Intracellular Delivery Considerations for RNAi Therapeutics - RNA Interference from Biology to Therapeutics - page 87

4.3.5 RNAi Therapeutic Release from Delivery Vectors

RNAi triggers can be delivered using a variety of vectors in which they are either
directly conjugated by a covalent bond to a carrier molecule or noncovalently com-
plexed or encapsulated in lipid or polymeric materials. Regardless of the delivery
method, RNAi molecules have to be released from the delivery vectors to become
biologically active. Most of the delivery vectors are designed based on the assump-
tion that it is ideal to release the RNAi molecules at the sites of their action rather
than relying on endogenous trafficking processes of naked RNAi molecules within
the cells [ 88 ]. At present, it is not clearly understood whether intracellular release of
RNAi triggers represents a significant barrier to delivery; vectors that permit spatial
control of RNAi release have been developed. Hydrolytic and reductive degradation
are the two main approaches to control intracellular cargo release. The rationale for
developing biodegradable delivery vectors is based on the requirement to control
RNAi molecule release and to lower the vector toxicity by degradation into less
toxic low molecular weight by-products that avoid intracellular accumulation of the
vector material.

4.3.5.1 Hydrolytically Degradable Delivery Vectors

Hydrolytically degradable vectors are usually based on polymers with degradable
ester or, less frequently, amide bonds [ 89 ] . For example, poly( b -amino esters)
(PBAE) have received much attention due to their favorable degradation profile
[ 90 ]. PBAE undergo hydrolysis in acidic environment to yield low molecular weight
b-amino acids and dialcohols [ 48 ]. Jere et al. used PBAE to deliver siRNA and
shRNA to lung cancer cells and achieved a nearly 1.5 times greater silencing in
addition to improving the safety profile of the delivery vector when compared with
control nondegradable PEI [ 49 ]. Saltzman and coworkers deployed a well-known
degradable polymer, poly(lactide- co -glycolide), for local delivery of siRNA to vagi-
nal mucosa [ 50 ]. This biocompatible and biodegradable polymer with favorable
sustained release characteristics showed promising properties for controlled siRNA
delivery [ 51, 52 ] .
Fischer et al. reported another interesting design of a hydrolytically degradable
vector. The authors synthesized several polycations with core-shell architecture that
contained a shell of amines attached via a hydrolyzable carbamate bond to a polyg-
lycerol core. It was suggested that enzymatic hydrolysis of the carbamates improved
intracellular release of siRNA and contributed to enhanced silencing activity [ 53 ] .
Natural polymers such as chitosan and atelocollagen represent another type of
degradable carriers for siRNA delivery [ 91- 93 ]. Chitosan is degraded enzymati-
cally by lysozyme and N -acetyl-glucosaminidase [ 94 ] and, is thus, expected that the
degradation and release of RNAi cargo may be triggered following intracellular
delivery of the chitosan-based vectors [ 95 ]. For example, Howard et al. described a
chitosan-based siRNA delivery system, which mediated efficient knockdown of