Polyvalent Oligonucleotide Gold Nanoparticle Conjugates as Delivery Vehicles for Platinum(IV) Warheads

Abstract

Amine-functionalized polyvalent oligonucleotide gold nanoparticles (DNA-Au NP) were derivatized with a cisplatin prodrug, and the resulting DNA-Au NP conjugates were used to internalize multiple platinum centers. A platinum(IV) complex, c,c,t-[Pt(NH3)2Cl2(OH)(O2CCH2CH2CO2H)], was tethered to the surface of DNA-Au NPs through amide linkages. The platinum-tethered gold nanoparticles (Pt-DNA-Au NPs) were taken into several cancer cells. The drop in intracellular pH facilitated reductive release of cisplatin from the prodrug, which then formed 1,2-d(GpG) intrastrand cross-links in the cell nuclei as confirmed by an antibody specific for this adduct. The cytotoxicity of the platinum(IV) complex increases significantly in several cancer cell lines when the complex is attached to the surface of the DNA-Au NPs and in some instances exceeds that of cisplatin.

Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

“…Cisplatin and c;t;c-½PtðNH 3 Þ 2 ðO 2 CCH 2 CH 2 COOHÞðOHÞCl 2 (4) were prepared as previously described (45). N,N′-dicylcohexylcarbodiimide (DCC), O-benzyl-Lserine, p-toluenesulfonic acid, sodium nitrite, NHS, EDC, paraformaldehyde, and N,N-diisopropylethylamine were purchased from Aldrich.…”

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

“…Then, the acidic tumor extracellular pH (pH e ∼6.5-7.2) (35, 36) triggers the release of small PAMAM prodrugs (∼5 nm) that enable deep and uniform tumor penetration to reach more cancer cells. Finally, the PAMAM prodrugs can be rapidly reduced in the reductive cytosol to release active and potent cisplatin to kill cancer cells and lead to robust antitumor efficacy (37).…”

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

“…In comparison, 11 hydrogels containing 2% PVA showed a moderate inhibition of cell growth by 45%, whereas hydrogels containing 4% PVA released the smallest amount of drug and induced an inhibition of cell growth by 20%. A large variation of cytotoxicity is seen in hydrogels of different PVA concentrations; the higher the PVA concentration, the lower the cytotoxicity, which is potentially from the slower rate of release of the drug.…”

“…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).…”