In developed countries, primary lung cancer mainly of epithelial origin is one of the main reasons for about 23% of all cancer associated deaths. Kaminskas et al. synthesised a DOX-conjugated dendrimer and administered it in the pulmonary route for enhanced drug delivery to lung metastases and improved cancer therapy. Twice a week intratracheal administration of dendrimers showed >95% decrease in lung tumour subsequently two weeks as compared with DOX solution administered intravenously reduced 30-50% of lung tumour (Kaminskas et al. 2012). Ayatollahi et al. designed a polyplex (functionalised РАМАМ dendrimers/aptamer/plasmid) for potent delivery of RNAi-related genes for lung cancer treatment. The РАМАМ dendrimers were functionalised using PEG and 10-bromodecanoic acid. Their outcome indicated 25% of gene silencing effect and induced 14% of late apoptosis effect with greater selectivity in targeted cancer cells (Ayatollahi et al. 2017).
Almuqbil et al developed a dendrimer-based nanoDDS that enhances and correlates the penetration of DOX in the 3D in vitro model of the lung tumour with its effectiveness. The basic components of the extracellular matrix (ECM), recognised as a physical barrier to the transport of DOX. are shown to generate spheroids produced with the human adenocarcinoma cells. DOX was conjugated to G4.0 succinamic acid-terminated-PAMAM dendrimers (G4SA) through an enzyme-liable tetrapeptide (G4SA-GFLG- DOX). MTT assay used to evaluate 2D cell viability by using free DOX, G4SA or G4SA-GFLG-DOX conjugates after 72 h of incubation. The G4SA-GFLG-DOX cell viability curve follows a very comparable DOX free profile, but it is upward with the half maximal inhibitory concentration (IC50) of 1.11 pM. It indicates that DOX was produced from the conjugate after it was internalised in the tumour cells and stored in the nucleus. The apoptosis test was conducted after 24 h incubation in both A549 cultural spheroids and co-culture A549/3T3 spheroids, and the finding suggested that the DOX and G4SAGFFLG- DOX tests for single culture spheroids have the same effect on apoptosis in all taken concentrations. The G4SA-GFLG-DOX nanocarriers, however, displayed enhanced behaviour in the 3D coculture system compared with free DOX at a concentration of 10 pM DOXeq, indicating an improved conjugate performance with more complicated and abounding ECM in the system. This research has shown that DOX-G4SA combination facilitates the penetration of DOX in an ECM-producing model of lung cancer co-culture and that this enhanced penetration is associated with an improved cytotoxic activity compared with free DOX (Almuqbil et al. 2020).
The mitochondria known as the powerhouse of cell regulate many biological mechanisms including cell metabolism and cell death. Recently, let-7b has been observed as tumour suppressor microRNA in human cell mitochondria targeting many genes of the respiratory chain associated with mitochondria. Maghsoudnia et al. fabricated nanocarriers of let-7b-PAMAM (G5)-TPP (triphenylphosphonium cation) and let-7b-PAMAM (G5)-TPP-HA (hyaluronic acid) to supply let-7b miRNA mimics in NSCLC mitochondria cells as a fascinating way of inhibiting cancer cells. The study found that no cell cytotoxicity in HA treated cells was observed compared to nontreated cells. Furthermore, the viability of the cells treated with various HA concentrations was not substantially different. The reduced cell toxicity of let- 7b-PAMAM-TPP-HA NPs was lower in comparison with Let-7b-PAMAM-TPP NPs to inhibit cancer cells. The introduction of TPP molecules to РАМАМ dendrimers will increase the cytotoxicity of the cell compared with unmodified dendrimers. since TPP itself may be destructive of РАМАМ (G5)-TPP biological membranes as an effective method of generation of the genes to supply microRNAs with mitochondria to offer a completely new way in NSC (Maghsoudnia et al. 2020).
FIGURE 13.7 Safety assessment of siRNA/AmPPD complexes both in vitro and in vivo. Toxicity assessment using the (A) MTT assay, (B) LDH assay on PC-3 prostate cancer cells (50 nM scramble siRNA. N/P ratio of 10) (mean ± SD. n = 3) and (C) haemolysis assay of the DSPE-KK2 (0.5, 1.2.5,5, 10,25,50 and 100 pM) and siRNA/DSPE-KK2complexes (N/P ratio of 10) (mean ± SD, n = 3) (Reproduced with permission from Dong et al. 2020).
Ovarian cancer is an extremely lethal gynaecologic disease, with the high-grade serous subtype predominantly associated with poor survival rates. Lack of early diagnostic biomarkers and prevalence of post-treatment recurrence create substantial challenges in the treatment of ovarian cancer. Liu et al revealed lipid-based dendrimer (РАМАМ G4.0) hybrid nanocarriers as an innovative DDS for PTX in therapy of the ovarian cancer. The resulting efficiency of drug encapsulation in the lipid-based dendrimer system was about 78.0±2.1% with 37-fold increased drug potency (Liu et al. 2015). Luong and others fabricated a liganddecorated nanoarchitecture dendrimer for enhanced solubility and specified delivery of anticancer flavonoid analogues to the cancer cells/tissues. The researchers used folate as a ligand, which was decorated on the surface of РАМАМ dendrimers for ultimate goal of enhanced water solubility of 3,4-difluorobenzylidene diferuloylmethane (CDF), highly hydrophobic but effective anticancer flavonoid (Luong et al. 2016).
Cruz et al. developed a new formulation using polyurea (PURE) dendrimers with the use of L-buthionine sulphoximine (L-BSO) (L-BSO@PUREG4-FA2) to test in vitro (GSH) synthesis on the restoration of ovarian cell cancer susceptibility to carboplatin, in the form of a folate-functional NP. Free L-BSO effectively decreases GSH bioavailability, impairing carboplatin tolerance. This effect of L-BSO has also been observed in the in vivo model of ovarian cancer, significantly reducing the size of subcutaneous tumours and GSH levels and peritoneal dissemination. L-BSO@PUREG4-FA2 nanoformulation is more successful in causing death of ovarian cancer cells than free L-BSO; and ovarian cancer cells are more vulnerable to L-BSO@PUREG4-FA, than non-cancer squamous cells (HaCaT), confirming abdominal-mediated putative treatment (Cruz et al. 2020).
The results of selenium containing chryside (SeChry) in three separate ovarian cell lines (ES2, OVCAR3 and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2) were examined by Santos et al. Findings demonstrate that SeChry does not affect cysteine uptake as well as being highly cytotoxic, but it increases GSH depletion and SeChry can induce oxidative stress.SeChry @PUREG4-FA NPs have increased the specificity of SeChry delivery to ovarian cancer cells, significantly reducing the toxicity to non-malignant cells. The study concluded that the SeChry@PUREG4-FA NPs as a potential method for enhancing ovarian cancer care underlie SeChry cytotoxicity in the case of GSH depletion and cystathionine P-synthase inhibition (Santos et al. 2019).
Oral and oropharyngeal cancer is the sixth most common cancer worldwide. The treatment outcome for oral cancer remains poor. Liu et al. investigated the anticancer activity of РАМАМ dendrimer-linked short hairpin RNA (shRNA) in contrast to hTERT in oral cancer, which resulted in induced cell growth and apoptosis of cancer cells (Liu et al. 2011). Other investigators employed G3.0 РАМАМ dendrimers and dimethylaminododecyl methacrylate (DMADDM) to design a biofilm adhesive for anti-caries action with enhanced re-mineralisation capabilities and biofilm regulation. This study showed no adverse effects on the dentin bond strength (Ge et al. 2017).
Breast cancer is the second important reason of women death worldwide. The triple negative breast cancer (TNBC) accounts for about 10-15% in women. Pourianazar and Gunduz fabricated CpG oligode- oxynucleotide (ODN)-loaded on РАМАМ dendrimers coated with magnetic NPs to deliver the oligonucleotides, genes and drugs and promoted cell death in breast cancer cells. These NPs with a magnetic core have 40±10 nm average size and efficiently bind to the CpG-ODN molecules. Thus, it resulted in induced apoptosis of tumour cells (SKBR3 and MDA-MB231) and was considered as an effective targeted DDS for CpG-ODN in the biomedical applications (Pourianazar and Gunduz, 2016). In another study, Ghosh et al. developed and analysed a targeting non-viral vector that efficiently delivered the specific gene and diagnosed TNBC. The carbon quantum dots were prepared using peels of sweet lemon and then conjugated with various generations of РАМАМ dendrimers. which resulted in a promising tool for the treatment of TNBC (Ghosh et al. 2019).
Torres-Perez et al. fabricated new one-step РАМАМ dendrimers loaded with methotrexate (MTX) and D-glucose (OS-PAMAM-MTX-GLU) and evaluated in TNBC cell line, (MDA-MB-231). The findings reveal that OS-PAMAM-MTX-GLU and controls have the primary and secondary amides characteristic of РАМАМ dendrimers. The OS-PAMAM-MTX-GLU decreases the cell viability of MDA-MB-231 cells up to 20% and is considerably higher than free MTX. without significantly affecting HaCaT cells. Cell uptake analysis found that glycosylation enhanced the internalisation of OS-РАМАМ conjugates in cancer cells relative to non-cancer cells. The uptake of OS-PAMAM-MTX-GLU inhibits MDA-MB-231 selectively, which is a desirable strategy for targeted breast cancer cell therapy (Torres-Perez et al. 2020).