Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Abstract

Title: Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin Article Type: Regular Paper Keywords: cancer; platinum; PAMAM dendrimer; cisplatin; guanosine; cytotoxicity; diffusion NMR. Abstract: Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion 1H NMR y and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH3)2}molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'GMP at temperatures of 60 oC for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%. We have revised the manuscript taking into account all your listed corrections and stylistic requirements.As siDNA and PBS were used only once in the manuscript we have now written these in full and not used them as abbreviations.For simplicity, we have made figure 5 just black and white and have changed the figure caption to reflect this. G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'GMP at temperatures of 60 o C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tu...

A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol

“…To implant the hydrogels a small incision was made in the skin of the mice near the tumour, the hydrogels were placed under the skin, which was then resealed with a clamp. Mice were weighed daily to monitor for toxic side effects and used as a general measure of systemic tolerability in the mice; a drop of 10% is used as the maximum tolerated 8 dose with a weight drops less than 10% considered tolerable [15].Tumour volumes on each day were estimated by calliper measurements assuming spherical geometry (volume = d 3 × π/6).…”

“…The first method is through better targeting of the drugs to tumours, thereby leaving healthy tissue unaffected [7]. A number of delivery systems, that target the tumour either passively or actively have been examined, such as: liposomes and micelles [8,9], polymers [10], nanoparticles [11][12][13], nanotubes [14] and dendrimers [15], as well as by the use of various targeting molecules, such as: folate and estrogen [16,17], aptamers [18], antibodies [19], magnetic fields [20] and DNA sequence selective agents [21,22] The second method by which the side effects of platinum drugs can be reduced is to change their pharmacokinetics (where and how a drug is transported and excreted in the body). The two biggest problems with platinum drug pharmacokinetics are their short blood serum halflifes (maximum concentration of cisplatin is achieved in less than 10 min before its serum 4 concentration drops significantly) and the extent of drug-protein binding (up to 90% of cisplatin is protein bound in the blood stream).…”

Nanotechnology-based approaches in anticancer research

“…109 Many researchers have also explored the feasibility of cisplatin incorporation in dendrimers. 102,110,111 Polyamidoamine dendrimer complexes are reported to be used for DNA delivery to cell nucleus due to their high transfection efficiency and very low toxicity. 102 They are favorite candidates to be used as the backbone of multitasking therapeutics because of their well-defined surface functionality, good water solubility, low polydispersity, and lack of immunogenicity.…”

Nanoparticles: The Future for Platinum Drugs or A Research Red Herring?

“…Recently a micelle formulation of oxaliplatin, Aroplatin™ (Aronex Pharmaceuticals, TX, USA), was withdrawn from commercial development [1]. Closer to the discovery end of the drug development pipeline, other types of nanoparticles are being examined, including: carbon nanotubes and nanohorns [5,6], mineral and metallic nanoparticles (silica, gold and gold-coated iron oxide) [7][8][9] and dendrimers [10,11].…”

“…This may stem from the reproducibility and variability in nanoparticle size from batch to batch, as is observed for metallic spheres and carbon nanotubes. Further to this, those nanoparticle systems that are polymer-or dendrimer-based may contain amine groups to which platinum drugs can irreversibly bind (i.e., polyamidoamine dendrimers) [10]. The extent of the irreversible binding can be time dependent, and unpredictable, affecting both the delivered dose and making storage more difficult.…”