 expression of a target gene in a comeal epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 2024202695   24 Apr 2024 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to a conjunctival epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a conjunctival epithelial cell in 5 vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in a conjunctival epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 10 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to a dermal epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a dermal epithelial cell in vivo, 15 comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in a dermal epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 20 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to a cholangiocyte in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a cholangiocyte in vivo, comprising 25 administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in a cholangiocyte in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 30 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to an enterocyte in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to an enterocyte in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more 2024202695   24 Apr 2024 RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in an enterocyte in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 5 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to a ductal epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a ductal epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the 10 one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in a ductal epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 15 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to a glandular epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a glandular epithelial cell in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the 20 one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in a glandular epithelial cell in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 25 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to a renal tubule in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to a renal tubule in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more 30 RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in a renal tubule in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 2024202695   24 Apr 2024 In some embodiments, disclosed herein are methods of delivering an oligomeric compound to an epithelial tumor (carcinoma) in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more oligomeric compound. In some embodiments, disclosed herein are methods of delivering an RNAi agent to an epithelial tumor 5 (carcinoma) in vivo, comprising administering to the subject one or more avP6 integrin ligands conjugated to the one or more RNAi agent. In some embodiments, disclosed herein are methods of inhibiting the expression of a target gene in an epithelial tumor (carcinoma) in vivo, the methods comprising administering to the subject an RNAi agent conjugated to one or more ligands having affinity for avP6 integrin. 10 As used herein, the term “alkyl” refers to a saturated aliphatic hydrocarbon group, straight chain or branched, having from 1 to 10 carbon atoms unless otherwise specified. For example, “C1-C6 alkyl” includes alkyl groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. Non-limiting examples of alkyl groups include methyl, ethyl, Ao-propyl, tert-15 butyl, n-hexyl. As used herein, the term “aminoalkyl” refers to an alky l group as defined above, substituted at any position with one or more amino groups as permitted by normal valency. The amino groups may be unsubstituted, monosubstituted, or di-substituted. Non-limiting examples of aminoalkyl groups include aminomethyl, dimethylaminomethyl, and 2-aminoprop-l-yl. 20 As used herein, the term “cycloalkyl” means a saturated or unsaturated nonaromatic hydrocarbon ring group having from 3 to 14 carbon atoms, unless otherwise specified. Nonlimiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, methylcyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and cyclohexyl. Cycloalkyds may 25 include multiple spiro- or fused rings. Cycloalkyl groups are optionally mono-, di-, tri-, tetra , or penta-substituted on any position as permitted by normal valency. As used herein, the term “alkenyl” refers to a non-aromatic hydrocarbon radical, straight, or branched, containing at least one carbon-carbon double bond, and having from 2 to 10 carbon 30 atoms unless otherwise specified. Up to five carbon-carbon double bonds may be present in such groups. For example, “C2-C6” alkenyl is defined as an alkenyl radical having from 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and cyclohexenyl. The straight, branched, or cyclic portion of the alkenyl group may contain double bonds and is optionally mono-, di-, tri-, tetra-, or penta-substituted on any 2024202695   24 Apr 2024 position as permitted by normal valency. The term “cycloalkenyl” means a monocyclic hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond. 5 As used herein, the term “alkynyl” refers to a hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms, unless otherwise specified, and containing at least one carbon-carbon triple bond. Up to 5 carbon-carbon triple bonds may be present. Thus, “C2-C6 alkynyl” means an alkynyl radical having from 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propvnyl, and 2-butynyl. The straight or 10 branched portion of the alkynyl group may be optionally mono-, di-, tri-, tetra-, or pentasubstituted on any position as permitted by normal valency. As used herein, “alkoxy!” or “alkoxy” refers to -O-alkyl radical having the indicated number of carbon atoms. For example, Ci-6 alkoxy is intended to include Ci, C2, C3, C4, C5, and Ce 15 alkoxy groups. For example, Ci-s alkoxy, is intended to include Ci, C2, C3, C4, Cs, Ce, C?, and Cs alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy. 20 As used herein, “keto” refers to any alkyl, alkenyl, alkynyl, cycloalkvl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl group as defined herein attached through a carbonyl bridge. Examples of keto groups include, but are not limited to, alkanoyl (e.g., acetyl, propionyl, butanoyl, pentanoyl, or hexanoyl), alkenoyl (e.g., acryloyl) alkvnoyl (e.g., ethynoyl, propynoyl, butynovl, pentynoyl, or hexynoyl), aryloyl (e.g., benzoyl), heteroaryloyl (e.g., 25 pyrroloyl, imidazoloyl, quinolinoyl, or pyridinoyl). As used herein, “alkoxycarbonyl” refers to any alkoxy group as defined above attached through a carbonyl bridge (i.e., -CXO)O-alkyl). Examples of alkoxy carbonyl groups include, but are not limited to, methoxy carbonyl, ethoxy carbonyl, iso-propoxy carbonyl, n-propoxy carbonyl, t-30 butoxycarbonyl, benzyloxycarbonyl, or n-pentoxycarbonyl. As used herein, “aryloxycarbonyl” refers to any aiyl group as defined herein attached through an oxycarbonyl bridge (i.e., -C(O)O-arvl). Examples of aryloxycarbonvl groups include, but are not limited to, phenoxy carbonyl and naphthyloxy carbonyl. 2024202695   24 Apr 2024 As used herein, “heteroaryl oxy carbonyl” refers to any heteroaryl group as defined herein attached through an oxy carbonyl bridge (i.e., -C(O)O-heteroaryl). Examples of heteroaryloxycarbonyl groups include, but are not limited to, 2-pyridyloxycarbonyl, 25   oxazolyloxycarbonyl, 4-thiazolyloxycarbonyl, or pyrimi dinyloxy carbonyl. As used herein, “aryl” or “aromatic” means any stable monocyclic or polycyclic carbon ring of up to 6 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, indanyl, and 10 biphenyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. Aryl groups are optionally mono-, di-, tri, tetra-, or penta-substituted on any position as permitted by normal valency. As used herein, the term “heteroaryl” represents a stable monocyclic or polycyclic ring of up 15 to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, benzimidazolonyl, benzoxazolonyl, quinolinyl, isoquinolinyl, dihydroisoindolonyl, imidazopyridinyl, 20 isoindolonyl, indazolvl, oxazolyl, oxadiazolyl, isoxazolvl, indolyl, pvrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and tetrahydroquinoline. “Heteroaryl” is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring. 25 Heteroaryl groups are optionally mono-, di-, tri-, tetra-, or penta-substituted on any position as permitted by normal valency. As used herein, the term “heterocycle,” “heterocyclic,” or “heterocyclyl” means a 3- to 14membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected 30 from the group consisting of O, N, and S, including polycyclic groups. As used herein, the term “heterocyclic” is also considered to be synonymous with the terms “heterocycle” and “heterocyclyl” and is understood as also having the same definitions set forth herein. “Heterocyclyl” includes the above mentioned heteroaryls, as well as dihydro and tetrahydro analogs thereof. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, 2024202695   24 Apr 2024 benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenvl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxooxazolidinyl, oxazolyl, oxazoline, 5 oxopiperazinyl, oxopyrrolidinyl, oxomorpholinyl, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyridinonyl, pyrimidyl, pyrimidinonyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, 10 piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,                     dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihvdroindolyl, dihydroisooxazolyl, dihydroisothiazolvl, dihydrooxadiazolyl, dihydrooxazolvl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, 15 dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dioxidothiomorpholinyl, methylenedi oxy benzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom. Heterocyclyl groups are optionally mono-, di-, tri-, tetra-, or penta-substituted on any position as permitted by normal valency. 20 As used herein, the terms “treat,” “treatment,” and the like, mean the methods or steps taken to provide relief from or alleviation of the number, severity, and / or frequency of one or more symptoms of a disease or condition in a subject. A; 25   Unless stated otherwise, use of the symbol * as used herein means that any group or groups may be linked thereto that is in accordance with the scope of the inventions described herein. As used herein, the term “isomers” refers to compounds that have identical molecular formulae, but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of 30   their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images are termed 2024202695   24 Apr 2024 “enantiomers,” or sometimes optical isomers. A carbon atom bonded to four non-identical substituents is termed a “chiral center.” As used herein, a linking group is one or more atoms that connects one molecule or portion of 5 a molecule to another to second molecule or second portion of a molecule. In the art, the terms linking group and spacers are sometimes used interchangeably. Similarly, as used in the art, the term scaffold is sometimes used interchangeably with a linking group. In some embodiments, a linking group can include a peptide-cleavable linking group. In some embodiments, a linking group can include or consist of the peptide FCitFP (SEQ ID NO: 131). 10 As used herein, the term “linked” when referring to the connection between two molecules means that two molecules are joined by a covalent bond or that two molecules are associated via noncovalent bonds (e.g., hydrogen bonds or ionic bonds). In some examples, where the term “linked” refers to the association between two molecules via noncovalent bonds, the 15 association between the two different molecules has a Kd of less than 1 x 10'4 M (e.g., less than 1 x 10'5 M, less than 1 x 10'6 M, or less than 1 x 10'7 M) in physiologically acceptable buffer (e.g., phosphate buffered saline). Unless stated, the term linked as used herein may refer to the connection between a first compound and a second compound either with or without any intervening atoms or groups of atoms. 20 As used herein, “standard amino acids” or “natural amino acids” include alanine, cysteine, aspartic acid (aspartate), glutamic acid (glutamate), phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine. 25 As used herein, “non-standard amino acids” include, but are not limited to, selenocysteine, pyrrolysine, N-formylmethionine, hydroxy proline, selenomethionine, a-Amino-isobutyric acid (Aib), L-a-amino-butyric acid (Abu), a,Y-diaminobutyric acid, dehydroalanine, norleucine, alloisoleucine, t-leucine, a-amino-n-heptanoic acid, a,P-diaminopropionic acid, P30 N-oxalyl-a,P-diaminopropionic acid, allothreonine, homocysteine, homoserine, P-homo-alanine (P3-hA), isovaline, norvaline (Nva), citrulline (Cit), ornithine, a-methyl-aspartate (aMeD), a-methyl-leucine (aMeL), N-methyl alanine, N-methyl-glycine (NMeG), N-methyl Leucine (NmcL), P-cyclohexyl-alanine (Cha), N-ethyl alanine, N,N-E-dimethyl lysine (K(Me)2), 2024202695   24 Apr 2024 is dimethyl arginine (R(Me)2), Dap(Ac), n-alkylated L-a amino acids, and other amino acid analogs or amino acid mimetics that function in a manner similar to the naturally occurring amino acids. 5 As used herein, unless specifically identified in a structure as having a particular conformation, for each structure in which asymmetric centers are present and thus give rise to enantiomers, diastereomers, or other stereoisomeric configurations, each structure disclosed herein is intended to represent all such possible isomers, including their optically pure and racemic forms. For example, the structures disclosed herein are intended to cover mixtures of 10 diastereomers as well as single stereoisomers. The person of ordinary skill in the art would readily understand and appreciate that the compounds and compositions disclosed herein may have certain atoms (e.g., N, O, or S atoms) in a protonated or deprotonated state, depending upon the environment in which the compound 15 or composition is placed. Accordingly, as used herein, the structures disclosed herein envisage that certain functional groups, such as, for example, OH, SH, or NH, may be protonated or deprotonated. The disclosure herein is intended to cover the disclosed compounds and compositions regardless of their state of protonation based on the pH of the environment, as would be readily understood by the person of ordinary skill in the art. 20 As used in a claim herein, the phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. When used in a claim herein, the phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. 25 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described 30 below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 2024202695   24 Apr 2024 Pharmacokinetics is a general concern for peptide-based drug products and pharmaceutical compositions that include peptides. Many peptides, for example, do not circulate in the blood for more than a few minutes due to enzymatic degradation. This often significantly reduces or even prevents their usefulness as therapeutic agents or as components of drug products. 5 Stability studies in various serum preparations (e.g., measuring in vitro degradation of peptides in serum and / or plasma), have become important screening assays in peptide-based drug development. As shown by, among other things, such studies, the avP6 integrin ligands disclosed herein are stable in serum and have affinity for, or can bind to, avP6 integrins. 10 Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Brief Description of the Drawings 15 FIG. 1 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein synthesized as a tetrafluorophenyl (TFP) ester. The avP6 integrin ligand includes a PEG20 (twenty (20) ethylene oxide (CH2-CH2-O) units) and an FCitFP linking group. 20 FIG. 2 represents the chemical structure of an example of an avP6 integrin ligands disclosed herein synthesized as a tetrafluorophenyl (TFP) ester. The avP6 integrin ligand includes a PEGs (five (5) ethylene oxide (CH2-CH2-O) units). FIG. 3 represents the chemical structure of an example of an avP6 integrin ligand disclosed 25          herein that includes CH3CO as an amine-terminal cap, a PEG20, and an FCitFP linking group. FIG. 4 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein that includes CH3CO as an amine-terminal cap and a PEGs. 30 FIG. 5 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein without an amine-terminal cap. The avP6 integrin ligand includes a PEG20 and an FCitFP linking group. 2024202695   24 Apr 2024 FIG. 6 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein without an amine-terminal cap. The avP6 integrin ligand includes a PEGs. 5 FIG. 7 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein that includes CHsCO as an amine-terminal cap. FIG. 8 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein that includes CH3CO as an amine-terminal cap, a PEG20, and an FCitFP linking 10          group. Further shown in the structure is a 20 kilodalton (kDa) PEG moiety. FIG. 9 represents the chemical structure of an example of an avP6 integrin ligand disclosed herein that includes CH3CO as an amine-terminal cap, a PEG20, and an FCitFP linking group. Further shown in the structure is a 20 kilodalton (kDa) PEG moiety, and the 15          structure is shown linked to an oligomeric compound, such as an RNAi agent. FIG. 10 represents the chemical structure of an example of a tridentate avP6 integrin ligand disclosed herein that includes CH3CO as an amine-terminal cap and a PEG5, linked to a bis-glutamic acid scaffold and a PEG-azide reactive group. 20 FIG. 11 represents the chemical structure of an example of a tridentate avP6 integrin ligand disclosed herein that includes CH3CO as an amine-terminal cap and a PEG5, linked to a bis-glutamic acid scaffold. 25 FIG. 12 is a graph showing Rat whole lung alpha ENaC expression in Sprague-Dawley rats of naked alpha-ENaC RNAi agent without a targeting ligand and the same alpha-ENaC RNAi agent conjugated to a poly-L-lysine scaffold and to the avP6 integrin ligand represented by the structure of Figure 4. 30                         Detailed Description Described herein are novel, engineered, non-naturally occurring peptide-based avP6 integrin ligands having serum stability and affinity for avP6 integrins. The avP6 integrin ligands can be used to target avP6 integrin expressing cells in vitro, in situ, ex vivo, and / or in vivo. In some 2024202695   24 Apr 2024 embodiments, the avP6 integrin ligands can be conjugated to one or more cargo molecules to direct the cargo molecules to avP6 integrin expressing cells in vitro, in situ, ex vivo, and / or in vivo. In some embodiments, the cargo molecules include or consist of pharmaceutically active compounds. In some embodiments, the avP6 integrin ligands disclosed herein are conjugated 5 to cargo molecules to direct the cargo molecules to epithelial cells in vivo. In some embodiments, the avP6 integrin ligands comprise: Z-RG'DLXaalXaa2L (SEQIDNO: 85) (Formula I) wherein 10 Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); 15 L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); and 20 Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art). 25 In some embodiments, the amine-terminal cap (Z) in Formula I comprises CHsCO (also referred to herein as ‘Ac’). In some embodiments, the amine-terminal cap (Z) in Formula I is CH3CO. In some embodiments, the avP6 integrin ligands comprise: 30                    R'G1DLXaa1Xaa2L (SEQ ID NO: 98) (Formula la) wherein R' is Dap(guanidino); and G1, D, L, Xaa1, and Xaa2 are each as defined for Formula I herein. 2024202695   24 Apr 2024 In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG1 DLXaa'Xaa'L (SEQ ID NO: 99) (Formula lb), wherein Z, R, G1, D, L, and Xaa1 are each as defined for Formula I herein; and 5 Xaau is a non-standard amino acid. In some embodiments, the avP6 integrin ligands comprise the general formula: Z-RG1 DLAXaauL (SEQ ID NO: 90) (Formula Ic), 10 wherein Z, R, G1, D, and L are each as defined for Formula I herein; A is L-alanine; and Xaau is a non-standard amino acid. 15 In some embodiments, avP6 integrin ligands are described, comprising: Z-RG1 DLXaa1Xaa2L-J-R1 (SEQ ID NO: 86) (Formula II) wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); 20 R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in 25          the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known 30           in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 2024202695   24 Apr 2024 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L-P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids 5          described herein or known in the art), or a combination thereof; and R1 is optional and, if present, includes PEG and / or a linking group. In some embodiments L is linked to J via an amide bond. In some embodiments, avP6 integrin ligands are described comprising: 10                 R'G'DLXaa'Xaa^-J-R1 (SEQ ID NO: 100) (Formula Ila) wherein R' is Dap(guanidino); and G1, D, L, Xaa1, Xaa2, J, and R1 are each as defined for Formula II herein. In some embodiments L is linked to J via an amide bond. 15 In some embodiments, avP6 integrin ligands can include a reactive group or protected reactive group, comprising: Z-RG'DLXaa'Xaa^-J-R'-R2 (SEQ ID NO: 87) (Formula III) wherein 20 Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); 25 L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); 30 Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); 2024202695   24 Apr 2024 J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a 5          amino acids (e.g., any of the L-a amino acids described herein or known in the art), L- P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; R1 is optional and, if present, includes PEG and / or a linking group, and 10 R2 comprises a reactive group or a protected reactive group. The reactive group or protected reactive group can be used to attach the avP6 integrin ligand to a molecule of interest, i.e., to a cargo molecule. In some embodiments, L is linked to J via an amide bond. 15 In some embodiments, avP6 integrin ligands are synthesized having a reactive group or protected reactive group, comprising the formula: R'G'DLXaa'Xaa^-J-R'-R2 (SEQ ID NO: 101) (Formula Illa) wherein 20 R' is Dap(guanidino); and G1, D, L, Xaa1, Xaa2, J, R1, and R2 are each as defined for Formula III herein. In some embodiments, one or more avP6 integrin ligand(s) can be conjugated to one or more cargo molecule(s), comprising: 25              (Z-RG1DLXaa1Xaa2L-J-R1)n-R3 (SEQ ID NO: 88) (Formula IV) wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; 30 G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known 2024202695   24 Apr 2024 in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known 5           in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 10           25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L-P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; 15 R1 is optional and, if present, includes polyethylene glycol (PEG) and / or a linking group; nis an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and 20 R3 comprises a cargo molecule. In some embodiments, L is linked to J via an amide bond. In some embodiments, the cargo molecule can be any molecule that is desired to be targeted to an avP6 integrin-expressing cell. In some embodiments, n is an integer between 1 and 4. In some embodiments, n is 1. In some embodiments, n is 3. When n is 1, the avP6 integrin ligand can be referred to herein as a 25 “monodentate” avP6 integrin ligand. When n is 3, the avP6 integrin ligand can be referred to herein as a “tridentate” avP6 integrin ligand. When n is 2, the avP6 integrin ligand can be referred to herein as a “bidentate” avP6 integrin ligand. When n is 4, the avP6 integrin ligand can be referred to herein as a “tetradentate” avP6 integrin ligand. 30 In some embodiments, one or more avP6 integrin ligand(s) can be conjugated to one or more cargo molecule(s), comprising: (R'G1DLXaa1Xaa2L-J-R1)n-R3 (SEQIDNO: 102) (Formula IVa) wherein R1 is Dap(guanidino); and 2024202695   24 Apr 2024 G1, D, L, Xaa1, Xaa2, J, R1, n, and R3 are each as defined for Formula IV herein. In some embodiments, L is linked to J via an amide bond. In some embodiments, n is an integer between 1 and 4. In some embodiments, n is 3. In some embodiments, the cargo molecule can 5 be any molecule that is desired to be targeted to an avP6 integrin-expressing cell. In some embodiments, one or more avP6 integrin ligands can be conjugated to one or more cargo molecules, comprising: (Z-RGlDLXaalXaa2L-J-Rl)n-R4-(R3)p (SEQIDNO: 89) (Formula V) 10 wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; G1 is L-glycine orN-methyl glycine; 15 D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino 20           acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); 25 J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L- 30          P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; R1 is optional and, if present, includes PEG and / or a linking group; 2024202695   24 Apr 2024 nis an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); 5 R4 is optional and, if present, comprises a scaffold and / or linking group that includes at least one attachment point for each ligand present (i.e., at least the number of attachment points equal to n) and at least one attachment point for each cargo molecule present (i.e., at least the number of attachment points equal to p); p is an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 10            19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and R3 comprises the one or more cargo molecule. In some embodiments L is linked to J via an amide bond. In some embodiments, the cargo 15 molecule can be any molecule that is desired to be targeted to an avP6 integrin-expressing cell. The avP6 integrin ligands disclosed herein may include one or more scaffolds. Scaffolds, also sometimes referred to in the art as linking groups or linkers, can be used to facilitate the linkage of one or more cargo molecules to one or more avP6 integrin ligands disclosed herein. Useful 20 scaffolds compatible with the ligands disclosed herein are generally known in the art. Nonlimiting examples of scaffolds that can be used with the avP6 integrin ligands disclosed herein include, but are not limited to polymers (e.g., polyacrylate polymers, polyvinyl ester polymers, etc.), amino-acid polymers (e.g., bis-glutamic acid, bis-lysine, poly-L-lysine PLL), etc.), and cysteine. In some embodiments, scaffolds can provide additional desirable properties in 25 addition to serving solely as a linker, such as, for example, enhancing pharmacokinetic (PK) properties. In some embodiments, one or more avP6 integrin ligands can be conjugated to one or more cargo molecules, comprising: 30 (R'G1DLXaa1Xaa2L-J-R1)n-R4-(R3)P (SEQIDNO: 103) (Formula Va) wherein R1 is Dap(guanidino); and G1, D, L, Xaa1, Xaa2, J, R1, n, R4, p, and R3 are each as defined for Formula V herein. 2024202695   24 Apr 2024 In some embodiments L is linked to J via an amide bond. The cargo molecule can be any molecule that is desired to be targeted to an avP6 integrin-expressing cell. In some embodiments, J in any of the formulae herein comprises one, two, three, or more than 5 three L-a amino acids, L-P amino acids, or a,a-disubstituted amino acids. The one, two, three, or more than three amino acids are independently naturally occurring L-a amino acids, naturally-occurring proteinogenic amino acids, naturally occurring standard amino acids (i.e., the 20 amino acids that are encoded directly by the codons of the universal genetic code, also termed coded amino acids of canonical amino acids), or non-standard amino acids (also termed 10 non-natural, non-coded, or non-canonical amino acids). Standard or natural amino acids include alanine, cysteine, aspartic acid (aspartate), glutamic acid (glutamate), phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine. 15 Non-standard amino acids include, but are not limited to, selenocysteine, pyrrolysine, N-formylmethionine, hydroxyproline, selenomethionine, a-Amino-isobutyric acid (Aib), L-a-amino-butyric acid (Abu), a,Y-diaminobutyric acid, dehydroalanine, norleucine, alloisoleucine, t-leucine, a-amino-n-heptanoic acid, a,P-diaminopropionic acid, P-N-oxalyl-a,P-20 diaminopropionic acid, allothreonine, homocysteine, homoserine, P-homo-alanine (P3-hA), isovaline, norvaline (Nva), citrulline (Cit), ornithine, a-methyl-aspartate (aMeD), a-methyl-leucine (aMeL), N-methyl alanine, N-methyl-glycine (NmcG), N-methyl Leucine (NmcL), P-cyclohexyl-alanine (Cha), N-ethyl alanine, N,N-E-dimethyl lysine (K(Me)2), dimethyl arginine (R(Me)2), Dap(Ac), n-alkylated L-a amino acids, and other amino acid analogs or amino acid 25 mimetics that function in a manner similar to the naturally occurring amino acids. In some embodiments, J includes at least one non-standard amino acid. In some embodiments, J is or comprises Aib, Cit, CitAib, CitAibL, CitE, CitF, CitG, CitK, CitP, CitQ, CitQL, EAib, FAib, KAib, PAib, QAib, RabuL, RAibL, RCitL, RDap(Ac)L, RLQ, or RNvaL. 30 In some embodiments, J in any of the formulae described herein includes or consists of Xaa3Xaa4L, wherein L is L-leucine; Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids 2024202695   24 Apr 2024 described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); and Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino 5 acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art). In some embodiments, J is or comprises Xaa3Xaa4, wherein Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid 10   (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); and Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art). 15 In some embodiments, the avP6 integrin ligands comprise: Z-RG1DLXaa1Xaa2LXaa3Xaa4L-R1 (SEQ ID NO: 92) (Formula VI) wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known 20            in the art); R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; 25 Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in 30          the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known 2024202695   24 Apr 2024 in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known 5           in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); and R1 is optional and, if present, comprises PEG and / or a linking group. In some embodiments, Xaa1 is an L-a amino acid, L-P amino acid, or a,a-disubstituted amino 10 acid. Xaa1 can be, but is not limited to, a naturally-occurring L-a amino acid, a naturally occurring proteinogenic amino acid, a naturally-occurring standard (i.e., the 20 amino acids that are encoded directly by the codons of the universal genetic code, also termed coded amino acids of canonical amino acids) amino acid, or a non-standard (also termed non-natural, noncoded, or non-canonical) amino acid. 15 In some embodiments, Xaa2 is an L-a amino acid, L-P amino acid, or a,a-disubstituted amino acid. Xaa2 can be, but is not limited to, a naturally-occurring L-a amino acid, a naturally occurring proteinogenic amino acid, a naturally-occurring standard (i.e., the 20 amino acids that are encoded directly by the codons of the universal genetic code, also termed coded amino 20 acids of canonical amino acids) amino acid, or a non-standard (also termed non-natural, noncoded, or non-canonical) amino acid. In some embodiments, Xaa3 is an L-a amino acid, L-P amino acid, or a,a-disubstituted amino acid. Xaa3 can be, but is not limited to, a naturally-occurring L-a amino acid, a naturally 25 occurring proteinogenic amino acid, a naturally-occurring standard (i.e., the 20 amino acids that are encoded directly by the codons of the universal genetic code, also termed coded amino acids of canonical amino acids) amino acid, or a non-standard (also termed non-natural, noncoded, or non-canonical) amino acid. 30 In some embodiments, Xaa4 is an L-a amino acid, L-P amino acid, or a,a-disubstituted amino acid. Xaa4 can be, but is not limited to, a naturally-occurring L-a amino acid, a naturally occurring proteinogenic amino acid, a naturally-occurring standard (i.e., the 20 amino acids that are encoded directly by the codons of the universal genetic code, also termed coded amino 2024202695   24 Apr 2024 acids of canonical amino acids) amino acid, or a non-standard (also termed non-natural, noncoded, or non-canonical) amino acid. In some embodiments, Xaa1 or Xaa2 is a non-standard amino acid. In some embodiments, 5 Xaa1 is a non-standard amino acid. In some embodiments, Xaa2 is a non-standard amino acid. In some embodiments, both Xaa1 and Xaa2 are non-standard amino acids. In some embodiments, Xaa1 and / or Xaa2 are Abu. In some embodiments, Xaa1 is Abu. In some embodiments, Xaa2 is Abu. 10 In some embodiments, Xaa1 or Xaa2 are uncharged. In some embodiments, Xaa1 is uncharged. In some embodiments, Xaa2 is uncharged. In some embodiments, Xaa1 and Xaa2 are uncharged. 15 In some embodiments, Xaa1 is uncharged and Xaa2 is a non-standard amino acid. In some embodiments Xaa2 is uncharged and Xaa1 is a non-standard amino acid. In some embodiments Xaa1 is uncharged and Xaa2 is Abu. In some embodiments Xaa2 is uncharged and Xaa1 is Abu. 20 In some embodiments, Xaa1 Xaa2 is AAbu, KAbu, EAbu, FAbu, QAbu, GAbu, PAbu, AK, AE, AF, AQ, AG, and AP, wherein A is L-alanine, Abu is L-a-aminobutyric acid, K is L-lysine, E is L-glutamic acid (glutamate), F is L-phenylalanine, Q is L-glutamine, G is L-glycine, and P is L-proline. 25 In some embodiments, RG1DLXaa1Xaa2L (SEQ ID NO: 117) is selected from the group consisting of: RGDLAAbuL (SEQ ID NO: 118), RGDLKAbuL (SEQ ID NO: 119), RGDLEAbuL (SEQ ID NO: 120), RGDLFAbuL (SEQ ID NO: 121), RGDLQAbuL (SEQ ID NO: 122), RGDLGAbuL (SEQ ID NO: 123), RGDLPAbuL (SEQ ID NO: 124), RGDLAKL (SEQ ID NO: 125), RGDLAEL (SEQ ID NO: 126), RGDLAFL (SEQ ID NO: 127), 30 RGDLAQL (SEQ ID NO: 128), RGDLAGL (SEQ ID NO: 129), and RGDLAPL (SEQ ID NO: 130); wherein, R is L-arginine; G is L-glycine; D is L-aspartic acid (aspartate); L is L-leucine; A is L-alanine; Abu is L-a-aminobutyric acid; K is L-lysine; E is L-glutamic acid (glutamate); F is L-phenylalanine; Q is L-glutamine; and P is L-proline. In some embodiments, G (L-glycine) in any of the preceding formulae is replaced with MeGly (N-methyl glycine). 2024202695   24 Apr 2024 In some embodiments, Xaa3 or Xaa4 is a non-standard amino acid. In some embodiments, Xaa3 is a non-standard amino acid. In some embodiments, Xaa4 is a non-standard amino acid. In some embodiments, both Xaa3 and Xaa4 are non-standard amino acids. 5 In some embodiments Xaa3 and / or Xaa4 are Cit. In some embodiments, Xaa3 is Cit. In some embodiments, Xaa4 is Cit. In some embodiments, Xaa3 or Xaa4 are uncharged. In some embodiments, Xaa3 is 10 uncharged. In some embodiments, Xaa4 is uncharged. In some embodiments, Xaa3 and Xaa4 are uncharged. In some embodiments Xaa3 is uncharged and Xaa4 is a non-standard amino acid. In some embodiments Xaa3 is uncharged and Xaa4 is a non-standard amino acid. In some 15 embodiments Xaa3 is Aib. In some embodiments Xaa4 is Aib. In some embodiments, Xaa3Xaa4 is CitAib, CitE, CitF, CitG, CitK, CitP, CitQ, EAib, FAib, KAib, PAib, or QAib, wherein Cit is citrulline, Aib is aminoisobutyric acid (a-methylalanine), K is L-lysine, E is L-glutamic acid (glutamate), F is L-phenylalanine, Q is L-glutamine, G is 20 L-glycine, and P is L-proline. In some embodiments, the avP6 integrin ligands comprise: R'G1DLXaa1Xaa2LXaa3Xaa4L-R1 (SEQ ID NO: 104) (Formula Via) wherein 25 R' is Dap(guanidino); and G1, D, L, Xaa1, Xaa2, Xaa3, Xaa4, and R1 are each as defined for Formula VI herein. In some embodiments, the avP6 integrin ligands comprise a reactive group or a protected reactive group and comprise: 30          (Z-RG1DLXaa1Xaa2L-J-R1)n-R4-(R2)P (SEQ ID NO: 105) (Formula VII) wherein Z is an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art); R is L-arginine; 2024202695   24 Apr 2024 G1 is L-glycine or N-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in 5          the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known 10           in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); J is optional and, if present, includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 15           25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30), L-a amino acids (e.g., any of the L-a amino acids described herein or known in the art), L-P amino acids (e.g., any of the L-P amino acids described herein or known in the art), or a,a-disubstituted amino acids (e.g., any of the a,a-disubstituted amino acids described herein or known in the art), or a combination thereof; 20 R1 is optional and, if present, includes polyethylene glycol (PEG) and / or a linking group; nis an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); 25 R4 is optional and, if present, comprises a scaffold and / or linking group that includes at least one attachment point for each ligand and at least one attachment point for each cargo molecule; p is an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 30            10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and R2 comprises a reactive group or a protected reactive group. 2024202695   24 Apr 2024 In some embodiments L is linked to J via an amide bond. In some embodiments, the avP6 integrin ligands that include on or more reactive groups or protected reactive groups can be reacted with a cargo molecule to form an avP6 integrin ligand-cargo molecule conjugate. 5 In some embodiments, the avP6 integrin ligands comprise a reactive group or a protected reactive group and comprise: (R'G1DLXaa1Xaa2L-J-R1)n-R4-(R2)P (SEQ ID NO: 106) (Formula Vila) wherein R' is Dap(guanidino); and 10       G1, D, L, Xaa1, Xaa2, J, R1, n, R4, p, and R2 are each as defined for Formula VII herein. In some embodiments L is linked to J via an amide bond. The cargo molecule can be any molecule that is desired to be targeted to an avP6 integrin-expressing cell. In some embodiments, particularly when only localized delivery is desired (e.g., by inhalation 15 or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal, or by topical administration), the avP6 integrin ligands can be synthesized without the presence of an amine terminal cap, provided that at least one or more amino acids are non-standard amino acids. In some embodiments, the avP6 integrin ligands comprise: RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII) 20 wherein R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); 25 L is L-leucine; Xaa1 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); 30 Xaa2 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); 2024202695   24 Apr 2024 Xaa3 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); 5 Xaa4 is an L-a amino acid (e.g., any of the L-a amino acids described herein or known in the art), an L-P amino acid (e.g., any of the L-P amino acids described herein or known in the art), or an a,a-disubstituted amino acid (e.g., any of the a,a-disubstituted amino acids described herein or known in the art); R1 is optional and, if present, includes PEG and / or a linking group; and 10 at least one of Xaa1, Xaa2, Xaa3, and Xaa4 is a non-standard amino acid. In some embodiments, the avP6 integrin ligands comprise: RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII), as each variable is defined above for Formula VIII, and wherein at least two of Xaa1, Xaa2, Xaa3, and Xaa4 is a 15 non-standard amino acid. In some embodiments, the avP6 integrin ligands comprise: RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII), as each variable is defined above for Formula VIII, and wherein at least three of Xaa1, Xaa2, Xaa3, and Xaa4 is a 20 non-standard amino acid. In some embodiments, the avP6 integrin ligands comprise: RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1 (SEQ ID NO: 96) (Formula VIII), as each variable is defined above for Formula VIII, and wherein Xaa2, Xaa3, and Xaa4 is a non-standard amino 25 acid. In some embodiments, the avP6 integrin ligands comprise: RG^LAAbuLCitAibL-R1 (SEQ ID NO: 97) (Formula Villa) wherein 30 R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; A is L-alanine; 2024202695   24 Apr 2024 Abu is L-a-amino-butyric acid; Cit is citrulline; Aib is a-amino-isobutyric acid; and R1 is optional and, if present, comprises PEG and / or a linking group. 5 In some embodiments, the avP6 integrin ligands include a reactive group or a protected reactive group and comprise: (RG1DLAAbuLCitAibL-R1)n-R4-(R2)P (SEQ ID NO: 107) (Formula Vlllb) wherein 10 R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); L is L-leucine; A is L-alanine; 15 Abu is L-a-amino-butyric acid; Cit is citrulline; Aib is a-amino-isobutyric acid; R1 is optional and, if present, comprises PEG and / or a linking group; nis an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20            19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); R4 is optional and, if present, comprises a scaffold or linking group that includes at least one attachment point for each ligand and at least attachment point for each cargo 25          molecule; p is an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and 30 R2 comprises a reactive group or a protected reactive group. In some embodiments, one or more cargo molecules are conjugated to one or more avP6 integrin ligands, and comprise: (RG'DLAAbuLCitAibL-R'jn-RMROp (SEQ ID NO: 108) (Formula VIIIc) 2024202695   24 Apr 2024 wherein R is L-arginine; G1 is L-glycine orN-methyl glycine; D is L-aspartic acid (L-aspartate); 5 L is L-leucine; R1 is optional and, if present, comprises PEG and / or a linking group; nis an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 10           15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); R4 is optional and, if present, comprises a scaffold or linking group that includes at least one attachment point for each ligand and at least attachment point for each cargo molecule; p is an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 15            19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; or 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 30, 15 to 25, 15 to 20, 20 to 30, 20 to 25, or 25 to 30); and R3 comprises the one or more cargo molecules. The one or more cargo molecules can be any molecule that is desired to be targeted to an avP6 20 integrin-expressing cell. As used herein, in some embodiments, R1 is present and comprises a PEG group having 1-100 ethylene oxide (CH2-CH2-O) units (e.g., 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, 1 to 5, 2 to 100, 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 25    30, 2 to 20, 2 to 10, 2 to 5, 5 to 100, 5 to 90, 5 to 80, 5 to 70, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 20, 5 to 10, 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20, 20 to 100, 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40, 20 to 30, 30 to 100, 30 to 90, 30 to 80, 30 to 70, 30 to 60, 30 to 50, 30 to 40, 40 to 100, 40 to 90, 40 to 80, 40 to 70, 40 to 60, 40 to 50, 50 to 100, 50 to 90, 50 to 80, 50 to 70, 50 to 60, 60 to 100, 60 to 90, 30   60 to 80, 60 to 70, 70 to 100, 70 to 90, 70 to 80, 80 to 100, 80 to 90, or 90 to 100 ethylene oxide units). In some embodiments, R1 is present and comprises a PEG group having 2-30 ethylene oxide units. In some embodiments, R1 is present and comprises a PEG group having 2-20 ethylene oxide units. In some embodiments, R1 is present and comprises a PEG group having 2-10 ethylene oxide units. In some embodiments, R1 is present and comprises a PEG group 2024202695   24 Apr 2024 having 5-20 ethylene oxide units. In some embodiments, R1 is present and comprises a PEG group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ethylene oxide units. 5 Reactive groups are well known in the art and provide for formation of covalent linkages between two molecules or reactants. Suitable reactive groups for use in the scope of the inventions herein include, but are not limited to: amino groups, amide groups, carboxylic acid groups, azides, alkynes, propargyl groups, BCN(biclclo[6.1.0]nonyne, DBCO(dibenzocyclooctyne) thiols, maleimide groups, aminooxy groups, N-10 hydroxysuccinimide (NHS) or other activated ester (for example, PNP, TFP, PFP), bromo groups, aldehydes, carbonates, tosylates, tetrazines, trans-cyclooctene (TCO), hydrazides, hydroxyl groups, disulfides, and orthopyridyl disulfide groups. Incorporation of reactive groups can facilitate conjugation of an avP6 integrin ligand disclosed 15 herein to a cargo molecule. Conjugation reactions are well known in the art and provide for formation of covalent linkages between two molecules or reactants. Suitable conjugation reactions for use in the scope of the inventions herein include, but are not limited to, amide coupling reaction, Michael addition reaction, hydrazone formation reaction and click chemistry cycloaddition reaction. 20 In some embodiments, the avP6 integrin targeting ligands disclosed herein are synthesized as a tetrafluorophenyl (TFP) ester, which can be displaced by a reactive amino group to attach a cargo molecule. 25 Protected reactive groups are also commonly used in the art. A protecting group provides temporary chemical transformation of a reactive group into a group that does not react under conditions where the non-protected group reacts, e.g, to provide chemo-selectivity in a subsequent chemical reaction. Suitable protected reactive groups for use in the scope of the inventions herein include, but are not limited to, BOC groups (t-butoxycarbonyl), Fmoc (9 30 fluorenylmethoxycarbonyl), carboxybenzyl (CBZ) groups, benzyl esters, and PBF (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl). A cargo molecule is any molecule for which targeting to an avP6 integrin or a cell expressing an avP6 integrin may be desired. A cargo molecule can be, but is not limited to, a 2024202695   24 Apr 2024 pharmaceutical ingredient, a drug product, a prodrug, a therapeutically valuable substance, a small molecule, an antibody, an antibody fragment, an immunoglobulin, a monoclonal antibody, a label or marker, a lipid, a natural or modified nucleic acid or polynucleotide, a peptide, a polymer, a polyamine, a protein, an aptamer, a toxin, a vitamin, a PEG, a hapten, a 5 digoxigenin, a biotin, a radioactive atom or molecule, or a fluorophore. In some embodiments, one or more cargo molecules (e.g., the same or different cargo molecules) are linked to one or more avP6 integrin ligands to target the cargo molecules to a cell expressing an avP6 integrin. In some embodiments, the one or more cargo molecules is a pharmaceutical ingredient or 10 pharmaceutical composition. In some embodiments, the one or more cargo molecules is an oligomeric compound. As used herein, an “oligomeric compound” is a nucleotide sequence containing about 10-50 (e.g., 10 to 48, 10 to 46, 10 to 44, 10 to 42, 10 to 40, 10 to 38, 10 to 36, 10 to 34, 10 to 32, 10 to 30, 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20, 10 to 18, 10 to 16, 10 to 14, 10 to 12, 12 to 50, 12 to 48, 12 to 46, 12 to 44, 12 to 42, 12 to 40, 12 to 38, 12 to 36, 15    12 to 34, 12 to 32, 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20, 12 to 18, 12 to 16, 12 to 14, 14 to 50, 14 to 48, 14 to 46, 14 to 44, 14 to 42, 14 to 40, 14 to 38, 14 to 36, 14 to 34, 14 to 32, 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20, 14 to 18, 14 to 16, 16 to 50, 16 to 48, 16 to 46, 16 to 44, 16 to 42, 16 to 40, 16 to 38, 16 to 36, 16 to 34, 16 to 32, 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20, 16 to 18, 18 to 50, 18 to 48, 18 to 46, 18 to 44, 20    18 to 42, 18 to 40, 18 to 38, 18 to 36, 18 to 34, 18 to 32, 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, 18 to 20, 20 to 50, 20 to 48, 20 to 46, 20 to 44, 20 to 42, 20 to 40, 20 to 38, 20 to 36, 20 to 34, 20 to 32, 20 to 30, 20 to 28, 20 to 26, 20 to 24, 20 to 22, 22 to 50, 22 to 48, 22 to 46, 22 to 44, 22 to 42, 22 to 40, 22 to 38, 22 to 36, 22 to 34, 22 to 32, 22 to 30, 22 to 28, 22 to 26, 22 to 24, 24 to 50, 24 to 48, 24 to 46, 24 to 44, 24 to 42, 24 to 40, 24 to 38, 24 to 36, 24 to 34, 25   24 to 32, 24 to 30, 24 to 28, 24 to 26, 26 to 50, 26 to 48, 26 to 46, 26 to 44, 26 to 42, 26 to 40, 26 to 38, 26 to 36, 26 to 34, 26 to 32, 26 to 30, 26 to 28, 28 to 50, 28 to 48, 28 to 46, 28 to 44, 28 to 42, 28 to 40, 28 to 38, 28 to 36, 28 to 34, 28 to 32, to 28 to 30, 30 to 50, 30 to 48, 30 to 46, 30 to 44, 30 to 42, 30 to 40, 30 to 38, 30 to 36, 30 to 34, 30 to 32, 32 to 50, 32 to 48, 32 to 46, 32 to 44, 32 to 42, 32 to 40, 32 to 38, 32 to 36, 32 to 34, 34 to 50, 34 to 48, 34 to 46, 34 to 30   44, 34 to 42, 34 to 40, 34 to 38, 34 to 36, 36 to 50, 36 to 48, 36 to 46, 36 to 44, 36 to 42, 36 to 40, 36 to 38, 38 to 50, 38 to 48, 38 to 46, 38 to 44, 38 to 42, 38 to 40, 40 to 50, 40 to 48, 40 to 46, 40 to 44, 40 to 42, 42 to 50, 42 to 48, 42 to 46, 42 to 44, 44 to 50, 44 to 48, 44 to 46, 46 to 50, 46 to 48, or 48 to 50) nucleotides or nucleotide base pairs. In some embodiments, an oligomeric compound has a nucleobase sequence that is at least partially complementary to a 2024202695   24 Apr 2024 coding sequence in an expressed target nucleic acid or target gene within a cell. In some embodiments, the oligomeric compounds, upon delivery to a cell expressing a gene, are able to inhibit the expression of the underlying gene, and are referred to herein as “expressioninhibiting oligomeric compounds.” The gene expression can be inhibited in vitro or in vivo. 5 “Oligomeric compounds” include, but are not limited to: oligonucleotides, single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), ribozymes, interfering RNA molecules, and dicer substrates. In some embodiments, an 10 oligomeric compound is a single-stranded oligomeric compound. In some embodiments, an oligomeric compound is a double-stranded oligomeric compound. In some embodiments, the one or more cargo molecules is / are an “RNAi agent,” which as defined herein is an agent that contains an RNA or RNA-like (e.g., chemically modified RNA) 15 oligonucleotide molecule that is capable of degrading or inhibiting translation of messenger RNA (mRNA) transcripts of a target mRNA in a sequence specific manner. As used herein, RNAi agents may operate through the RNA interference mechanism (i.e., inducing RNA interference through interaction with the RNA interference pathway machinery (RNA-induced silencing complex or RISC) of mammalian cells), or by any alternative mechanism(s) or 20 pathway(s). While it is believed that RNAi agents, as that term is used herein, operate primarily through the RNA interference mechanism, the disclosed RNAi agents are not bound by or limited to any particular pathway or mechanism of action. RNAi agents include, but are not limited to: single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double-stranded RNAs (dsRNA), micro RNAs (miRNAs), short 25 hairpin RNAs (shRNA), and dicer substrates. Typically, RNAi agents can be comprised of at least a sense strand (also referred to as a passenger strand) that includes a first sequence, and an antisense strand (also referred to as a guide strand) that includes a second sequence. The length of an RNAi agent sense and 30 antisense strands can each be 16 to 49 nucleotides in length. In some embodiments, the sense and antisense strands of an RNAi agent are independently 17 to 26 nucleotides in length. In some embodiments, the sense and antisense strands are independently 19 to 26 nucleotides in length. In some embodiments, the sense and antisense strands are independently 21 to 26 nucleotides in length. In some embodiments, the sense and antisense strands are independently 2024202695   24 Apr 2024 21 to 24 nucleotides in length. The sense and antisense strands can be either the same length or different lengths. The RNAi agents include an antisense strand sequence that is at least partially complementary to a sequence in the target gene, and upon delivery to a cell expressing the target, an RNAi agent may inhibit the expression of one or more target genes in vivo or in 5 vitro. Oligomeric compounds generally, and RNAi agents specifically, may be comprised of modified nucleotides and / or one or more non-phosphodiester linkages. As used herein, a “modified nucleotide” is a nucleotide other than a ribonucleotide (2'-hydroxyl nucleotide). In 10 some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%) of the nucleotides are modified nucleotides. As used herein, modified nucleotides include, but are not limited to, deoxyribonucleotides, nucleotide mimics, abasic nucleotides, 2'-modified nucleotides, 3' to 3' linkages (inverted) nucleotides, non-natural base-comprising nucleotides, bridged nucleotides, 15 peptide nucleic acids, 2',3'-seco nucleotide mimics (unlocked nucleobase analogues, locked nucleotides, 3'-O-methoxy (2' intemucleoside linked) nucleotides, 2'-F-Arabino nucleotides, 5'-Me, 2'-fluoro nucleotide, morpholino nucleotides, vinyl phosphonate deoxyribonucleotides, vinyl phosphonate containing nucleotides, and cyclopropyl phosphonate containing nucleotides. 2'-modified nucleotides (i.e. anucleotide with agroup other than ahydroxyl group 20 at the 2' position of the five-membered sugar ring) include, but are not limited to, 2'-O-methyl nucleotides, 2'-deoxy-2'-fluoro nucleotides, 2'-deoxy nucleotides, 2'-methoxyethyl (2'-O-2-methoxylethyl) nucleotides, 2'-amino nucleotides, and 2'-alkyl nucleotides. Moreover, one or more nucleotides of an oligomeric compound, such as an RNAi agent, may 25 be linked by non-standard linkages or backbones (i.e., modified intemucleoside linkages or modified backbones). A modified intemucleoside linkage may be a non-phosphate-containing covalent intemucleoside linkage. Modified intemucleoside linkages or backbones include, but are not limited to, 5’-phosphorothioate groups, chiral phosphorothioates, thiophosphates, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, alkyl phosphonates (e.g., 30 methyl phosphonates or 3'-alkylene phosphonates), chiral phosphonates, phosphinates, phosphoramidates (e.g., 3'-amino phosphoramidate, aminoalkylphosphoramidates, or thionophosphoramidates), thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of 2024202695   24 Apr 2024 boranophosphates, or boranophosphates having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. It is not necessary for all positions in a given compound to be uniformly modified. Conversely, 5 more than one modification may be incorporated in a single oligomeric compound or even in a single nucleotide thereof. The RNAi agent sense strands and antisense strands may be synthesized and / or modified by methods known in the art. For example, the disclosure of RNAi agents directed to the inhibition 10 of alpha-ENaC expression may be found, for example, in International Patent Application Publication No. WO 2008 / 152131, which is incorporated by reference herein in its entirety. Additional disclosures related to RNAi agents may be found, for example, in the disclosure of modifications may be found, for example, in International Patent Application No. PCT / US2017 / 0455446 to Arrowhead Pharmaceuticals, Inc., which also is incorporated by 15 reference herein in its entirety. In some embodiments, the one or more cargo molecule(s) can include or consist of a PEG moiety that can acts as a pharmacokinetic (PK) modulator. In some embodiments, the one or more cargo molecules can include a PEG moiety having about 20-900 ethylene oxide 20   (CH2-CH2-O) units (e.g., 20 to 850, 20 to 800, 20 to 750, 20 to 700, 20 to 650, 20 to 600, 20 to 550, 20 to 500, 20 to 450, 20 to 400, 20 to 350, 20 to 300, 20 to 250, 20 to 200, 20 to 150, 20 to 100, 20 to 75, 20 to 50, 100 to 850, 100 to 800, 100 to 750, 100 to 700, 100 to 650, 100 to 600, 100 to 550, 100 to 500, 100 to 450, 100 to 400, 100 to 350, 100 to 300, 100 to 250, 100 to 200, 100 to 150, 200 to 850, 200 to 800, 200 to 750, 200 to 700, 200 to 650, 200 to 600, 200 25 to 550, 200 to 500, 200 to 450, 200 to 400, 200 to 350, 200 to 300, 200 to 250, 250 to 900, 250 to 850, 250 to 800, 250 to 750, 250 to 700, 250 to 650, 250 to 600, 250 to 550, 250 to 500, 250 to 450, 250 to 400, 250 to 350, 250 to 300, 300 to 900, 300 to 850, 300 to 800, 300 to 750, 300 to 700, 300 to 650, 300 to 600, 300 to 550, 300 to 500, 300 to 450, 300 to 400, 300 to 350, 350 to 900, 350 to 850, 350 to 800, 350 to 750, 350 to 700, 350 to 650, 350 to 600, 350 to 550, 350 30 to 500, 350 to 450, 350 to 400, 400 to 900, 400 to 850, 400 to 800, 400 to 750, 400 to 700, 400 to 650, 400 to 600, 400 to 550, 400 to 500, 400 to 450, 450 to 900, 450 to 850, 450 to 800, 450 to 750, 450 to 700, 450 to 650, 450 to 600, 450 to 550, 450 to 500, 500 to 900, 500 to 850, 500 to 800, 500 to 750, 500 to 700, 500 to 650, 500 to 600, 500 to 550, 550 to 900, 550 to 850, 550 to 800, 550 to 750, 550 to 700, 550 to 650, 550 to 600, 600 to 900, 600 to 850, 600 to 800, 600 2024202695   24 Apr 2024 to 750, 600 to 700, 600 to 650, 650 to 900, 650 to 850, 650 to 800, 650 to 750, 650 to 700, 700 to 900, 700 to 850, 700 to 800, 700 to 750, 750 to 900, 750 to 850, 750 to 800, 800 to 900, 850 to 900, or 850 to 900 ethylene oxide units). In some embodiments, the one or more cargo molecule(s) consist of a PEG moiety having approximately 455 ethylene oxide units (about 20 5 kilodalton (kDa) molecular weight). In some embodiments, a PEG moiety has a molecular weight of about 2 kilodaltons. In some embodiments, a PEG moiety has a molecular weight of about 20 kilodaltons. In some embodiments, a PEG moiety has a molecular weight of about 40 kilodaltons. The PEG moieties described herein may be linear or branched. The PEG moieties may be discrete (monodispersed) or non-discrete (polydispersed). PEG moieties for 10 use as a PK enhancing cargo molecule may be purchase commercially. In some embodiments, the one or more cargo molecule(s) include a PEG moiety that can act as a PK modulator or enhancer, as well as a different cargo molecule, such as a pharmaceutically active ingredient or compound. 15 The described avP6 integrin ligands include salts or solvates thereof. Solvates of an avP6 ligand is taken to mean adductions of inert solvent molecules onto the avP6 integrin ligand which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or addition compounds with alcohols, such as, for example, with methanol or ethanol. 20 Free amino groups or free hydroxyl groups can be provided as substituents of avP6 integrin ligands with corresponding protecting groups. The avP6 integrin ligands also include, e.g., derivatives, i.e., avP6 integrin ligands modified 25 with, for example, alkyl or acyl groups, sugars or oligopeptides, which are cleaved either in vitro or in an organism. In some embodiments, an avP6 integrin ligand disclosed herein facilitates the delivery of a cargo molecule into the cytosol of a cell presenting an avP6 integrin on its surface, either 30 through ligand-mediated endocytosis, pinocytosis, or by other means. In some embodiments, an avP6 integrin ligand disclosed herein facilitates the delivery of a cargo molecule to the plasma membrane of a cell presenting an avP6 integrin. In some embodiments, the avP6 integrin ligand comprises the structure represented by: 2024202695   24 Apr 2024 HN (SEQ ID NO: 109) (Formula IX), wherein Z comprises an amine-terminal cap (e.g., any of the amine-terminal caps described herein or known in the art), and R5 and R6 are the side chains of amino acids Xaa1 and Xaa2, 5 respectively. In some embodiments, the avP6 integrin ligands comprise the following structures, wherein Z and R1 are as defined for Formula III and Formula IV herein, and R7 can be OH, J, J-R1, J-R’-R2. or Y-R^R3 (as those are each defined for Formula III and Formula IV herein): 2024202695   24 Apr 2024 (SEQ ID NO: 111) (Formula XI) (SEQ ID NO: 113) (Formula XIII) 2024202695   24 Apr 2024 (SEQ ID NO: 116) (Formula XVI) 2024202695   24 Apr 2024 In some embodiments, the described avP6 ligands showed increased serum stability compared to the naturally occurring avP6 integrin-binding peptide RGDLATLRQL (SEQ ID NO: 1). As shown in the Examples herein, only about 5% of the naturally occurring peptide RGDLATLRQL (SEQ ID NO: 1) is detectable after 4 h incubation at 37°C in mouse plasma. 5 The peptide RGDLATLRQL (SEQ ID NO: 1) was undetectable after 8 hours at 37°C in mouse plasma. In some embodiments, an avP6 integrin ligand disclosed herein exhibits greater than 20% of the ligand remaining detected by HLPC after 12-hour incubation at 37°C in mouse plasma. While having increased serum stability from the natural peptide, the described avP6 integrin ligands retained binding to (affinity for) the avP6 integrin. 10 Pharmaceutical Compositions In some embodiments, the present disclosure provides pharmaceutical compositions that include or consist of or consist essentially of one or more of the avP6 integrin ligands disclosed herein. 15 As used herein, a “pharmaceutical composition” comprises a pharmacologically effective amount of an Active Pharmaceutical Ingredient (API), and optionally one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical ingredient (API, therapeutic product) that 20 are intentionally included in the drug delivery system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients may act to a) aid in processing of the drug delivery system during manufacture, b) protect, support or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and / or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API 25 during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance. Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery 30 enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents. 2024202695   24 Apr 2024 The pharmaceutical compositions described herein can contain other additional components commonly found in pharmaceutical compositions. In some embodiments, the additional component is a pharmaceutically-active material. Pharmaceutically-active materials include, but are not limited to: anti-pruritics, astringents, local anesthetics, or anti-inflammatory agents 5   (e.g., antihistamine, diphenhydramine, etc.), small molecule drug, antibody, antibody fragment, aptamers, and / or vaccine. The pharmaceutical compositions may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the 10 variation of osmotic pressure, buffers, coating agents, or antioxidants. They may also contain other therapeutically valuable agents. The pharmaceutical compositions can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration 15 can be made by any way commonly known in the art, such as, but not limited to, topical (e.g., by a transdermal patch), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal), epidermal, transdermal, oral or parenteral. Parenteral administration includes, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal (e.g., via an 20 implanted device), intracranial, intraparenchymal, intrathecal, and intraventricular, administration. In some embodiments, the pharmaceutical compositions described herein are administered by subcutaneous injection. The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out 25 rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels, or solutions; or parenterally, for example using injectable solutions. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation 30 of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, 2024202695   24 Apr 2024 water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include 5 isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 10 Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile 15 powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Formulations suitable for intra-articular administration can be in the form of a sterile aqueous 20 preparation of any of the ligands described herein that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present any of the ligands described herein for both intra-articular and ophthalmic administration. 25 The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those 30 skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. 2024202695   24 Apr 2024 A pharmaceutical composition can contain other additional components commonly found in pharmaceutical compositions. Such additional components include, but are not limited to: antipruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine, etc.). As used herein, “pharmacologically effective amount,” 5 “therapeutically effective amount,” or simply “effective amount” refers to that amount of an the pharmaceutically active agent to produce a pharmacological, therapeutic or preventive result. Medicaments containing an avP6 ligand are also an object of the present invention, as are 10 processes for the manufacture of such medicaments, which processes comprise bringing one or more compounds containing a avP6 ligand, and, if desired, one or more other therapeutically valuable substances, into a dosage form suitable for administration to human subjects. Cells, Tissues, andNon-Human Organisms 15 Cells, tissues, and non-human organisms that include at least one of the avP6 ligands described herein is contemplated. The cell, tissue, or non-human organism is made by delivering the avP6 ligand to the cell, tissue, or non-human organism by any means available in the art. In some embodiments, the cell is a mammalian cell, including, but not limited to, a human cell. 20 The described avP6 ligands and pharmaceutical compositions comprising avP6 ligands disclosed herein may be packaged or included in a kit, container, pack, or dispenser. The avP6 ligands and pharmaceutical compositions comprising the avP6 ligands may be packaged in prefilled syringes or vials. 25 The above provided embodiments and items are now illustrated with the following, nonlimiting examples. Examples Example 1. Synthesis of avp6 Ligands for Serum Stability Studies 30 Chem-Matrix Rink Amide resin was placed in fritted polypropylene syringe and agitated in DCM for 30 minutes prior to use. The following standard solid phase peptide synthesis conditions were used. Fmoc deprotections were carried out by soaking 40 ml of a piperidine:DMF solution (20:80 v / v) per 1 mmole of resin for 20 min. Amide couplings were 2024202695   24 Apr 2024 carried out by soaking the resin with 4 molar eq. Fmoc-amino acid, 4 molar eq. HBTU and 10 molar eq. Diisopropylethylamine in DMF at 0.1 M concentration of Fmoc-amino acid in DMF for 40 minutes. Fmoc-Dap(DNP)-OH was used to attach the DNP chromophore to the resin, and the peptide was synthesized off the Dap a-amine. Cleavage from the resin was carried out 5 in a trifluoroacetic acid solution for 2 hours. The solvent was reduced to 10% original volume via pressurized air and precipitated using Et20. Microcleavage via TFA and analytical HPLC-MS verified identity of product. The peptides were then purified to > 95 % purity on a preparative scale Shimadzu HPLC using a Supelco “Discovery BIO” wide pore C18 column (25 cm x 21 mm, 10 um particles) eluting with linear gradients of approximately 1 ml / min. 10 Purity was assessed using an analytical Shimadzu HPLC equipped with a Waters XBridge BEH130 C18 column (250 mm x 6.6 mm, 5pm particles) using a 10-90% B solvent over 50 minutes. A solvent denotes H2O:F3CCO2H 100:0.1 v / v, B solvent denoted CH3CN: F3CCO2H 100:0.1 v / v. 15 O’ +O Fmoc-Dap(DNP)-OH Example 2. Serum Stability of avfi6 Ligands Serum stability of avP6 ligands were tested by incubating the avP6 ligands in mouse serum and analyzing the percentage of undigested peptide at various time points. Undigested avP6 20 ligand was determined by analytical HPLC. Individual stock solutions of the avP6 ligands were prepared by dissolving the peptides in H2O at >10 mg / ml concentration. Concentration of avP6 ligand was assessed using UV / Vis absorption (DNP : X=365, €=17300 M'Cm '). The avP6 ligand was diluted to 1 mg / ml ligand in 90% mouse plasma and placed in an incubator at 37°C. At the given time points (4, 8, 12, and 24 hours), the sample was injected onto an analytical 25 HPLC (Shimadzu HPLC) equipped with a Waters XBridge BEH130 C18 column (250 mm x 2024202695   24 Apr 2024 6.6 mm, 5pm particles) using a 10-90% B solvent over 50 minutes. A solvent denotes H2O:F3CCO2H 100:0.1 v / v; B solvent denotes CHsCN: F3CCO2H 100:0.1 v / v. Percent ligand remaining following serum incubation was calculated using the 5 following equation: % remaining = [(Area at t=x) + (Area at / =0)] x 100% wherein Area at t=0 was the area under the peak of the ligand immediately after diluting the ligand in the plasma and Area at t=x was the area under the peak of the peptide at the time = x. 10 Each peptide was covalently linked to cargo molecule PEGs-Dap(DNP), The PEGs-Dap(DNP) was then use to facilitate analysis. Peptide derivatives were linked to cargo molecule PEG8-Dap(DNP) and incubated in mouse 15 serum at 37°C for 4, 8, 12, or 24 hours. Peptide derivative stability was measured by HPLC. Data is shown in the following Table 1 (amine-terminal cap and Xaa'Xaa2 are underlined): Table 1. Serum Stability of avfi6 Ligands Peptide derivative SEQ ID NO. t = 4h % rem t = 8 h aining t = 12h t = 24 h RGDLATLRQL 1 5 <0.1 <0.1 Ac-RGDLATLTQL 2 90 67 34 RGDLAAbuLCitAibL 3 48 16 5 Ac-RGDLAAbuLCitAibL 4 94 82 72 Ac-RGDLAAbuLCitAibL 4 86 75 67 41 Ac-RGDLAAbuLCitAib 5 95 82 73 48 Ac-RGDLAAbuLCit 6 88 77 69 44 2024202695   24 Apr 2024 Ac-RGDLAAbuL 7 91 85 80 69 Ac-RGDLAAbuLCitAib 5 72 Ac-RGDLAAbuLCitK 8 35 Ac-RGDLAAbuLCitE 9 79 Ac-RGDLAAbuLCitF 10 22 Ac-RGDLAAbuLCitO 11 insoluble Ac-RGDLAAbuLCitG 12 49 Ac-RGDLAAbuLCitAib 5 72 Ac-RGDLAAbuLKAib 13 35 Ac-RGDLAAbuLEAib 14 79 Ac-RGDLAAbuLFAib 15 22 Ac-RGDLAAbuLQAib 16 insoluble Ac-RGDLAAbuLGAib 17 49 Ac-RGDLAAbuLCitAib 5 52 CH3CH2CO-RGDLAAbuLCitAib 18 49 CHsfCfEECO-RGDLAAbuLCitAib 19 49 CHsfCfEECO-RGDLAAbuLCitAib 20 58 CHsfCfEECO-RGDLAAbuLCitAib 21 51 Ac-RGDLAAbuLCitAib 5 87 Ac-RGDLKAbuLCitAib 22 71 Ac-RGDLEAbuLCitAib 23 98 Ac-RGDLFAbuLCitAib 24 64 Ac-RGDLQAbuLCitAib 25 87 Ac-RGDLAAbuLCitAib 5 85 Ac-RGDLPAbuLCitAib 26 91 Ac-RGDLAKLCitAib 27 72 Ac-RGDLAELCitAib 28 96 Ac-RGDLAFLCitAib 29 88 Ac-RGDLAAbuLCitAib 5 72 Ac-RGDLGAbuLCitAib 30 82 Ac-RGDLAGLCitAib 31 92 Ac-RGDLAPLCitAib 32 84 Ac-RGDLAAbuLCitP 33 68 Ac-RGDLAAbuLCit 6 79 As shown herein, the presence of an amine-terminal cap (Z) can provide increased serum stability. Further, as shown herein, the presence of a non-standard amino acids at Xaa1, Xaa2, 2024202695   24 Apr 2024 and / or J (e.g., Xaa3 and Xaa4) in the formulae disclosed herein, also provide increased serum stability compared to the natural peptide of SEQ ID NO: 1. Example 3. Integrin Binding of avfi6 Ligands 5 A. av / 36 ligand-cargo molecule conjugation. Each avP6 ligand was attached to a reversibly modified 1170-100B polymer cargo molecule. The 1170-100B polymer cargo molecule (a 56:44 ethoxy ethylamine acrylate:propyl acrylate copolymer having a MW of about 45000) was labeled with Cy5 (NHS linker) and combined with aldehyde-PEG24-ACit at a weight ratio of 2:1 (polymer:aldehyde-PEG24-ACit) in 50 mM HEPES pH 9.0 buffer for 1 h at RT to form 10 (aldehyde-PEG24-ACit)n-1170-100B wherein n is an integer greater than 0. Typically, n was about 10. aldehyde-PEG24-ACit (n = 24) The aldehyde-PEG24-ACit-modified polymer was then reacted with PEGn-ACit at a weight 15 ratio of 1:8 (polymer:PEGn-ACit) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT to form (aldehyde-PEG24-ACit)n-l 170-100B-(CitA-PEGi2)m, wherein m is an integer greater than 0. PEG12-ACit (n = 11) The modified polymer was then purified using a sephadex G-50 spin column and concentration 20 determined: 2024202695   24 Apr 2024 zmg\ conj. Cy5 fluorescence post-purification mg polymer —r = -----„------------------------- x —- coni, pre-purification Vml' conj. Cy5 fluorescence pre-purification ml Each avP6 ligand was modified with HyNic to facilitate conjugation to the cargo molecule. Purified polymer was combined with avP6 ligand-(PEG)s-K-HyNic at a weight ratio of 1:1.9 5 (polymer: avP6 ligand) in 50 mM NaOAC-HOAc, pH 5.0 buffer at RT overnight to form the avP6 ligand-polymer conjugate. The avP6 ligand-polymer conjugate was purified using a sephadex G-50 spin column. _N HN O (PEG)s-K-HyNic _N HN HN^^O 10                                                          o 2024202695   24 Apr 2024 AvP6 ligand-(PEG)s-K-HyNic Conjugation efficiency was quantified by measuring Absorbance of the avP6-polymer conjugate at 354 nmusing an extinction coefficient of 2.9* 101 M 'em 1 for bis-aryl hydrazone 5 bond. Molar concentration of polymer (mM) weight concentration of polymer (mg / ml) molecular weight of polymer (Dalton) Molar concentration of avp6 (mM) |A354(conj. -avp6) — 24354(conj. no avp6 control)] “                   29 molar concentration of avp6 (mM) 10         Number of avB6 per polymer = —----------------—--------- molar concentration of polymer (mM) avP6-polymer conjugates were diluted with isotonic glucose solution to desired concentrations for further analysis. B. av^6 ligand binding (flow cytometric analyses). To assess for specificity of binding of the 15 avP6 ligands to the avP6 integrin, each avP6 ligand or negative control peptide was conjugated to a Cy5-labeled polymer (as described above) and evaluated for binding to cells. HUH7 (human hepatocellular carcinoma) and SKOV3 (human ovarian carcinoma) cells were determined to exhibit very low avP6 cell surface expression and were employed as the negative-control cell lines. H2009 (human lung epithelial adenocarcinoma) and CAP AN-2 20 (human pancreas adenocarcinoma) cells served as the avP6 positive-control cell lines. Cells were detached from culturing flasks with Accutase, washed in PBS, and seeded into 5 ml polystyrene round-bottom tubes at 200,000 cells in 200 pl complete media (culturing media with supplements and fetal calf serum). avP6 ligand-polymer conjugates or no-ligand-polymer conjugates were added at 5 pg / ml (polymer-Cy5 concentration) to cells, mixed and incubated 25 at 37°C for 3 h. Incubation at 37°C facilitated ligand / receptor interaction which may result in static binding to the extracellular cell surface and / or internalized ligand / receptor complexes. The mixture was re-suspended at 1 h intervals. Following a 3 h incubation, cells were washed 2* with 4 ml chilled buffer (PBS-2% FCS) and re-suspended in 200 pl buffer containing 10 pM SYTOX blue stain for live / dead cell gating. Samples were analyzed on a BD Biosciences 30 Canto II cytometer equipped with a violet (405nm), blue (488nm) and red (633nm) lasers. 2024202695   24 Apr 2024 Viable cells were initially gated as the SYTOX blue negative population on the C detector with the violet laser. These viable cells were then assessed for conjugate binding / uptake with the red laser as the Mean Fluorescence Intensity (MFI) of the Cy5 fluorophore. Data analyses were performed with FlowJo vlO.l software. A specific MFI Ratio (sMFIr) for each avP6 ligand 5 was determined by the formula: specific sample MFI value / no-ligand MFI value. As shown in Table 2, below, only peptide Ac-RGDLAAbuLCitAibL showed modest binding 10 to SKOV3 cells. This peptide showed no significant binding to HUH7 cells. Thus, none of the peptides tested exhibited non-specific binding. Negative control peptides AcRGaMeDLAAbuLCitAib, AcRGDaMeLAAbuLCitAib, RGELATLRQL, AcCitGDLATLCitQL, AcK(Me)2GDLATLRQL, and AcR(Me)2GDLATLRQL, which do not contain an RGD, did not show significant binding to H2009 or CAP AN-2 avP6 integrin-15 positive control cells, indicating a lack of affinity for the avP6 integrin. Most of the other peptides showed binding to H2009 or CAP AN-2 cells that was comparable or higher than for the natural peptides, RGDLATLRQL and RGDLATL, indicating good affinity to the avP6 integrin. 20 Table 2. avP6 Ligand Binding to avP6 Integrin Expressing (H2009 and CAPAN-2) and Non-Expressing Cells (HUH7 and SKOV3) Peptide SEQ ID NO. MFI HUH 7 SKOV3 H200 9 CAPAN-2 Ac-RGDLAAbuLCitAibL 4 1.0 3.2 7.7 Ac-RGaMeDLAAbuLCitAib 34 0.9 0.9 1.0 Ac-RGDaMeLAAbuLCitAib 35 0.9 0.8 0.9 Ac-RGDLAAbuL 7 0.9 2.6 7.9 Ac-RGDLAAbuLAib 36 0.9 3.2 8.9 RGDLATLRQL 1 1.4 4.7 RGELATLRQL (RGE control) 37 0.99 RGDLATLRQLEEEK-(HyNic) 38 6.5 meta-guanidino-benzoic-GDLATLRQL 39 4.5 Ac-RGDLATLRQL 2 4.7 2024202695   24 Apr 2024 Me-RGDLATLRQL 40 4.8 Guanidinyl-RGDLATLRQL 41 4.3 MeO-PEG8-RGDLATLRQL 42 2.5 Ac-RGDLALLRQL 43 6.06 Ac-RGDLAAbuLRQL 44 6.47 Ac-RGDLAILRQL 45 6.22 Ac-RGDLAVLRQL 46 6.23 Ac-CitGDLATLRQL 47 2.45 Ac-RGDLATLCitQL 48 3.94 Ac-CitGDLATLCitQL 49 0.99 Ac-RGDLATLRAbuL 50 4.26 Ac-RGDLATLRAibL 51 3.9 Ac-RGDLATLRDap(Ac)L 52 4.18 Ac-RGDLATLRCitL 53 4.07 Ac-RGDLATLRNvaL 54 4.26 RGDLATLRQL 55 4.32 Ac-RGDLAAbuLCitAibL 4 2.25 4.55 Ac-K(Me)2GDLATLRQL 56 0.9 1.1 Ac-R(Me)2GDLATLRQL 57 0.9 1 Dap(guanidino)-GDLATLRQL 58 1.4 3.4 des-amino-RGDLATLRQL 59 0.8 1.1 Ac-RGDL03-hATLRQL 60 1.2 4.5 Ac-RGDLAibTLRQL 61 1.4 4 Ac-RGDLChaTLRQL 62 1 5.1 RGDLATLRQ 63 1.6 4.7 RGDLATLR 64 1.4 4.6 RGDLATL 65 1.2 2.9 RGDLAT 66 0.9 1.3 Ac-RGDLAibAbuLCitAib 67 Ac-RGDLP3-hAAbuLCitAib 68 2.34 Ac-RGDLChaAbuLCitAib 69 1.6 Ac-RNmcGDLATLRQL 70 0.97 4.61 Ac-RGDLAAbuLCitAib 5 4.7 Ac-RNMeGDLAAbuLCitAib 71 2.6 Ac-RGDNMeLAAbuLCitAib 72 1 Ac-RGDLAAbuNMeLCitAib 73 1.3 CH3CH2-RGDLAAbuLCitAib 74 4.4 2024202695   24 Apr 2024 Ac-RGDLAAbuL Ac-RGDLAAbuLCitAibL RGDLAAbuLCitAibL Ac-RGDLATLRQL CH3O(CH2CH2O)5CH2CH2CO-RGDLAAbuLCitAib CH3O(CH2CH2O)3CH2CH2CO-RGDLAAbuLCitAib CH3O(CH2CH2O)2CH2CH2CO-RGDLAAbuLCitAib CH3O(CH2CH2O)iCH2CH2CO-RGDLAAbuLCitAib CH3(CH2)4CO-RGDLAAbuLCitAib CH3(CH2)3CO-RGDLAAbuLCitAib CH3(CH2)2CORGDLAAbuLCitAib CH3(CH2)iCO-RGDLAAbuLCitAib Ac-RGDLAAbuLCitAib Ac-RGDLAAbuLCitG Ac-RGDLAAbuLCitQ Ac-RGDLAAbuLCitF Ac-RGDLAAbuLCitE Ac-RGDLAAbuLCitK Ac-RGDLAAbuLPAib Ac-RGDLAAbuLFAib Ac-RGDLAAbuLCit Ac-RGDLAPLCitAib Ac-RGDLAQLCitAib Ac-RGDLAFLCitAib Ac-RGDLAELCitAib Ac-RGDLAKLCitAib Ac-RGDLPAbuLCitAib Ac-RGDLGAbuLCitAib Ac-RGDLQAbuLCitAib Ac-RGDLFAbuLCitAib Ac-RGDLEAbuLCitAib Ac-RGDLKAbuLCitAib Ac-RGDaMeLAAbuLCitAib Ac-RGaMeDLAAbuLCitAib CH3(CH2)4-RGDLAAbuLCitAib CH3(CH2)3-RGDLAAbuLCitAib CH3(CH2)2-RGDLAAbuLCitAib 4^ 84 83 82 00 1—* 21 20 1—* 80 Ui 12 1—* 1—* 1—* o 00 79 1—* Ui 32 78 29 28 27 26 30 25 24 23 22 35 34 77 76 75 2.6 4.6 4.6 4.7 1.6 3.6 3.8 3.9 4.1 4.3 4.2 3.8 4.8 4.4 4- Ui bJ 1.6 3.6 3.3 2.8 3.6 2.4 3.6 1—* 2.7 2.6 3.6 1—* 1—* 4.1 4.7 3.9 WO 2018 / 085415                                                 PCT / US2017 / 059550 2024202695   24 Apr 2024 Ac-RGDLAAbuLAib 36 3.2 Ac-RGDLAAbuLKAib 13 5.4 Ac-RGDLAAbuLEAib 14 1.9 Ac-RGDLAAbuLGAib 17 4 Ac-RGDLAAbuLCitP 33 4 Ac-RGDLAAbuLQAib 16 4.4 Ac-RGDLAGLCitAib 31 3.8 Certain abbreviations of non-standard amino acids and other chemical groups identified in the preceding table have the chemical structures as follows: O Cit is citrulline Aib is a-amino-isobutyric acid Abu is L-a-amino-butyric acid O Cha is P-cyclohexyl alanine 10 aMeL is a-methyl leucine 2024202695   24 Apr 2024 O K(Me)2 is N,N-e-dimethyl lysine R(Me)2 is dimethyl arginine NmcG is N-methyl glycine 10 NmcL is N-methyl leucine des-amino-R is des-amino-arginine 2024202695   24 Apr 2024 P3-hA is P-homo-alanine                 meta-guanidino-benzoic HhU NH2 O                                  O Guanidinyl-R is guanidinyl-arginine MeO-PEG8 5 Example 4. In vivo intratracheal administration of RNAi agents targeting alpha-ENaC conjugated to avp6 integrin ligands in rats Double-stranded oligonucleotide compositions that included a sense strand and an antisense strand each having fewer than 26 nucleotides (i.e., a type of RNAi agent), were synthesized 10 according to phosphoramidite technology on solid phase in accordance with general procedures known in the art and commonly used in oligonucleotide synthesis. The syntheses of RNAi agents herein were performed on a solid support made of controlled pore glass purchased commercially (CPG, 500 A or 600A, obtained from Prime Synthesis, Aston, PA, USA), using either a MerMade96E® (Bioautomation), aMerMadel2® (Bioautomation), or an OP Pilot 100 15 (GE Healthcare) for synthesis depending on scale. All RNA and 2'-modified RNA phosphoramidites were purchased commercially (Thermo Fisher Scientific (Milwaukee, WI, USA). For cleavage and deprotection, after finalization of the solid phase synthesis, the dried solid support was treated with a 1:1 volume solution of 40 wt. % methylamine in water and 28% ammonium hydroxide solution (Aldrich) for 1.5 hours at 30°C. The solution was 20 evaporated and the solid residue was reconstituted in water. For purification, crude oligomers were purified by anionic exchange HPLC using a TSKgel SuperQ-5PW 13pm column and Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile and buffer B was the same as buffer A with the addition of 1.5 M sodium chloride. UV traces at 260 nm were recorded. Appropriate fractions were pooled then run on size 25 exclusion HPLC using a GE Healthcare XK 26 / 40 column packed with Sephadex G-25 fine 2024202695   24 Apr 2024 with a running buffer of lOOmM ammonium bicarbonate, pH 6.7 and 20% Acetonitrile. For annealing, complementary strands were mixed by combining equimolar RNA solutions (sense and antisense) in IxPBS (Phosphate-Buffered Saline, lx, Coming, Cellgro) to form the RNAi agents. Some RNAi agents were lyophilized and stored at -15 to -25°C. Duplex concentration 5 was determined by measuring the solution absorbance on a UV-Vis spectrometer in lx PBS. The solution absorbance at 260 nm was then multiplied by a conversion factor and the dilution factor to determine the duplex concentration. Unless otherwise stated, all conversion factor was 0.037 mg / (mL-cm). For some experiments, a conversion factor was calculated from an experimentally determined extinction coefficient. 10 The RNAi agents synthesized for Example 4 included an antisense strand having a nucleobase sequence at least partially complementary to the gene expressing the alpha subunit of the amiloride-sensitive epithelial sodium channel (commonly referred to as alpha-ENaC or SCNN1A). The alpha-ENaC RNAi agents were designed to be capable of degrading or 15 inhibiting translation of messenger RNA (mRNA) transcripts of alpha-ENaC in a sequence specific manner, thereby inhibiting expression of the alpha-ENaC gene. The RNAi agents were comprised of modified nucleotides and more than one non-phosphodiester linkage. On study day 1 and day 2, male Sprague-Dawley rats were administered a dose of 200 20 microliters intratracheally via a microsprayer device (Penn Century, Philadelphia, PA), which included the following dosing groups: (1) 5% dextrose in water vehicle (D5W); (2) 1.5 mg / kg of an alpha-ENaC RNAi agent without a ligand (“naked RNAi agent”), formulated in 5% dextrose; (3) 1.5 mg / kg of an alpha-ENaC RNAi agent conjugated to the avP6 integrin ligand of Figure 3 (with the avP6 integrin ligand conjugated at the 5’ terminal end of the sense strand), 25 formulated in 5% dextrose; or (4) 1.5 mg / kg of alpha-ENaC RNAi agent conjugated to an inactivated avP6 integrin ligand having the structure Ac-RGELAAbuL-CitAibL (SEQ ID NO: 132) to serve as a negative control ligand. The aspartic acid (D) in the ‘RGD’ motif is believed to be required for ligand binding to alpha-v integrin receptors, and the ligands with the substitution of glutamic acid (E) have significantly reduced av integrin binding affinities. The 30 same alpha-ENaC RNAi agent was used in Groups 2, 3, and 4. The avP6 integrin ligand used was synthesized as a TFP ester (as shown in Figure 1) using general peptide synthesis techniques well known in the art and similar to those set forth in Example 1 herein, with the exception of the resin cleavage, which was achieved using 20% 2024202695   24 Apr 2024 HFIP (hexofluoroisopropanol) in DCM (dichloromethane) for 30 minutes to one hour, in place of TFA cleavage. The 5’ terminal end of the sense strand of the RNAi agent was modified with a Ce amine (-NH2). The TFP-ester avP6 integrin ligand was then conjugated to the amino group located at the 5’ terminal end of modified sense strand of the RNAi agent using 3 5 equivalents of the TFP-ester avP6 integrin ligand in DMSO:water 9:1 and excess amount of triethylamine as base, at room temperature. Purification was conducted by adding ACN into the solution to precipitate the product and dry under high vacuum. Four (4) rats were dosed per group. Rats were euthanized on study day 5, and total RNA was 10 isolated from both lungs following collection and homogenization. mRNA abundance of alpha-ENaC was quantitated by probe-based quantitative PCR, normalized to GAPDH expression and expressed as fraction of vehicle control group (geometric mean, + / - 95% confidence interval). 15 Table 3. Relative alpha-ENaC expression of mRNA Normalized to Control of Example 4 Group Relative Expression (Geometric Mean) Lower / Upper 95% Confidence Interval (1) 5% dextrose vehicle 1.000 0.77 / 1.30 (2) Naked RNAi agent (no ligand) 0.54 0.24 / 1.22 (3) avP6 ligand Figure 3-RNAi agent conjugate 0.22 0.11 / 0.44 (4) RGE-control ligand-RNAi agent conjugate 0.43 0.26 / 0.73 As shown in Table 3, above, the avP6 ligand of Figure 3 conjugated to an alpha-ENaC RNAi agent showed increased relative knockdown of alpha-ENaC mRNA (approximately 78% 20 knockdown), compared to naked RNAi agent (46% knockdown) and RNAi agent conjugated to the RGE-control ligand (57% knockdown) of the alpha-ENaC lung target in vivo. Example 5. In vivo intratracheal administration of RNAi agents targeting alpha-ENaC conjugated to avp6 integrin ligands in rats 25 Alpha-ENaC RNAi agents similar to those described in Example 4 were synthesized following the same synthesis procedures. On study day 1 and day 2, male Sprague-Dawley rats were administered a dose of 200 microliters via a microsprayer device (Penn Century, Philadelphia, PA), which included the following dosing groups: (1) D5W vehicle; (2) 1.5 mg / kg of an RNAi agent without a ligand (“naked RNAi agent”), formulated in D5W; (3) 1.5 mg / kg of an alpha- 2024202695   24 Apr 2024 ENaC RNAi agent conjugated to the avP6 integrin ligand of Figure 3, formulated in D5W; or (4) 1.5 mg / kg of an alpha-ENaC RNAi agent conjugated to a tridentate avP6 integrin ligand, having the structure shown in Figure 11. The RNAi agents were designed to inhibit the expression of the alpha-ENaC gene. The same alpha-ENaC RNAi agent was used in Groups 5   2, 3, and 4. The 5’ terminal end of the sense strand of the RNAi agents were modified with a Ce amine (-NH2) as in Example 4. The avP6 integrin ligands of Figure 3 were synthesized and conjugated to the alpha-ENaC RNAi agents following the same procedures of Example 4. When conjugating to avb6 ligand shown in Figure 11, the alpha-ENaC-RNAi agent was first functionalized with DBCO-PEG5-NHS ester by conjugating to the 5’ amine functionalized 10   terminal end of the sense strand using triethylamine as base. The tridentate avb6 integrin ligand was synthesized having a PEG-azide reactive group, as shown in Figure 10. After precipitation in a phosphate buffered saline / acetonitrile solvent system, the tridentate avb6 integrin ligand was conjugated to the RNAi agent using copper-free cycloaddition. 15 Five (5) rats were dosed per group. Rats were euthanized on study day 5, and total RNA was isolated from both lungs following collection and homogenization. mRNA abundance of the target was quantitated by probe-based quantitative PCR, normalized to GAPDH expression and expressed as fraction of vehicle control group (geometric mean, + / - 95% confidence interval). 20 Table 4. Relative alpha-ENaC expression of mRNA Normalized to Control of Example 5 Group Relative Expression (Geometric mean) Lower / Upper 95% Confidence Interval (1) 5% dextrose vehicle 1.000 0.72 / 1.40 (2) Naked RNAi agent (no ligand) 0.34 0.25 / 0.45 (3) avP6 ligand Figure 3-RNAi agent conjugate 0.29 0.15 / 0.55 (4) [avP6 ligand Figure 11 ((i.e., avP6 ligand)3)]-RNAi agent conjugate 0.21 0.09 / 0.51 As shown in Table 4, above, conjugating three avP6 ligands (forming a “tridentate” ligand) as shown in Figure 11, to an alpha-ENaC RNAi agent, showed increased relative knockdown 25 (approximately 79%), compared to RNAi agent conjugated to one avP6 ligand (Figure 3) (71%) and naked RNAi agent (66%) in vivo. 2024202695   24 Apr 2024 Example 6. In vivo intratracheal administration of RNAi agents targeting alpha-ENaC conjugated to avp6 integrin ligands in rats Alpha-ENaC RNAi agents similar to those described in Example 4 were synthesized following the same synthesis procedures. On study day 1 and day 2, male Sprague-Dawley 5 rats were administered a dose of 200 microliters via a microsprayer device (Penn Century, Philadelphia, PA), which included the following dosing groups: (1) D5W vehicle; (2) 3 mg / kg of an RNAi agent without a ligand (“naked RNAi agent”), formulated in D5W; or (3) 3.0 mg / kg of an alpha-ENaC RNAi agent conjugated to the avP6 integrin ligand of Figure 3, formulated in D5W. The alpha-ENaC RNAi agent and avP6 integrin ligands were 10 synthesized and conjugated according to the same procedures set forth in Example 4. Five (5) rats were dosed per group. Rats were euthanized on study day 5, and total RNA was isolated from both lungs following collection and homogenization. mRNA abundance of the target was quantitated by probe-based quantitative PCR, normalized to GAPDH expression and 15 expressed as fraction of vehicle control group (geometric mean, + / - 95% confidence interval). Table 5. Relative alpha-ENaC expression of mRNA Normalized to Control of Example 6 Group Relative Expression (Geometric mean) Lower / Upper 95% Confidence Interval (1) 5% dextrose vehicle 1.000 0.76 / 1.31 (2) Naked RNAi agent (no ligand) 0.49 0.42 / 0.56 (3) avP6 ligand Figure 3-RNAi agent conjugate 0.17 0.12 / 23 20 As shown in Table 5, above, the avP6 ligand of Figure 3 conjugated to an RNAi agent showed increased relative knockdown (approximately 83% knockdown), compared to naked RNAi agent (approximately 51% knockdown) of the lung target in vivo. Example 7. In vivo oropharyngeal aspiration of RNAi agents targeting a gene expressed 25 in the lung conjugated to avp6 integrin ligands in rats Alpha-ENaC RNAi agents similar to those described in Example 4 were synthesized following the same synthesis procedures. On study day 1, male Sprague-Dawley rats were administered via oropharyngeal aspiration a dose of 200 microliters, which included the 2024202695   24 Apr 2024 following dosing groups: (1) isotonic saline; (2) 0.5 mg / kg of an RNAi agent targeting alpha-ENaC conjugated to the avP6 integrin ligand of Figure 3, formulated in isotonic saline; or (3) 0.5 mg / kg of an RNAi agent targeting alpha-ENaC conjugated to the avP6 integrin ligand of Figure 5, formulated in isotonic saline. The same alpha-ENaC RNAi agents were used for 5 Groups 2 and 3. The 5’ terminal end of the sense strand of the RNAi agent was modified with a Ce amine (-NH2), as set forth in Example 4. The alpha-ENaC RNAi agent and avP6 integrin ligands of Figure 3 were synthesized and conjugated according to same procedures set forth in Example 4. For the avP6 integrin ligands of Figure 5 were synthesized as a TFP-ester, and additionally the N-terminal of the avP6 integrin ligand was protected by an fmoc 10 group. The conjugation to the RNAi agent was then carried out in the same manner as set forth in Example 4, followed by fmoc deprotection using triethylamine as base. Five (5) rats were dosed per group. Rats were euthanized on study day 9, and total RNA was isolated from both lungs following collection and homogenization. mRNA abundance of the 15 target was quantitated by probe-based quantitative PCR, normalized to GAPDH expression and expressed as fraction of vehicle control group (geometric mean, + / - 95% confidence interval). Table 6. Relative alpha-ENaC expression of mRNA Normalized to Control of Example 20   7 Group Relative Expression (Geometric mean) Lower / Upper 95% Confidence Interval (1) Isotonic Saline 1.000 0.85 / 1.17 (2) avP6 ligand Figure 3-RNAi agent conjugate 0.632 0.49 / 0.80 (3) avP6 ligand Figure 5-RNAi agent conjugate 0.592 0.50 / 0.70 As shown in Table 6, above, both the avP6 ligands of Figure 3 and Figure 5 conjugated to an RNAi agent showed knockdown of the alpha-ENaC lung target in vivo. 25 Example 8. In vivo Intratracheal Administration of RNAi Agents Targeting alpha-ENaC Conjugated to avp6 Integrin Ligands and Poly-L-lysine Scaffold in Rats Alpha-ENaC RNAi agents similar to those described in Example 4 were synthesized following the same synthesis procedures. On study day 1 and day 2, male Sprague-Dawley rats were 2024202695   24 Apr 2024 administered a dose of 200 microliters via a microsprayer device (Penn Century, Philadelphia, PA) of either: (1) D5W (5% dextrose in water); (2) 0.5 mg / kg of an RNAi agent without a ligand (“naked RNAi agent”), formulated in D5W; (3) 1.5 mg / kg a naked RNAi agent, formulated in D5W; (4) 5 mg / kg of a naked RNAi agent, formulated in D5W; (5) 0.5 mg / kg of 5 an alpha-ENaC RNAi agent conjugated to the avP6 integrin ligand of Figure 4, via a poly-L- lysine (PLL) scaffold, formulated in D5W; (6) 1.5 mg / kg of an alpha-ENaC RNAi agent conjugated to the avP6 integrin ligand of Figure 4, via a PLL scaffold, formulated in D5W; or (7) 5 mg / kg of an alpha-ENaC RNAi agent conjugated to the avP6 integrin ligand of Figure 4, via a PLL scaffold formulated in D5W. The RNAi agents were designed to inhibit the 10 expression of the alpha-ENaC gene. The same alpha-ENaC RNAi agent was used in Groups 2 through 7. The avP6 integrin ligand was initially synthesized as a TFP-ester (shown in Figure 2). The PLL scaffold used in Groups 5, 6 and 7 of Example 8 was approximately one-hundred (100) L-lysine monomeric units (approximately 12 kilodaltons). The poly-L-lysine polymer was modified with 3 equivalents of SMPT (4-succinimidyloxycarbonyl-alpha-methyl-a(2- 15 pyridyldithio)toluene) and the 5’ amine of the (Ce amine modified) sense strand of the RNAi agent was modified with SATA (N-succinimidyl S-acetylthioacetate). Next, the avP6 integrin ligand of Figure 2 (15 equivalents) was added as a solid and stirred for one hour. Then a protease-cleavable functionalized alanine-citrulline-PEGi2 (10 equivalents; functionalized with para-nitrophenylcarbonate) was added. After 15 minutes, SATA-modified RNAi agent 20 (one equivalent) was added dropwise maintaining a pH at 8.6. The remaining lysine groups were functionalized with protease-cleavable functionalized alanine-citrulline-PEGn. The product was purified by tangential flow filtration. Five (5) rats were dosed per group. Rats were euthanized on study day 5, and total RNA was 25 isolated from both lungs following collection and homogenization. mRNA abundance of the target was quantitated by probe-based quantitative PCR, normalized to GAPDH expression and expressed as fraction of vehicle control group (geometric mean, + / - 95% confidence interval). The data are reported in the graph of Figure 12. 30 As shown in Figure 12, the avP6 ligand of Figure 4 conjugated to a poly-L-lysine scaffold and an RNAi agent showed increased relative knockdown at all three dose levels compared to naked RNAi agent (68% knockdown versus 47% knockdown at the 0.5 mg / kg dose, 78% knockdown versus 47% knockdown at the 1.5 mg / kg dose, and 86% knockdown versus 75% knockdown at the 5 mg / kg dose). 2024202695   24 Apr 2024 Example 9. Selective uptake of labeled av / 36 ligand conjugates by primary epithelial cells in vitro Primary human lung epithelial, endothelial and smooth muscle cells were cultured and 5 exposed for 24 hours to: (1) a Cy3-labeled (red) polyacrylate polymer scaffold without a ligand (no ligand-conjugate); or (2) a Cy3-labeled (red) polyacrylate polymer scaffold conjugated to conjugated to the avP6 integrin ligand of Figure 7 (avP6 ligand-conjugate). Cells were stained with FITC-phalloidin (F-actin, green) and Hoechst stain (DNA, blue) and imaged by fluorescence microscopy. 10 Fluorescence microscopy images were prepared using standard methods known in the art. The fluorescence images showed that Cy3 labeled-conjugates without an avP6 integrin ligand were not internalized by any cell type. The Cy3 conjugates with the avP6 ligand of Figure 7, however, were internalized by primary lung epithelial cells (as shown by an accumulation of 15 red signal within endosomal compartments of primary lung epithelial cells in the image), but were not internalized by the primary endothelial and smooth muscle cells. This shows that the avP6 integrin ligands disclosed herein are capable of being selectively internalized by epithelial cells expressing avP6 integrin. 20 Example 10. Selective uptake of labeled ocv / 36 ligand conjugates by epithelial tissues in vivo C57bl / 6 mice were injected with an intravenous dose of 120 micrograms of: (1) a Cy3-labeled (red) polyacrylate polymer scaffold without a ligand (no ligand-conjugate) or (2) a Cy3-labeled (red) polyacrylate polymer scaffold conjugated to conjugated to the avP6 25 integrin ligand of Figure 7 (avP6 ligand-conjugate) or (3) a Cy3-labeled (red) polyacrylate polymer scaffold conjugated to an inactivated avP6 integrin ligand having the structure Ac-RGELAAbuL-CitAibL (SEQ ID NO: 132), which as previously described in Example 4 is used as a negative control ligand. Twenty-four hours after injection, mice were sacrificed and tissues harvested, fixed, processed and sectioned. Tissue sections were stained with 30 FITC-phalloidin (F-actin, green) and Hoechst stain (DNA, blue) and imaged by fluorescence microscopy. 2024202695   24 Apr 2024 A. Lung Bronchiolar Epithelial Cells. Fluorescence microscopy images of lung bronchiolar epithelial cells from the mice of Example 10 were prepared using standard methods. From these images, Cy3-labeled conjugates (shown by red markings in the images) with the avP6 ligand of Figure 7 were selectively internalized into endosomal compartments 5 by lung bronchiolar epithelial cells in vivo, whereas essentially no epithelial internalization was observed with constructs that included no ligand or RGE-ligand control conjugates (i.e., no red was apparent in these images). B. Renal Epithelial Tissues. Fluorescence microscopy images of rental tubular epithelial 10 tissues from the mice of Example 10 were prepared using standard methods. From these images, Cy3-labeled conjugates with the avP6 ligand of Figure 7 were selectively internalized into endosomal compartments by renal tubular epithelial cells in vivo (shown by red markings in the images), whereas essentially no epithelial internalization was observed with no ligand control conjugates. 15 C. Gastrointestinal Tract Epithelial Cells. Fluorescence microscopy images of rental epithelial tissues from the mice of Example 10 were prepared using standard methods. Cy3-labeled conjugates with the avP6 ligand of Figure 7 were selectively internalized into endosomal compartments by GI tract epithelial cells in vivo in both small intestines and 20 gallbladder (shown by red markings in the images), whereas essentially no epithelial internalization was observed with the no ligand control conjugates. Other Embodiments 25 It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 2024202695   29 Apr 2026 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior 5 publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the 10 context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

1. An avP6 integrin ligand comprising:RG1DLXaa1Xaa2L-Xaa3Xaa4L-R1(SEQ ID NO: 96) (Formula VIII) whereinR is L-arginine;G1 is L-glycine or N-methyl glycine;D is L-aspartic acid (L-aspartate);L is L-leucine;Xaa1 is an L-a amino acid, an L-P amino acid, or an a,a-disubstituted amino acid;Xaa2 is an L-a amino acid, an L—P amino acid, or an a,a-disubstituted amino acid;Xaa3 is an L-a amino acid, an L-P amino acid, or an a,a-disubstituted amino acid;Xaa4 is an L-a amino acid, an L-P amino acid, or an a,a-disubstituted amino acid; and R1 is optional and, if present, includes PEG and / or a linking group;wherein at least two of Xaa1, Xaa2, Xaa3, and Xaa4 are non-standard amino acids independently selected from the group consisting of selenocysteine, pyrrolysine, N-formylmethionine, hydroxyproline, selenomethionine, a-Amino-isobutyric acid (Aib), L-a-amino-butyric acid (Abu), a,Y—diaminobutyric acid, dehydroalanine, norleucine, alloisoleucine, t-leucine, a-amino-n-heptanoic acid, a,P-diaminopropionic acid, P-N-oxalyl-a,P-diaminopropionic acid, allothreonine, homocysteine, homoserine, P-homo-alanine (P3hA), isovaline, norvaline (Nva), citrulline (Cit), ornithine, a-methyl-aspartate (aMeD), a-methyl-leucine (aMeL), N-methyl alanine, N-methyl-glycine (NMeG), N-methyl Leucine (NMeL), P-cyclohexyl-alanine (Cha), N-ethyl alanine, N,N-s-dimethyl lysine (K(Me)2), dimethyl arginine (R(Me)2), Dap(Ac), and n-alkylated L-a amino acids,wherein Xaa2 is Abu, and / orwherein at least two of Xaa1, Xaa2, Xaa3, and Xaa4 are non-standard amino acids independently selected from the group consisting of Cit and Aib; andwherein the avP6 integrin ligand comprises an amine-terminal cap.

2. The avP6 integrin ligand of claim 1, wherein Xaa1 is L-alanine.

3. The avP6 integrin ligand of claim 1 or claim 2, wherein R1 comprises a polyethyleneglycol having 2-20 ethylene oxide units.2024202695   25 Jun 20264. The avP6 integrin ligand of any one of claims 1-3, wherein the amine terminal cap is selected from the group consisting of: CH3CO, CH3CH2CO, CH3(CH2)2CO, (CH3)2CHCO, CH3(CH2)3CO, (CH3)2CHCH2CO, CH3CH2CH(CH3)CO, (CH3)3CCO, CH3(CH2)4CO, CH3SO2, CH3CH2SO2, CH3(CH2)2SO2, (CH3)2CHSO2, CH3(CH2)3SO2, (CH3)2CHCH2SO2, CH3CH2CH(CH3)SO2, (CH3)3CSO2, PhCO, PhSO2, alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, methyl, ethyl, propyl, butyl, pentyl, NH2NH, PEG, guanidinyl, CH3OCH2CH2OCH2CH2CO, CH3O(CH2CH2O)2CH2CH2CO, CH3O(CH2CH2O)3CH2CH2CO, CH3O(CH2CH2O)4CH2CH2CO, CH3O(CH2CH2O)5CH2CH2CO, CH3OCH2CH2OCH2CO, CH3O(CH2CH2O)2CH2CO, CH3O(CH2CH2O)3CH2CO, CH3O(CH2CH2O)4CH2CO, CH3O(CH2CH2O)5CH2CO, CH3OCH2CH2OCO, CH3O(CH2CH2O)2CO, CH3O(CH2CH2O)3CO, CH3O(CH2CH2O)4CO, CH3O(CH2CH2O)5CO, HOCH2CH2OCH2CH2CO, HO(CH2CH2O)2CH2CH2CO, HO(CH2CH2O)3CH2CH2CO, HO(CH2CH2O)4CH2CH2CO, HO(CH2CH2O)5CH2CH2CO, HOCH2CH2OCH2CO, HO(CH2CH2O)2CH2CO, HO(CH2CH2O)3CH2CO, HO(CH2CH2O)4CH2CO, HO(CH2CH2O)5CH2CO, HOCH2CH2OCO, HO(CH2CH2O)2CO, HO(CH2CH2O)3CO, HO(CH2CH2O)4CO, HO(CH2CH2O)5CO, CH3CH2OCH2CH2OCH2CH2CO, CH3CH2O(CH2CH2O)2CH2CH2CO, CH3CH2O(CH2CH2O)3CH2CH2CO, CH3CH2O(CH2CH2O)4CH2CH2CO, CH3CH2O(CH2CH2O)5CH2CH2CO, CH3CH2OCH2CH2OCH2CO, CH3CH2O(CH2CH2O)2CH2CO, CH3CH2O(CH2CH2O)3CH2CO, CH3CH2O(CH2CH2O)4CH2CO, CH3CH2O(CH2CH2O)5CH2CO, CH3CH2OCH2CH2OCO, CH3CH2O(CH2CH2O)2CO, CH3CH2O(CH2CH2O)3CO, CH3CH2O(CH2CH2O)4CO, CH3CH2O(CH2CH2O)5CO, CH3OCH2CH2CO, HOCH2CH2CO, and CH3CH2OCH2CH2CO.

5. The avP6 integrin ligand of any one of claims 1-3, wherein the amine terminal cap is CH3CO.

6. The avP6 integrin ligand of any one of claims 1-5, wherein the avP6 integrin ligand is conjugated via a linker to a cargo molecule that comprises a small molecule, an antibody, an antibody fragment, an immunoglobulin, a monoclonal antibody, a label or marker, a lipid, a natural or modified nucleic acid or polynucleotide, a peptide, an aptamer, a polymer, a polyamine, a protein, a toxin, a vitamin, a polyethylene glycol, a hapten, a digoxigenin, a biotin, a radioactive atom or molecule, or a fluorophore.2024202695   25 Jun 20267. The avP6 integrin ligand of any one of claims 1-6, wherein the avP6 integrin ligand is conjugated to a cargo molecule that comprises an active pharmaceutical ingredient.

8. The avP6 integrin ligand of any one of claims 1-7, wherein the avP6 integrin ligand is conjugated to a cargo molecule that comprises an oligomeric compound.

9. The avP6 integrin ligand of claim 8, wherein the oligomeric compound is an RNAiagent.

10. The avP6 integrin ligand of claim9, wherein the RNAi agent is selected from the group consisting of single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double-stranded RNAs (dsRNAs), micro RNAs (miRNAs), short hairpin RNAs (shRNAs), and dicer substrates.

11. A composition comprising the avP6 integrin ligand of any one of claims 1-10, and a pharmaceutically acceptable excipient.

12. A method of delivering one or more cargo molecules to a cell in vivo, the method comprising administering to the cell the avP6 integrin ligand of any one of claims 1-5 that is conjugated to the one or more cargo molecules.

13. The method of claim 12, wherein the cell is selected from the group consisting of: type I and II alveolar epithelial cell, goblet cell, secretory epithelial cell, ciliated epithelial cell, corneal and conjunctival epithelial cell, dermal epithelial cell, cholangiocyte, enterocyte, ductal epithelial cell, glandular epithelial cell, renal tubule, and epithelial tumors (carcinomas).

14. The method of claim 12 or claim 13, wherein the one or more cargo molecules comprises an oligomeric compound.

15. A method of inhibiting the expression of a target gene in a cell in vivo, the method comprising administering to the cell the avP6 integrin ligand of any one of claims 1-5 that is conjugated to a cargo molecule that comprises an oligomeric compound.2024202695   25 Jun 202616.    The method of claim 15, wherein the oligomeric compound is an RNAi agent.

17. The method of claim 16, wherein the RNAi agent is selected from the group consistingof single-stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double-stranded RNAs (dsRNAs), micro RNAs (miRNAs), short hairpin RNAs (shRNAs), and dicer substrates.

18. The method of any one of claims 15-17, wherein the cell is selected from the group consisting of: type I and II alveolar epithelial cell, goblet cell, secretory epithelial cell, ciliated epithelial cell, corneal and conjunctival epithelial cell, dermal epithelial cell, cholangiocyte, enterocyte, ductal epithelial cell, glandular epithelial cell, renal tubule, and epithelial tumors (carcinomas).

19. Use of the av06 integrin ligand of any one of claims 8-10 in the manufacture of a medicament for treating cancer in a subject in need thereof by inhibiting expression of a target gene in a cell of the subject.

20. A method of treating cancer, the method comprising administering the av06 integrin ligand of any one of claims 8-10 to a subject in need thereof, wherein the administration of the avP6 integrin ligand inhibits expression of a target gene in a cell of the subject.

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