Micelle-like Nanoparticles as Carriers for DNA and siRNA

Abstract

Gene therapy represents a potential efficient approach of disease prevention and therapy. However, due to their poor in vivo stability, gene molecules need to be associated with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. Cationic polymeric nanoparticles are popular carriers for small interfering RNA (siRNA) and DNA-based therapeutics for which efficient and safe delivery are important factors that need to be optimized. Micelle-like nanoparticles (MNP) (half micelles, half polymeric nanoparticles) can overcome some of the disadvantages of such cationic carriers by unifying in one single carrier the best of both delivery systems. In this review, we will discuss how the unique properties of MNP including self-assembly, condensation and protection of nucleic acids, improved cell association and gene transfection, and low toxicity may contribute to the successful application of siRNA- and DNA-based therapeutics into the clinic. Recent developments of MNP involving the addition of stimulus-sensitive functions to respond specifically to pathological or externally applied “triggers” (e.g., temperature, pH or enzymatic catalysis, light, or magnetic fields) will be discussed. Finally, we will overview the use of MNP as two-in-one carriers for the simultaneous delivery of different agents (small molecules, imaging agents) and nucleic acid combinations.

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

“…On the other hand, there is another limitation, how to reach a significant dose inside the cell to achieve efficient inhibition of miRNA. These limitations can be listed as follows: 1) slow penetration of miRNAs into tumor tissues due to mechanical and biological barriers, 2) quick degradation of unprocessed miRNA mimics and miRNA antagonists and clearance from the blood circulation, 3) miRNA (ssRNA or dsRNA homologue)-mediated immunotoxicity, 4) neurotoxicity due to exposure to miRNAs, 5) inefficient gene silencing due to poor intracellular delivery and aggregation of naked miRNAs within the endosomes, 6) miRNA-mediated off-target effects, 7) altered function of therapeutic miRNAs due to saturated or insufficient miRNA processing enzymes (154)(155)(156)(157). Clinical trials are ongoing and several therapeutics-associated companies are engaged in overcoming these challenges to accomplish the most efficient result (109).…”

Copolymer micelles function as pH-responsive nanocarriers to enhance the cytotoxicity of a HER2 aptamer in HER2-positive breast cancer cells

“…34,35 The PDPA core serves as a pH sensor, which is hydrophobic at physiological pH (pH .7.4) and becomes hydrophilic at acidic conditions due to protonation of di-isopropylamin. 36,37 Thus, the pH-responsive MNPs are stable at pH 7.4 but swell and disaggregate at a pH ,6.0. MNPs composed of PEG 8 -PDPA 100 -PEG 8 have been proven to possess a range of desirable properties, such as low cytotoxicity, superior efficiency to deliver small chemical drugs, and considerable lysosomal accumulation after cellular uptake.…”

“…37,39 Moreover, pH-sensitive release of HApt from MNPs in the endosomal or lysosomal compartments (pH 4.0-6.5) would result in rapid intracellular release of HApt in the target cells. 53,54 Our lysosome activity inhibition experiments confirmed that the release of HApt inside the cell was dependent on low lysosomal pH.…”

Engineering biodegradable micelles of polyethylenimine-based amphiphilic block copolymers for efficient DNA and siRNA delivery

“…In recent years, polymeric micelles have attracted interest due to their potential applications in nanomedicine [25][26][27]. They are usually formed by self-assembly of amphiphilic block-or graft-copolymers with a typical core-shell morphology.…”

“…They are usually formed by self-assembly of amphiphilic block-or graft-copolymers with a typical core-shell morphology. Compared to homo-polymers like PEI, polymeric micelles might offer several unique advantageous features for nucleic acid delivery such as the capacity to condense and protect the nucleic acid segment, while showing a higher colloidal stability, longer in vivo circulation time, improved cell association and internalization, enhanced transfection efficiency as well as lower toxicity [26,28]. Importantly, their physical and biological properties can be easily tuned by using multiple copolymers with different shell-forming blocks to form co-assembled micellar structures [27,29,30].…”