Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof

A modified polyacetal of Formula (VI):

• wherein:
• each of W1, W2, W3, W4, W5 and W6, independently, is a covalent bond or —C(O)—Y— with —C(O) connected to the polyacetal backbone;
• Y is —[C(R9R10)]a— or —[C(R9R10)]a—X1—[C(R9R10)]b—;
• X1 is an oxygen atom, a sulfur atom or —NR11;
• each of R9 and R10 independently is hydrogen, C1-6 alkyl, C6-10 aryl, 5 to 12-membered heteroaryl or C3-8 cycloalkyl;
• R11 is hydrogen, C1-6 alkyl, C6-10 aryl, 5 to 12-membered heteroaryl, C3-8 cycloalkyl or —C(O)—C1-3 alkyl;
• Z9 is Z6-T1 or Z8;
• T1 is —Z7—R6;
• Z8 is a linear or branched polyamino moiety substituted with one or more —Z7—R6 and optionally substituted with one or more substituents selected from the group consisting of -Q-R1, -Q-R3, -Q-R4, and -Q-R5;
• each Q independently is a covalent bond or —C(O)—;
• each of Z1, Z2, Z3, Z4, Z5, and Z6, independently, is a covalent bond, —NR17, or —NR17R18—, in which each of R17 and R18 independently is H, C2-8 alkyl, or —C2-10 alkyl-N(Rx)—, Rx being H or an amino acid attached to the nitrogen via the carbonyl group of the amino acid;
• or R17 and R18, together with the nitrogen atom to which they are attached form a 4 to 7-membered heterocycloalkyl ring containing 0 or 1 additional heteroatom selected from N, O, and S;
• each Z7 independently is —C(O)-T2-T3- or —N(R′)-T2-T3- with T3 connected to R6, in which R′ is H or C1-6 alkyl, T2 is selected from alkylthioaryl, arylthioalkyl, alkylthioalkyl, arylthioaryl, alkyldithioaryl, aryldithioalkyl, alkyldithioalkyl and aryldithioaryl, and T3 is a covalent bond, —C(O)N(R″)—C1-8 alkyl, —N(R″)C(O)—C1-8 alkyl, or C1-8 alkyl, in which R″ is H or C1-6 alkyl;
• each of a and b independently is an integer between 1 and 6 inclusive;
• each of n, n1, n2, n3, n4, n5, and n6 is the molar fraction of the corresponding polyacetal unit ranging between 0 and 1;
• n+n1+n2+n3+n4+n5+n6=1;
• provided that neither n nor n6 is 0;
• R1 is a targeting group for a selected tissue, pathogen, cell, or cellular location;
• R2 is a charge group optionally substituted with one or more substituents selected from the group consisting of -Q-R1, -Q-R3, -Q-R4, and -Q-R5;
• R3 is a charge-modifying group;
• R4 is a hydrophobic group;
• R5 is a protective group;
• R6 is a polynucleotide;
• the ratio (m1) of the number of R1 to the total number of polyacetal units of the polyacetal is 0 to 0.25;
• the ratio (m3) of the number of R3 to the total number of polyacetal units of the polyacetal is 0 to 100;
• the ratio (m4) of the number of R4 to the total number of polyacetal units of the polyacetal is 0 to 30;
• the ratio (m5) of the number of R5 to the total number of polyacetal units of the polyacetal is 0 to 0.03;
• the ratio (m6) of the number of R6 to the total number of polyacetal units of the polyacetal is 0.0004 to 0.10;
• and
• the polyacetal backbone has a molecular weight of about 10 kDa to about 250 kDa.