Poster Session:PS 0554 ; Oncology : Anticancer Drug Transport to Breast Cancer Cells Using Mineral Nanoparticles

( Chia Yuen Chong ),( Iekhsan Othman ),( Ezharul Hoque Chowdhury ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: The current conventional way of chemotherapy using anti-cancer drugs has caused many side effects to patients. There are a high number of patients reporting intolerable symptoms, including nausea and vomiting, tiredness, depression, and more that results in poor quality of life. This is mainly due to non-selective cytotoxic effect of anticancer drugs that not only kill the cancer cells, but also affect the normal healthy cells. Eventually, these unbearable adverse effects increase the number of patients abandoning treatment, and in some others delaying their treatment progress. The pH sensitive carbonate apatite (CA), a major component of hard tissues in the body, has evolved as an effi cient non-viral inorganic DNA nanocarrier. Due to heterogenous charge distribution and being armed with ability to prevent crystal growth for generation of nanoscale particles, CA nanoparticles offer an ideal way to deliver anticancer drugs to targeted cancer cells via endocytosis. Methods: Bio-functionalized nanoparticles with loaded drugs were fabricated and characterized by measurement of particle size, zeta potential and drug binding affi nity. Breast cancer cell lines, MCF-7 and 4T1 were cultured, maintained and seeded in a 24- well plate. Drug-loaded CA particles were incubated with the seeded cells for 48 hours before analysis of cell viability by MTT assay. Results: We found that cell treatment with drug-loaded CA particles have lower cell viability in comparison to cell treatment with only free drugs. And this result is consistent in all different drug concentrations being tested. Conclusions: It is likely that the CA has a promising future for clinical cancer treatment in increasing the effectiveness of chemotherapy and concurrently reducing its side effect.

Active targeting via ligand-anchored pH-responsive strontium nanoparticles for efficient nucleic acid delivery into breast cancer cellsActive targeting via ligand-anchored pH-responsive strontium nanoparticles for efficient nucleic acid delivery into bre

Bakhtiar Athirah,Liew Qing Xin,Ng Khuen Yen,Chowdhury Ezharul Hoque 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.2

Purpose Gene therapy is a promising and novel therapeutic strategy for many mutated gene-associated diseases, including breast cancer. However, it poses significant biological drawbacks such as rapid clearance from the circulatory system and low cellular uptake of the exogenously delivered functional nucleic acids. The development of efficient and biocompatible carriers for genetic materials has been extensively explored in the literature, and the functionalization of nanoparticles (NPs) with cancer cell-recognizing ligands has become an attractive approach to promote tumor targetability and efficient cellular internalization via endocytosis. Methods This study introduced self-assembling targeting ligands, including transferrin and fibronectin with the ability to electrostatically interact with strontium nanoparticles (SNPs), and then analyzed their influence on size and zeta potential of the resultant hybrid SNPs, cellular uptake and expression efficiency of transgene-loaded hybrid NPs. Results Smaller ligand-coated SNPs (LCSNPs) remarkably increased gene transfection activity in both MCF-7 and 4T1 cells as well as nucleic acid localization into tumor tissues with improved tumor regression activity in a 4T1-tumor xenograft mouse model. Conclusion LCSNPs-mediated delivery of p53 gene and MAPK siRNA provided a proof-of-concept for the functionalized nanocarrier formulation in order to inhibit breast cancer cell growth.

Mitigating off-target distribution and enhancing cytotoxicity in breast cancer cells with alpha-ketoglutaric acid-modified Fe/Mg-CA nanoparticles

Haque Sheikh Tanzina,Karim Md. Emranul,Othman Iekhsan,Chowdhury Ezharul Hoque 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.3

In this work, pH-sensitive alpha-ketoglutaric acid-modified Fe/Mg-carbonate apatite (α-KAM-Fe/Mg-CA) NPs were introduced and found to be capable of promoting the selective delivery of cancer-killing drug doxorubicin (DOX) in breast cancer cells, while simultaneously mitigating DOX toxicity on normal cells.As part of the characterization and evaluation of α-KAM-Fe/Mg-CA NPs to target breast cancer cells, a series of assessments were performed, which included size measurements, morphological analysis, FTIR, cytotoxicity assessment, hemolysis, drug binding, cellular uptake, and pH-responsive drug release tests. Liquid chromatography-mass spectrometry was used to conduct the protein corona analysis of α-KAM-Fe/Mg-CA using 10% FBS (fetal bovine serum) and mice plasma. Furthermore, to investigate the distribution of DOX-loaded α-KAM-Fe/Mg-CA NPs in major tissues and the tumor, a biodistribution investigation was conducted in mammary tumor-induced Balb/c mouse models 24 h after the intravenous administration of DOX-loaded α-KAM-Fe/Mg-CA NPs.The in vitro pH-dependent release of DOX over time demonstrated that α-KAM-Fe/Mg-CA NPs were pH-responsive and degraded rapidly at acidic pH levels. When compared to free DOX, the DOX-loaded α-KAM-Fe/Mg-CA NPs demonstrated a potent antiproliferative effect on breast cancer cells. Confocal microscopy confirmed the effective internalization of DOX-loaded α-KAM-Fe/Mg-CA NPs in breast cancer cells. The protein corona analysis revealed an affinity for dysopsonins (serum albumin, apolipoproteins) and transport proteins that may assist in extending their blood circulation period. Furthermore, biodistribution data of DOX-loaded α-KAM-Fe/Mg-CA NPs in the mammary tumor-induced Balb/c mouse model indicated extended circulation in the bloodstream, reduced non-target distribution in major tissues, and increased drug accumulation in the tumor.The results obtained suggest that α-KAM-Fe/Mg-CA NPs may emerge as a prospective candidate for delivering therapeutic cargos to treat malignant mammary tumors.

In vivo evaluation of biodistribution and toxicity of pH-responsive strontium nanoparticles for gene deliveryIn vivo evaluation of biodistribution and toxicity of pH-responsive strontium nanoparticles for gene delivery

Bakhtiar Athirah,Neah Aik Seng,Ng Khuen Yen,Chowdhury Ezharul Hoque 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.1

Purpose Low efficacy of parenteral administration of naked therapeutic genes is associated with the presence of biological barriers including circulatory monocytes that clear and eliminate foreign materials via reticuloendothelial system. Chemically synthesized inorganic strontium nanoparticles (SNPs) present a way to improve the delivery of genetic content to the targeted tissues of mammary carcinoma while protecting the load from premature degradation. Methods Biodistribution profiles in the brain, liver, spleen, kidneys, lung, and mammary tumor of BALB/c mice were investigated at 1, 2 and 4 h following intravenous administration of fluorescent siRNA-loaded SNPs. Following SNPs-mediated in vivo delivery of p53 gene and MAPK siRNA, the effects of exogenous p53 expression and silencing of endogenous MAPK were analyzed via tumor size measurement over 14 days. Results SNPs mainly accumulate in the liver and kidney with notable deposition in the brain, lung, spleen, and tumor tissues. However, higher salt concentrations hindered the optimal localization of SNPs in tumor tissues. Despite lower residual accumulation in tumor tissues, mice treated with SNPs carrying either p53 gene or MAPK siRNA demonstrated slower tumor growth than those treated with the naked gene or siRNA. Unlike p53 gene, higher siRNA concentration resulted in lower regression activity of the carcinoma tissues, which might be due to unexpected off-target effects. Conclusion The effective role of SNPs in overcoming biological barriers in vivo and supporting gene trafficking for substantial nucleic acid activities at the targeted tissues provides an opportunity for future novel therapeutic strategies for breast cancer.

Scope and challenges of nanoparticle-based mRNA delivery in cancer treatment

Md. Emranul Karim,Sheikh Tanzina Haque,Hamed Al-Busaidi,Athirah Bakhtiar,Kyi Kyi Tha,Mark M. Banaszak Holl,Ezharul Hoque Chowdhury 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.12

Messenger RNA (mRNA) recently emerged asan appealing alternative to treat and prevent diseases rangingfrom cancer and Alzheimer’s disease to COVID-19 withsignifi cant clinical outputs. The in vitro-transcribed mRNAhas been engineered to mimic the structure of natural mRNAfor vaccination, cancer immunotherapy and protein replacementtherapy. In past decades, signifi cant progress has beennoticed in unveiling the molecular pathways of mRNA,controlling its translatability and stability, and its evolutionarydefense mechanism. However, numerous unsolvedstructural, biological, and technical diffi culties hamper thesuccessful implementation of systemic delivery of mRNAfor safer human consumption. Advances in designing and manufacturing mRNA and selecting innovative deliveryvehicles are mandatory to address the unresolved issuesand achieve the full potential of mRNA drugs. Despite thesubstantial eff orts made to improve the intracellular deliveryof mRNA drugs, challenges associated with diverse applicationsin diff erent routes still exist. This study examines thecurrent progress of mRNA therapeutics and advancementsin designing biomaterials and delivery strategies, the existingtranslational challenges of clinical tractability and theprospects of overcoming any challenges related to mRNA.

A comparative evaluation of anti-tumor activity following oral and intravenous delivery of doxorubicin in a xenograft model of breast tumor

Rehan Farah,Emranul Karim Md.,Ahemad Nafees,Farooq Shaikh Mohd.,Gupta Manish,Gan Siew Hua,Chowdhury Ezharul Hoque 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.6

Purpose Natural materials have been extensively studied for oral drug delivery due to their biodegradability and other unique properties. In the current research, we fabricated sodium caseinate nanomicelles (NaCNs) using casein as a natural polymer to develop a controlled-release oral delivery system that would improve the therapeutic potential of doxorubicin (DOX) and reduce its toxicity. Methods DOX-loaded NaCNs were synthesized and thoroughly characterized, then subjected to in vivo anti-tumor evaluation and bio-distribution analysis in a 4T1-induced breast cancer model. Results Our findings indicated that the tumor would shrink by eight-fold in the group orally treated with DOX-NaCNs when compared to free DOX. The tumor accumulated drug 1.27-fold more from the orally administered DOX-NaCNs compared to the intravenously administered DOX-NaCNs, 6.8-fold more compared to free DOX, and 8.34-times more compared to orally administered free DOX. In comparison, the orally administered DOX-NaCNs lead to a significant reduction in tumor size (5.66 ± 4.36 mm3) compared to intravenously administered DOX-NaCNs (10.29 ± 4.86 mm3) on day 17 of the experiment. NaCNs were well tolerated at a single dose of 2000 mg/kg in an acute oral toxicity study. Conclusion The enhanced anti-tumor effects of oral DOX-NaCNs might be related to the controlled release of DOX from the delivery system when compared to free DOX and the intravenous formulation of DOX-NaCNs. Moreover, NaCNs is recognized as a safe and non-toxic delivery system with excellent bio-distribution profile and high anti-tumor effects that has a potential for oral chemotherapy.