Therapeutic and Biomedical Applications of Dendrimer-Based Formulation
Dendrimers have various points of interest as they may be utilised as vehicles or platforms for diagnosis and treatment. Moreover, dendrimers preclude the drug instability as being monomolecular polymer micelles. Then again, because of flexible size (varied according to generation) of dendrimers, they have vast application in biomedical engineering.
Due to the well-defined architecture (multivalences) of dendrimers, drugs can be attached covalently to their periphery. This property of dendrimers was very fruitful to develop it as a potential carrier for anticancer agents.
Zhang et al. have reported the development of pH-sensitive multifunctional doxorubicin (DOX) conjugated РАМАМ dendrimers as a unique platform for targeted cancer chemotherapy (Zhang et al. 2018). One of the potent anticancer drugs, paclitaxel, has poor aqueous solubility. After conjugating anticancer drug (paclitaxel) with РАМАМ G4 dendrimer having hydroxyl end groups, an enhanced solubility and cytotoxicity were observed. Tenfold enhanced cytotoxicity was reported in terms of conjugated paclitaxel than the non-conjugated anti-cancer drug (paclitaxel) (Jones et al. 2012; Khandare et al. 2006). In another study, cancerous tissue targeting efficiency of anti-Human growth factor receptor-2 (HER2) monoclonal antibodies was reported. HER2 specific (monoclonal antibody) was conjugated with РАМАМ G5 dendrimer. The developed dendrimer-antibody conjugate demonstrated fast and effective cellular internalisation devoid of discrepancies in selectivity of targeting during internalisation process with free antibody. Animal studies data also revealed the targeting of HER2-expressing tumours by the conjugated monoclonal antibody (Shukla et al. 2006).
Chittasupho and co-authors developed a doxycycline conjugated РАМАМ dendrimers. The effects of doxycycline conjugated РАМАМ were investigated on cytotoxicity, cellular binding and migration of ВТ-549-Luc and T47D breast cancer cells. The drug conjugated dendrimers were modified with LFC131 peptide. It has capability to distinguish CXCR4. which is expressed on the surface of breast tumour cells. The developed formulation (LFC131-DOX-D4) displayed considerably better cellular toxicity in vitro, as related to non-targeting dendrimers (Chittasupho et al. 2017). In another study four different poloxamer (F108. F68, P123 and F127) were conjugated with РАМАМ G4. and 5-fluorouracil was taken as a model drug. Higher drug payload was observed with poloxamer PI23 conjugated РАМАМ G4 compared with other poloxamer grades. The optimised drug-loaded dendrimer exhibited higher antiproliferative action against MCF-7 breast cancer cell line (Nguyen et al. 2017). Dendrimers as a carrier for herbal drugs have been established by numerous investigators. A natural alkaloid. Berberine, showing promising anticancer action is less studied because of its low pharmacokinetic performance. Gupta et al. developed berberine conjugated G4 РАМАМ dendrimer for effective delivery of berberine. The outcomes of MTT assay showed substantially better antiproliferative activity against MDA-MB-468 and MCF-7 breast cancer cells with РАМАМ berberine conjugate. Additionally, the developed conjugate formulation was reported biocompatible and safe. In vivo studies exhibited remarkable improvement in pharmacokinetic parameters (area under the curve and half-life) (Gupta et al. 2017). A nucleoside analogue, cytosine arabinoside (Ara-C), is one of the naturally active agents having promising anti-tumour activity, but its use is limited due to insufficient uptake and accretion of therapeutic molecules within the tumours. Szulc et al. developed maltose-modified glycodendrimers (PPI-m OS) containing Ara-C triphosphate (Ara-CTP) for the treatment of leukaemia. The developed Ara-CTP dendrimers conjugate showed enhanced cytotoxic activity against 1301 leukemic cells equated to pure Ara-C and Ara-CTP. Authors further reported that such improved uptake as well as cytotoxicity of Ara-CTP-dendrimers with blocked human equilibrative nucleoside transporter (hENTl) might be applied as potential therapy for acute lymphoblastic leukemia cells (Szulc et al. 2016).
A dendritic polyester system based on monomers 2,2-bis(hydroxymethyl)propionic acid attached to DOX or hydroxyl-terminated generation 4 РАМАМ in conjugation with PTX through a union with succinic acid has shown great anticancer activity against ovarian cancer cells (Castro et al. 2018). However, at present the dendrimers used as drug-carriers do not satisfactorily meet the necessary characteristic of an ideal dendrimer for targeted drug delivery. However, the development and study of new dendrimers drug-carriers continues to be an important tool in the cancer therapy (Prasad and Srivastava 2020).
Gene, Enzyme and Protein Carrier System
Vectors are responsible for the transfer of genes into the nucleus. Various studies are being carried out by utilising dendrimers as a carrier or vector without harming or disabling the nucleic acid such as DNA. A well-known dendrimer, РАМАМ dendrimer has been explored as vectors for gene therapy. The amino groups present on the surface of РАМАМ react and form complexes with the phosphate groups of nucleic acids. Furthermore, the complex dendrimers are able to transport a higher quantity of biological material such as DNA, RNA, protein and enzymes, contrasted to that of viruses (Klajnert and Bryszewska 2001).
Nitrogen core dendrimer containing polypropyl ether imine (PETIM) has been reported by Lakshminarayanan et al., which have complexation with DNA and delivery of gene abilities. Quantitative luciferase assay showed hundred fold gene transfection related to poly(ethylene imine) branched polymer comprising equal figure of cationic sites as the dendrimer (Lakshminarayanan et al. 2013). Lungs delivery of siRNA is very challenging resulting very lower bioavailability. Additionally, the formulation development, stability and maintaining the activity of free siRNA after pulmonary administration by inhalation is a difficult task. In vitro transfection efficacy of a triphenylphosphonium altered РАМАМ G4 dendrimer (G4NH2-TPP) was studied by Bielski E et al. They developed dendriplex conjugates comprising 12 TPP molecules complexed with siRNA on the surface. The highest in vitro gene knockdown proficiency was observed. Furthermore, 12 TPP-dendriplex-loaded mannitol microparticles were formulated to establish the efficacy of TPP-dendriplexes for pulmonary applications. A deep lung deposition of dendriplexes was found deprived of any impact on the in-vitro gene giveaway effectiveness of the siRNA (Bielski et al. 2017). Wang X et al. studied the performance of large therapeutic molecules like proteins by incorporating into dendrimers. They developed a series of conjugates (in various molar ratios) by the active ester method containing therapeutically active protein like streptokinase (SK) and РАМАМ G3.5 dendrimers. It was observed that the conjugate having equimolar (1:1) ratio exhibited significant enzymatic activity. However, SK-PAMAM conjugates with high molar ratios (1:20 and 1:10 of РАМАМ: SK) displayed lesser enzymatic activities but prolonged thrombolytic action in plasma. Therefore, it was concluded that based on the molar ratio of protein and РАМАМ, enzymatic activity of therapeutic molecules could be altered as per need and thus employs the possible application of dendrimers (Wang et al. 2007).