TITLE:
pH-responsive magnesium- and carbonate-substituted apatite nano-crystals for efficient and cell-targeted delivery of transgenes
AUTHORS:
Ezharul Hoque Chowdhury
KEYWORDS:
Gene Therapy; Nanoparticles; Particle Dissolution; Ca/Mgpi; Carbonate Apatite; Endosome, Nucleus; Gene Expression
JOURNAL NAME:
Open Journal of Genetics,
Vol.3 No.2A,
June
26,
2013
ABSTRACT:
The short half-lives due
to the enzymatic degradation in blood, the lack of tissue targetability and
the incapability to passively diffuse across the plasma membrane and smoothly
traffic across the harsh intracelluar environment are the major shortcomings
for nucleic acid-based potential
therapeutics, such as recombinant plasmid and antisense oligonucleotides
or small interferring RNA (siRNA). Plasmid DNA containing a gene of interest could
have immense impact as a promising therapeutic drug for treating genetic as
well as acquired human diseases at the molecular level with high level of
efficacy and precision. Thus both viral and non-viral synthetic vectors have
been developed in the past decades to address the aforementioned challenges of
naked DNA. While in the viral particles plasmid DNA is integrated into the viral
genome, in most non-viral cases the DNA being anionic in nature is
electrostatically associated with a cationic lipid or polymer forming lipoplex
or polyplex, respectively, or a cationized inorganic gold, silica or iron oxide
particle. Due to the potential immunogenicity and carcinogenicity issues with
the viral particles, non-viral vectors have drawn much more attention for the
clinical evaluation. However, the main concern of using non-biodegradable particles,
specially the inorganic ones, is the adverse effects owing to their long term
interactions with body components. We have recently developed biodegradable
pH-sensitive inorganic nanoparticles of Mg/CaPi and carbonate apatite for
efficient transgene delivery to primary, cancer and embryonic stem cells, by
virtue of their high affinity binding with the DNA, ability to contact the cell
membrane by ionic or ligand-receptor interactions and fast dissolution kinectis
in endosomal acidic pH facilitating release of the DNA from the dissolving
particles and also from the endosomes.