PH-responsive strontium nanoparticles for targeted gene therapy against mammary carcinoma cells

Genetic intervention via the delivery of functional genes such as plasmid DNA(pDNA)and short-interfering RNA(siRNA)offers a great way to treat many single or multiple genetic defects effectively,including mammary carcinoma.Delivery of naked therapeutic genes or siRNAs is,however,short-lived due to biological clearance by scavenging nucleases and circulating monocytes.Low cellular internalization of negatively-charged nucleic acids further causes low transfection or silencing activity.Development of safe and effectual gene vectors is therefore undeniably crucial to the success of nucleic acid delivery.Inorganic nanoparticles have attracted considerable attention in the recent years due to their high loading capacity and encapsulation activity.Here we introduce strontium salt-based nanoparticles,namely,strontium sulfate,strontium sulfite and strontium fluoride as new inorganic nanocarriers.Generated strontium salt particles were found to be nanosized with high affinity towards negatively-charged pDNA and siRNA.Degradation of the particles was seen with a drop in pH,suggesting their capacity to respond to pH change and undergo dissolution at endosomal pH to release the genetic materials.While the particles are relatively nontoxic towards the cells,siRNA-loaded SrF 2 and SrSO 3 particles exerted superior transgene expression and knockdown activity of MAPK and AKT,leading to inhibition of their phosphorylation to a distinctive extent in both MCF-7 and 4T1 cells.Strontium salt nanoparticles have thus emerged as a promising tool for applications in cancer gene therapy.

pH-responsive magnesium- and carbonate-substituted apatite nano-crystals for efficient and cell-targeted delivery of transgenes

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.

Growth factor receptors: promising drug targets in cancer

Genetic,epigenetic and somatic changes deregulate the expression of growth factor receptors(GFRs),leading to cancer initiation and progression.Tumor cell growth and survival are orchestrated by clonal expansion and evasion of apoptotic signals in cancer cells.The growth of cells is further supported by angiogenesis and metastasis to distant organs.High expression of GFRs also contributes to the development of resistance.Therefore,therapeutics to target GFRs is a potentially attractive molecular approach to treat cancer more effectively.In this review,we have discussed the contribution of GFRs to cancer development and addressed molecular approaches undertaken to inhibit GFR-mediated pathways.A wide number of monoclonal antibodies(mAbs)and protein kinase inhibitors targeting these GFR-mediated functions are in clinical trials to treat human malignancies.However,most drugs that target GFRs lead to the development of drug resistance and generate adverse effects.Nucleic acid-based therapeutics,e.g.short interfering RNA(siRNA)could be harnessed to selectively silence GFR genes in cancer cells.Different polymer,liposome-based nanocarriers,and the most recently developed pH-sensitive inorganic carbonate apatite nanoparticles have been used in cell culture and preclinical trials for cytoplasmic delivery of the siRNAs targeting different GFR genes.siRNA-based therapeutics have been shown to have signifi cant potential to suppress GFR expression and functions and thus could be developed as molecular therapeutics.Multi-targeting of tumors at different levels by combining various approaches along with chemotherapy would be a promising therapeutic approach to fight the disease.Suitable nanocarriers capable of entrapping siRNA,mAb,GFR inhibitors and classical drugs targeting GFR have potential therapeutic applications.

Strategies to assemble therapeutic and imaging molecules into inorganic nanocarriers

Inorganic nanocarriers are potent candidates for delivering conventional anticancer drugs,nucleic acid-based therapeutics,and imaging agents,influencing their blood half-lives,tumor targetability,and bioactivity.In addition to the high surface area-to-volume ratio,they exhibit excellent scalability in synthesis,controllable shape and size,facile surface modification,inertness,stability,and unique optical and magnetic properties.However,only a limited number of inorganic nanocarriers have been so far approved for clinical applications due to burst drug release,poor target specificity,and toxicity.To overcome these barriers,understanding the principles involved in loading therapeutic and imaging molecules into these nanoparticles(NPs)and the strategies employed in enhancing sustainability and targetability of the resultant complexes and ensuring the release of the payloads in extracellular and intracellular compartments of the target site is of paramount importance.Therefore,we will shed light on various loading mechanisms harnessed for different inorganic NPs,particularly involving physical entrapment into porous/hollow nanostructures,ionic interactions with native and surface-modified NPs,covalent bonding to surface-functionalized nanomaterials,hydrophobic binding,affinity-based interactions,and intercalation through co-precipitation or anion exchange reaction.