Prostate cancer targeting strategies using biodegradable-based polymeric nanoparticles potentials and future

INTRODUCTION

Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone, consisting of four main domains: the N-terminal domain, the DNA-binding domain, the hinge region, and the ligand-binding domain. ARs plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC) and these cells targeted receptors undergo a crucial changes in the prostate cancer such as gene point mutation that are found with a percentage of 15–30% of the prostate cancer accompanied by a decreased specificity of the agonist, moreover, within 30–50% of prostate cancer, there is an ARs over expression which also participates in the tumor cell’s resistance. Another significant change is the alteration in androgen biosynthesis due to the change of the synthesis enzymes in addition to the ability of abnormal prostatic cells to produce androgen in an independent manner of the adrenal glands and keeps these androgen in a considerable level which is enough for these cells to survive, another change to the ARs is the alteration in ARs cofactor tm which also leads to the uncontrolled growth of prostate cancer, above that the active antigen receptors splice variants without ligand, and some of these variants are more abundant in prostate cancer the thing that increase the cancer cells resistance to treatment procedures.^[1] For the above mentioned characteristics, ARs are considered as a candidate for therapeutic agents targeting.

Prostat specific membrane antigen (PSMA) that is overexpressed in the majority of prostat cancer cases has been investigated to be as a good target for several prostat cancer treatment approaches. ^[2]

Prostate cancer treatment requires precise targeting approaches. Key molecular targets include ARs, PSMA, and CD44, as well as tumor microenvironment elements such as stromal and immune cells. Understanding these pathways is critical for developing efficient nanoparticle-based therapies.^[3,4]

Micro-RNAs (miRNA) are 22 nucleotides small non+coding RNA, also play a significant role in the cell gene regulation, and may be used for cancer diagnostic and therapy.^[5]

Biodegradable polymeric-based nanoparticles are a candidates that might change the prostate cancer treatment profile due to their ability to deliver medications in a targeted manner, the possibility to overcome conventional chemotherapy limitations, such as the undesired adverse reaction, and cancer cell chemotherapy resistance.^[6] Furthermore, biodegradable polymeric nanoparticles as a drug delivery system have many unique properties, which are not only limited to the improvement of solubility of loaded drug material but also the possible alteration in the drug pharmacokinetics and consequently active ingredient bioavailability improvement.^[7]

DISCUSSION

Date and thoughts were arranged and connected in such a way to give hints to the potential future investigations with an aim to improve the whole sight of prostate cancer treatment methodologies.

Yang et al. found that poly(dl-lactic-co-glycolic acid PLGA nanoparticles loaded with short heparin RNA conjugated with PSMA aptamer A10 (on the surface), we’re able to increase cellular uptake in addition to gen silencing in mice,furthermore these results was validated using different kinds of prostat cancer cell lines, so that by a tow injections of these nanoparticles a significant reduce in tumer cells was noticed within tow only tow weeks.^[8]

Afsharzadeh et al.^[9] reported that polyethylene glycol (PEG)-poly lactic acid (PLA) nanoparticles loaded with galbanic acid and docetaxel, and grafted with ((S)-2-(3-((S)-5-amino-1-carboxypentyl) ureido) pentanedioic acid (a small molecule inhibitor used in targeting PSMA in prostate cancer, were able to increase the cancer cellular uptake (in prostate cancer cell line) and to reveal a prolonged circulation in comparison with traditional treatment approaches.^[9]

Raspantini et al. reported that polycaprolactone-dl-α-tocopherol-PEG-1000 nanoparticles loaded with docetaxel were able to inhibit P-glycoprotein (an efflux pump related with multi-drug resistance in cancer treatment), and when used in an in vivo model, the output revealed a tumor decrease of about 40.1% in comparison of 18.0% in docetaxel traditional treatment, respectively.^[10]

Fang et al. reported that PLGA/PEG nanoparticles loaded with docetaxel and grafted with Wy5a aptamer, which was screened for targeting CRPC, were able within an in vivo study to give a more efficient anti-tumor impact with a minimum systemic toxicity.^[11] Furthermore, similar findings were reported by Farokhzad et al., who found that PLGA-block-PEG loaded with docetaxel and functionalized with A10 2'-fluoropyrimidine RNA aptamers that were able to target the PSMA antigen, and the in vivo results revealed that a single intratumoral injection of these bioconjugated nanoparticles gave a total decrease in prostate cancer cells.^[12]

Gaur et al. found that miRNA 34-a loaded chitosan nanoparticles inhibited prostate tumor growth as the miRNA34-a induced tumor cell apoptosis in cancer prostate cells.^[13]

Wand et al. found that a docetaxel and fingolimod loaded PLGA nanoparticles and coated with a lipid layer, revealed a specific cancer cells targeting in a mouse model for human prostat cancer with a significant side effects reduce in comparison to that induced by Fingolimod alone.^[14]

Song et al. revealed that hyaluronic acid/zeolite nanoplatform were able to release doxorubicin in a controlled manner to the prostat tumor cells either in vitro or in vivo.^[15] Furthermore, Menon et al. reported that PLGA conjugated with prostate cancer cell penetrating peptide-R11 and loaded with radiation material (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one) was able to target the prostate cancer cells in a sustained release kinetics for 3 weeks.^[16]

Lee et al. revealed that chemically modified chitosan nanoparticles by N-acetyl histidine glycol were able to target gastric - releasing peptide receptors that are usually overexposed in prostat cancer.^[17] Zhang et al. also found that docetaxel and AR siRNA-loaded nanocomplex based on polyethylene amine/PLGA and grafted with PEG-polyaspartic acid have the ability to target PSMA with a prolonged drug release profile with an enhanced anti-tumor effect.^[18]

Recently, Fang et al. have reported that prostate cancer tumor microenvironment elements, such as myeloid-derived suppressor cells, tumor-associated macrophages, in addition to cancer-associated fibroblasts, are considered a rich area for prostate cancer targeting as they play a crucial role in the tumorigenesis, development, and metastasis, signifying the prostate cancer tumor microenvironment in the future targeting approaches and strategies.^[19] However, with all the above-mentioned advantages of biodegradable polymeric nanoparticles as a drug delivery systems, some limitations should be taken into consideration regarding the polymeric nanoparticles cytotoxicity for the normal cells, for example, Chiua et al. reported that PLGA nanoparticles with active targeting properties have higher cytotoxicity and cellular uptake of drugs compared to non-targeting nanoparticles, regardless of the types of cells studied. The size and zeta potential of PLGA nanoparticles play a critical role in these nanoparticles cytotoxicity.^[20] Moreover, another challenges for polymeric nanoparticles are related its biodistribution especially liver uptake and renal clearance that are mainly attributed to the physicochemical properties of these carriers such as size, core, surface functionality, and charge, in addition to active targeting ligands.^[21]

CONCLUSION

It is clear that biodegradable polymeric based nanoparticles are a promising candidates for prostate cancer treatment, owing to its biocompatibility and low cytotoxicity and its ability to deliver the anticancer drug in a sustained manner and with the precise design of multifunctional biodegradable polymeric nanoplatforms including stimuli responsive carriers a more efficient and selective selective treatment can be achieved.