Drug Delivery Application of Dendrimer-Based Formulation

Dendrimers are characterised by the distinctive properties such as monodispersity, internal cavities and flexible surface modification. Besides these properties, other important features which make them a promising drug delivery system include their exceptional cellular uptake, several functionalities and ability to bind with high molecular weight compounds and increased their retention time. Furthermore, nanosize of dendrimer promotes the passive targeting of therapeutics to cancerous tissues through the improved permeation and retention effect (Kumar et al. 2015; Najlah et al. 2007; Saovapakhiran et al. 2009). The increased retention and permeability effect facilitates them for targeted drug delivery of macromolecules. Kitchens et al, in one of his permeability studies on Caco-2 cell using cationic dendrimers like PAMAM-NH, (G₀-G₄), recommended that the РАМАМ cationic dendrimers with -NH, terminal groups may effectively passage via biological membranes almost certainly through both endocytosis and paracellular channels (Kitchens et al. 2005). Patri et al established the targeting attributes of FA enabled cationic G,-PAMAM dendrimer using anticancer drug ‘methotrexate’ as therapeutic molecules. A receptor-mediated drug carrier system exhibiting elevated selectivity for KB cells with sustain release of drug was investigated (Patri et al. 2005). Due to specific nonstructural characteristics and monitored particle size, dendrimers have turned into fascinating bits and pieces for biochemical applications. In recent times, consolidating the distinguishing properties of dendrimer with various NPs like magnetic nanoparticles (MNPs) has been worked out to accomplish enhanced therapeutics and biomedical applications (Taheri-Kafrani et al. 2017).

Dendrimers have shown promise in various medical applications including diagnosis, drug delivery, transfection and therapy. A dendrimer-based cancer treatment, DTXSPL8783, is being investigated in clinical trials; a phase 1 study of this agent is under way in patients with advanced cancer (Caster et al. 2017). A dendrimeric antiviral/antibiotic compound, Vivagel (Starpharma). is in phase 3 clinical trials for bacterial vaginosis (BV). This unique nanodrug incorporates naphthalene disulphate groups on the surface of dendrimers. Phase 2 data have indicated high rates of clinical and pathologic cure of BV, as evidenced by symptomatic improvement and clear laboratory results, respectively. However, phase 3 data have been equivocal, with high rates of symptomatic improvement but lower rates of clinical laboratory cure being observed. Vivagel has also exhibited potent in vitro activity against HIV and herpes simplex virus. Phase 1 studies have indicated that vaginal use of this nanoformulation is well tolerated and that antiviral activity is retained by cervicovaginal fluids in most patients up to 24 hours after administration (Price et al. 2011). Vivagel is available in Australia as a condom lubricant. A list of dendrimer-based products that were approved and currently under clinical trial is summarised in Table 14.1.

TABLE 14.1

List of dendrimer-based products currently approved or under clinical trial

14.4.1 Transdermal Drug Delivery System

Transdermal delivery systems of drugs have been helpful to surmount the gastrointestinal and renal adverse effect of various non-steroidal anti-inflammatory drugs. Besides that, they show an extended drug release effect by controlling blood levels over a longer period. Application of dendrimers in the transdermal drug delivery system has been studied by various researchers by incorporating the drug into suitable vehicles. Chauhan and co-authors in one of the studies established the transdermal transport by employing indomethacin-loaded cationic РАМАМ dendrimers (Kawaguchi et al. 1995). Manikkath et al. demonstrated the collective impacts of dendrimers associated with arginine-based peptide and moderate frequency ultrasound on the transdermal penetration of ketoprofen. The amalgamation of ultrasound and peptide dendrimers showed a collective effect and showed a high drug plasma concentration compared to passive delivery in an animal model. Administration of ketoprofen through the transdermal route using dendrimers reported the same assimilation and plasma drug concentration as was with oral deliver)' (Manikkath et al. 2017).

14.4.2 Oral Drug Delivery System

Oral delivery is most applicable among all others because of ease of administration and the patient compliance. Due to lipophilicity and low permeability, anticancer drugs restrict their ingestion via the oral route, still they are commonly used as they are economic and also promote the use of more chronic treatment regimens (Csaba et al. 2006; Malingre et al. 2001). To overcome the drawbacks associated with these drugs, promising results were found in various studies when dendrimers were used as the drug delivery vehicles. Jevprasesphant et al studied the permeation of РАМАМ dendrimers and surface modified РАМАМ dendrimers across the Caco-2 cell monolayers and accomplished that РАМАМ dendrimers and lauroyl conjugated РАМАМ dendrimers could proficiently pass through epithelial pathways via transcellular and paracellular pathways (Gothwal et al. 2015). In another study, modified РАМАМ dendrimers with propranolol were studied for transport through Caco-2 cell line. It was showed that propranolol-PAMAM dendrimers might diminish the influence of P-glycoprotein (P-gp) transport on the absorption of propranolol in intestine. Conclusion referred that P-gp efflux transport can be avoided by dendrimers and hence improved the oral drug administration (D’emanuele et al. 2004). Najlah et al. formulated naproxen dendrimer conjugates using two different linkers (diethylene glycol and lactate ester) and examined the transepithelial permeability of the conjugates through oral delivery. The authors also investigated the stability of these conjugates in 80% human plasma and 50% liver homogenate. The results demonstrated that both these linker conjugated dendrimers showed considerably significant impact on the stability of the developed system. Compared to diethylene glycol like conjugates, lactate ester linked conjugates showed more stability in blood plasma and displayed reduced hydrolysis in liver homogenate, whereas the diethylene glycol linker-based conjugate showed high chemical stability with rapid release of therapeutic molecules in both plasma and liver homogenate. The conclusion established that the dendritic conjugate of naproxen can augment the oral bioavailability and lactate ester linker conjugate may act as a potential carrier for monitored release of drug (Najlah et al. 2007).

14.4.3 Ocular Drug Delivery System

The topical usage of active therapeutics for the therapy of ocular diseases is the main route. In general, topical ocular delivery of drugs has very low bioavailability due to the loss of drugs by tear turnover, blinking of eye and nasolacrimal drainage of fluid. Prolonged retention and enhanced corneal permeation are the major factors to improve ocular availability of drugs (Nanjwade et al. 2009; D'emanuele et al. 2004). Dendrimers have been effectively employed for the ocular administration of drugs. РАМАМ dendrimers have been successfully applied with hydroxyl or carboxyl end functionalities for ophthalmic administration of drugs. Such dendrimers enhance the corneal contact time of pilocarpine (Vandamme and Brobeck 2005). Ocular absorption of dexamethasone (DEX) was found to be improved by conjugating it with РАМАМ dendrimers. MTT assay demonstrated that all the groups showed in cell viability as compared to DEX solution. An increase transcorneal permeation was also reported after applying PAMAM-DEX (Yavuz et al. 2015). Different studies have been performed in order to assess the proficiency of dendrimers as a carrier of therapeutics (Tolia and Choi 2008: Oliveira et al. 2010).

14.4.4 Drug Delivery and Targeting to Bone

Dendrimers in bone targeting have been also used as potential delivery systems. Yamashita and coworkers developed PEG-conjugated cationic G3-PAMAM dendrimers for bone targeting in order to treat bone diseases. РАМАМ backbones were conjugated with different carboxylic groups (succinic acid, aspartic acid, aconitic acid and glutamic acid). Four different types of РАМАМ dendrimers were developed. PEG was used for PEGylation, and surface modified PEGylated carboxylic acid-PAMAM dendrimers were synthesised. An intra-bone delivery study revealed that fluorescein isothiocyanate-labelled PEGylated (5)-Aspartic acid (Asp)-PAMAM amassed in large quantity on the bone surfaces (quiescent and eroded). These surfaces are accountable for bone disorders such as osteoporosis and rheumatoid arthritis (Yamashita et al. 2017).