Biodegradable polymer-based nanoparticles for gene delivery – potentials and limitations

INTRODUCTION

Gene therapy represents one of the most challenging and promising areas for investigation and nanoparticles based on biodegradable polymers are one of the most powerful tools for gene delivery, because of the ability to improve the solubility, stability, circulation half-life and bio-distribution of the encapsulated agent and the continuous progress in this field will provide potential treatment alternatives for previously considered incurable diseases,^[1,2] because the non-biodegradable vectors might have a severe toxicity due to its the accumulation at the Targeted site or tissue,^[3] and in spite of the progress that has been made in gene delivery by adeno-associated virus as a gene carrier the toxicity and improving long-term efficacy are still challenges,^[4] polymer degradation is induced by different agents such as radiation, humidity, temperature, magnetic field, mechanical force, and biochemical factors,^[5] so the careful consideration of the physical and the chemical properties of the bio-degradable polymers and the optimization of the parameters of the formulation process of the nanoparticles coupled with the deep comprehension of biological barriers role are considered as the key elements toward a successful and effective therapeutic nanoparticles.

The article was structured and arranged in such a way as to address the feasibility and the limitations of the different biodegradable polymer-based nano-systems for gene delivery.

DISCUSSION

Thoughts were arranged and connected in a simplified way with an aim to give hints for the needed future works to reach the ideal conditions for gene delivery using biodegradable polymeric nanoparticles.

Bozkir and Saka et al., in a study to investigate the effect of chitosan molecular structure on plasmid DNA release from the nanoparticles that were prepared using this polymer found that the plasmid DNA-chitosan nanoparticles prepared with high deacetylation degree (92.7%, 98.0%, and 90.4%) were able to protect the encapsulated pDNA from nuclease degradation With a release profile of 24 h and that chitosan cytotoxicity is dependent on cell line type, particle size, so that it prefers cancerous cell in comparison with other cells regardless of the particles charge^[6] and in another study, Da Luz et al. reported that the poly lactic acid nanoparticles induced an alteration in human lung epithelial A549 cells and consequently a modification in the biological functions.^[7]

Mundargi et al. reported that poly(d,l-lactic-co-glycolide) and its derivatives have been studied for preparing nano/micro-particles that have the ability to encapsulate many macromolecular drugs such as genes, proteins, vaccines, antigens, and human growth factors, and several micro-particle dosage forms are available in the market.^[8] However, poly(lactic-co-glycolic acid (PLGA) nanoparticles with active targeting properties may induce a higher incidence of cytotoxicity and a higher cellular uptake of therapeutic molecules in comparison with non-targeting nanoparticles, regardless of the types of cells studied. Furthermore, other factors such as size and zeta potential of PLGA nanoparticles have a significant effects regarding the resultant cytotoxicity.^[9]

Zwiorek et al. reported that cationic gelatin nanoparticles have the ability to be used for gene delivery.^[10] Moreover, Yasmin et al., reported that quantum dots coating with gelatin can reduce these quantum dots’ potential cytotoxicity,^[11] and within the same context, Yildirim et al., revealed that gelatin nanoparticle elasticity plays a significant role in gelatin nanoparticle interaction with macrophages and consequently the cellular uptake.^[12]

Severino et al. referred that sodium alginate with its own physicochemical characteristics can be modified so that to be used in specific targeting; however, every physicochemical modification may induce a new toxicological profile for the new delivery system.^[13]

Alallam et al., reported that coating Clustered Regularly Interspaced Short Palindromic Repeats plasmid-loaded sodium alginate nanoparticles with chitosan modified the physicochemical properties of the nanoparticles toward more plasmid DNA protection and stability and consequently a better release profile.^[14]

Palamà et al., reported that mRNA-protamine complex encapsulated by poly(ε-caprolactone) (PCL) nanoparticles with a size of about 247 nm in diameter with a core–shell structure and PH dependent release were able to release 25% of the mRNA after 48 h post-incubation at a PH of 7.4, and a 60% of the mRNA at a PH of 5.0 These nanoparticles revealed no cytotoxicity to NIH 3T3 fibroblasts, HeLa cells and MG63 osteoblasts up to 8 days of incubation.^[15] However, other studies indicated that PCL is hydrophobic, making it difficult to interact with cells, the thing that will negatively affect its efficiency.^[16]

In a comparison study using chitosan and chitosan/hyaluronic acid polymers, respectively, in nanoparticles preparation for Small Interfering RNA delivery to A549-Luc cells, Al-Qadi et al., found that the formula with hyaluronic acid revealed a better release profile by 25%.^[17]

Khademi et al., revealed that the system of integrated core/shell nanoparticles composed of hyaluronic acid and nuclear targeting group AS1411 (guanosine-rich, 26-base oligonucleotide aptamer that targets and binds to nucleolin, a protein overexpressed on the surface of many cancer cells). And chitosan as a nanoparticles core had the ability to specifically deliver CRISPR/Cas9 is (a gen editing technology) to target cells nuclei in vitro in addition to the ability to inhibit tumor cells (in vivo),^[18] however Jiang-Hui Wang, et al., referred that the effect of hyaluronidase on the degradability of the hyaluronic acid-based nanoparticles should be taken into consideration in terms of release kinetics and should fully investigated as reported by.^[19] Recently, biodegradable polymers have been used for MicroRNA as reported by Gaur et al. who found that MicroRNA 34-a-loaded chitosan nanoparticles were able to inhibit the prostate tumor growth as the miRNA34-a-induced tumor cell apoptosis in cancer prostatic cells.^[20]

CONCLUSION

The age of the biodegradable polymeric nanoparticles as a gene delivery systems is still at the early stages and biocompatibility and biodegradability of these systems are not the only determinant factor for its safe use in gene delivery, so more deep investigation is required at three levels, the first is at the in vivo trials toward the evaluation of each polymer and its derivatives in connection with each specific target tissue concerning the potential cytotoxicity, the second is the formulation parameters influence on the fate of the resultant nanoparticles, the third is deep investigation of the binding nature of the DNA material to the carrier polymer and the adhesion of the polymer to the site of action at the molecular levels in addition to the polymer degradation and the DNA release profile, taking into consideration the biological barriers that play a critical role in the whole process.