Genetically Engineered Nanoparticles of Asymmetric Triblock Polypeptide with a Platinum(IV) Cargo Outperforms a Platinum(II) Analog and Free Drug in a Murine Cancer Model.

The development of platinum(Pt)-drugs for cancer therapy has stalled, as no new Pt-drugs have been approved in over a decade. Packaging small molecule drugs into nanoparticles is a way to enhance their therapeutic efficacy. To date, there has been no direct comparison of relative merits of the choice of Pt oxidation state in the same nanoparticle system that would allow its optimal design. To address this lacuna, we designed a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped micelles and chelates Pt(II) or enables covalent conjugation of Pt(IV) with similar morphology and stability. Both ATBP-Pt(II) and ATBP-Pt(IV) nanoparticles enhanced the half-life of Pt by ∼45-fold, but ATBP-Pt(IV) had superior tumor regression efficacy compared to ATBP-Pt(II) and cisplatin. These results suggest loading Pt(IV) into genetically engineered nanoparticles may yield a new generation of more effective platinum-drug nanoformulations.

Controlling One-Electron vs Two-Electron Pathways in the Multi-Electron Redox Cycle of Nickel Diethyldithiocarbamate.

The unique redox cycle of NiII(dtc)2, where dtc- is N,N-diethyldithiocarbamate, in acetonitrile displays 2e- redox chemistry upon oxidation from NiII(dtc)2 → [NiIV(dtc)3]+ but 1e- redox chemistry upon reduction from [NiIV(dtc)3]+ → NiIII(dtc)3 → NiII(dtc)2. The underlying reasons for this cycle lie in the structural changes that occur between four-coordinate NiII(dtc)2 and six-coordinate [NiIV(dtc)3]+. Cyclic voltammetry (CV) experiments show that these 1e- and 2e- pathways can be controlled by the addition of pyridine-based ligands (L) to the electrolyte solution. Specifically, the addition of these ligands resulted in a 1e- ligand-coupled electron transfer (LCET) redox wave, which produced a mixture of pyridine-bound Ni(III) complexes, [NiIII(dtc)2(L)]+, and [NiIII(dtc)2(L)2]+. Although the complexes could not be isolated, electron paramagnetic resonance (EPR) measurements using a chemical oxidant in the presence of 4-methoxypyridine confirmed the formation of trans-[NiIII(dtc)2(L)2]+. Density functional theory calculations were also used to support the formation of pyridine coordinated Ni(III) complexes through structural optimization and calculation of EPR parameters. The reversibility of the LCET process was found to be dependent on both the basicity of the pyridine ligand and the scan rate of the CV experiment. For strongly basic pyridines (e.g., 4-methoxypyridine) and/or fast scan rates, high reversibility was achieved, allowing [NiIII(dtc)2(L)x]+ to be reduced directly back to NiII(dtc)2 + xL. For weakly basic pyridines (e.g., 3-bromopyridine) and/or slow scan rates, [NiIII(dtc)2(L)x]+ decayed irreversibly to form [NiIV(dtc)3]+. Detailed kinetics studies using CV reveal that [NiIII(dtc)2(L)]+ and [NiIII(dtc)2(L)2]+ decay by parallel pathways due to a small equilibrium between the two species. The rate constants for ligand dissociation ([NiIII(dtc)2(L)2]+ → [NiIII(dtc)2(L)]+ + L) along with decomposition of [NiIII(dtc)2(L)]+ and [NiIII(dtc)2(L)2]+ species were found to increase with the electron-withdrawing character of the pyridine ligand, indicating pyridine dissociation is likely the rate-limiting step for decomposition of these complexes. These studies establish a general trend for kinetically trapping 1e- intermediates along a 2e- oxidation path.

Towards developing a criterion to characterize non-covalent bonds: a quantum mechanical study.

Chemical bonds are central to chemistry, biology, and allied fields, but still, the criterion to characterize an interaction as a non-covalent bond has not been studied rigorously. Therefore, in this study, we have attempted to characterize the non-covalent bonds by considering a total of 85 model systems depicting different chemical bonds comprising 43 non-covalent and 42 other bonds such as covalent, ionic, and coordinate bonds. The characterization has been done based on interaction energy, energy decomposition analysis (EDA), the NCI plot, and the analysis of topological properties of electron density. The interaction energy values, energy decomposition analysis, and NCI plot give insights into the full understanding of bond strength and its nature, but they fail to distinctively characterize the interaction as a non-covalent bond. Herein, a special criterion has been developed based on the topological parameters to characterize an interaction as a non-covalent bond. Topological parameters illustrate that the values of both ∇2ρ and H(r) are positive with a value of ρ < 0.03 a.u. and [-G(r)/V(r)] ≥ 1.00 for the non-covalent bonds. The value of ρ increases up to 0.06 a.u. with a positive value of ∇2ρ and a negative value of H(r) if the non-covalent bond is partially covalent in nature. The analysis of G(r) suggests that it dominates the H(r) of non-covalent bonds with greater than 50% contribution, whereas the contribution of G(r) varies between 35 and 50% in the case of bonds which are partially covalent in nature. The criterion based on topological parameters is likely to be very helpful to comprehend and ascertain the non-covalent bonds in the chemical as well as complex biological systems.

Genetically Encoded Stealth Nanoparticles of a Zwitterionic Polypeptide-Paclitaxel Conjugate Have a Wider Therapeutic Window than Abraxane in Multiple Tumor Models.

Small-molecule therapeutics demonstrate suboptimal pharmacokinetics and bioavailability due to their hydrophobicity and size. One way to overcome these limitations-and improve their efficacy-is to use "stealth" macromolecular carriers that evade uptake by the reticuloendothelial system. Although unstructured polypeptides are of increasing interest as macromolecular drug carriers, current recombinant polypeptides in the clinical pipeline typically lack stealth properties. We address this challenge by developing new unstructured polypeptides, called zwitterionic polypeptides (ZIPPs), that exhibit "stealth" behavior in vivo. We show that conjugating paclitaxel to a ZIPP imparts amphiphilicity to the polypeptide chain that is sufficient to drive its self-assembly into micelles. This in turn increases the half-life of paclitaxel by 17-fold compared to free paclitaxel, and by 1.6-fold compared to the nonstealth control, i.e., ELP-paclitaxel. Treatment of mice bearing highly aggressive prostate or colon cancer with a single dose of ZIPP-paclitaxel nanoparticles leads to near-complete eradication of the tumor, and these nanoparticles have a wider therapeutic window than Abraxane, an FDA-approved taxane nanoformulation.

Heuristics for the Optimal Presentation of Bioactive Peptides on Polypeptide Micelles.

Bioactive peptides describe a very large group of compounds with diverse functions and wide applications, and their multivalent display by nanoparticles can maximize their activities. However, the lack of a universal nanoparticle platform and design rules for their optimal presentation limits the development and application of peptide ligand-decorated nanoparticles. To address this need, we developed a multivalent nanoparticle platform to study the impact of nanoparticle surface hydrophilicity and charge on peptide targeting and internalization by tumor cells. This system consists of micelles of a recombinant elastin-like polypeptide diblock copolymer (ELPBC) that present genetically encoded peptides at the micelle surface without perturbing the size, shape, stability, or peptide valency of the micelle, regardless of the peptide type. We created the largest extant set of 98 combinations of 15 tumor-homing peptides that are presented on the corona of this ELPBC micelle via 8 different peptide linkers that vary in their length and charge and also created control micelles that present the linker only. Analysis of the structure-function relationship of tumor cell targeting by this set of peptide-decorated nanoparticles enabled us to derive heuristics to optimize the delivery of peptides based on their physicochemical properties and to identify a peptide that is likely to be a widely useful ligand for targeting across nanoparticle types. This study shows that ELPBC micelles are a robust and convenient system for the presentation of diverse peptides and provides useful insights into the appropriate presentation of structurally diverse peptide ligands on nanoparticles based on their physicochemical properties.

Conjugate of Doxorubicin to Albumin-Binding Peptide Outperforms Aldoxorubicin.

Short circulation time and off-target toxicity are the main challenges faced by small-molecule chemotherapeutics. To overcome these shortcomings, an albumin-binding peptide conjugate of chemotherapeutics is developed that binds specifically to endogenous albumin and harnesses its favorable pharmacokinetics and pharmacodynamics for drug delivery to tumors. A protein-G-derived albumin-binding domain (ABD) is conjugated with doxorubicin (Dox) via a pH-sensitive linker. One to two Dox molecules are conjugated to ABD without loss of aqueous solubility. The albumin-binding ABD-Dox conjugate exhibits nanomolar affinity for human and mouse albumin, and upon administration in mice, shows a plasma half-life of 29.4 h, which is close to that of mouse albumin. Additionally, 2 h after administration, ABD-Dox exhibits an approximately 4-fold higher concentration in the tumor than free Dox. Free Dox clears quickly from the tumor, while ABD-Dox maintains a steady concentration in the tumor for at least 72 h, so that its relative accumulation at 72 h is ≈120-fold greater than that of free Dox. The improved pharmacokinetics and biodistribution of ABD-Dox result in enhanced therapeutic efficacy in syngeneic C26 colon carcinoma and MIA PaCa-2 pancreatic tumor xenografts, compared with free Dox and aldoxorubicin, an albumin-reactive Dox prodrug currently in clinical development.

Nitric Oxide Dioxygenase Activity of a Nitrosyl Complex of Cobalt(II) Porphyrinate in the Presence of Hydrogen Peroxide via Putative Peroxynitrite Intermediate.

The reaction of a cobalt porphyrin complex, [(F8TPP)Co], 1 {F8TPP = 5,10,15,20- tetrakis(2,6-difluorophenyl)porphyrinate dianion} in dichloromethane with nitric oxide (NO) led to the nitrosyl complex, [(F8TPP)Co(NO)], 2. Spectroscopic studies and structural characterization revealed it as a bent nitrosyl of {CoNO}8 description. It was stable in the presence of dioxygen. However, it reacts with H2O2 in acetonitrile (or THF) solution at -40 °C (or -80 °C) to result in the corresponding Co(III)-nitrate complex, [(F8TPP)Co(NO3)], 3. The reaction presumably proceeds via the formation of a Co-peroxynitrite intermediate. X-Band electron paramagnetic resonance and electrospray ionization-mass spectroscopic studies suggest the intermediate formation of the [(porphyrin)Co(III)-O•] radical, which in turn supports the generation of the corresponding Co(IV)-oxo species during the reaction. This is in accord with the homolytic cleavage of the O-O bond in heme-peroxynitrite proposed in the nitric oxide dioxygenases activity. In addition, the characteristic peroxynitrite-induced phenol ring reaction was also observed.

Differential Cationization of Fatty Acids with Monovalent Cations Studied by ESI-MS/MS and Computational Approach.

RATIONALE: The intercellular and intracellular transport of charged species (Na+ /K+ ) entail interaction of the ions with neutral organic molecules and formation of adduct ions. The rate of transport of the ions across the cell membrane(s) may depend on the stability of the adduct ions, which in turn rely on structural aspects of the organic molecules that interact with the ions. METHODS: Positive ion ESI mass spectra were recorded for the solutions containing fatty acids (FAs) and monovalent cations (X=Li+ , Na+ , K+ , Rb+ and Cs+ ). Product ion spectra of the [FA+X]+ ions were recorded at different collision energies. Theoretical studies were exploited under both gas phase and solvent phase to investigate the structural effects of the fatty acids during cationization. Stability of [FA+X]+ adduct ions were further estimated by means of AIM topological analyses and interaction energy (IE) values. RESULTS: Positive ion ESI-MS analyses of the solution of FAs and X+ ions showed preferential binding of the K+ ions to FAs. The K+ ion binding increased with the increase in number of double bonds of FAs, while decreased with increase in the number of carbons of FAs. Dissociation curves of [FA+X]+ ions indicated the relative stability order of the [FA+X]+ ions and it was in line with the observed trends in ESI-MS. The solvent phase computational studies divulged the mode of binding and the binding efficiencies of different FAs with monovalent cations. CONCLUSIONS: Among the studied monovalent cations, the cationization of FAs follow the order K+ >>Na+ >Li+ >Rb+ >Cs+ . The docosahexaenoic acid showed high efficiency in binding with K+ ion. The K+ ion binding efficiency of FAs depends on the number of double bonds in unsaturated FAs and the carbon chain length in saturated FAs. The cationization trends of FAs obtained from the ESI-MS, ESI-MS/MS analyses were in good agreement with solvent phase computational studies.

Nanocatalysts for hydrogen evolution reactions.

Hydrogen fuel is among the cleanest renewable resources and is the best alternative to fossil fuels for the future. Hydrogen can be best produced by means of electrolysis or photoelectrolysis of water among the various routes available for hydrogen production. So far, Pt has been recognized as the best electrode material for electrochemical hydrogen production. However, the cost of the catalyst, activity, and durability make Pt-catalyzed hydrogen production unsuitable on a commercial scale. It has hence become imperative to explore low-cost, highly active and durable HER catalysts to replace platinum as a catalyst. This perspective provides key concepts and the current status of the research on the properties of nanocatalysts that influence the hydrogen evolution reaction. Important structural features controlling the surface chemistry (i.e. facets, defects, dopants), nature of supports (graphene, CNTs, black phosphorus), role of heteroatoms, media and morphology are the key points of discussion in this perspective.

Probing the Most Stable Isomer of Zirconium Bis(phenoxy-imine) Cation: A Computational Investigation.

The possibility of coexistence of multiple isomers for zirconium bis(phenoxy-imine) catalyst has been systematically studied by computational approaches. The energetics among the five different isomers of neutral Zr-catalyst have been assessed quantum mechanically. The results suggest that isomer cis-N/trans-O/cis-Me is the most stable among the five isomers in accordance with the general observations of these kinds of phenoxy-imine catalyst. However, for the polymerization reaction, the active species is known to be the cationic form of the Zr-catalyst. The Zr-cation can exist in three different isomers, viz., cis-N/trans-O (A), cis-N/cis-O (B), and trans-N/cis-O (C), and the presence of flexible ligands makes the modeling considerably challenging to determine the most preferable isomers. For the efficient modeling, altogether 80 different structures for each of the three cationic isomers have been generated by using molecular dynamics simulations, and subsequently, the quantum mechanical optimization of these structures has been performed to obtain the most preferable conformation for each isomer. The existing probability derived from the obtained free energy values suggests that isomer C is comparable with isomer A. Even more, isomer A of the cation can be present in two different conformations, where the orientation of side groups is altered at the imine nitrogen atoms. The transition state calculations also confirm that the Zr-cation can exist as a mixture of three structures, "up-down" and "down-down" orientations of the isomers A along with isomer C's "up-up" orientation. However, by varying the substituents at imine nitrogen atoms, one could modulate multimodal to unimodal polymerization behavior of the Zr-catalysts. We believe that this study should provide a starting point for theoretically exploring the mechanistic pathway of the complicated polymerization reactions.

Nitric Oxide Reactivity of a Cu(II) Complex of an Imidazole-Based Ligand: Aromatic C-Nitrosation Followed by the Formation of N-Nitrosohydroxylaminato Complex.

A binuclear Cu(II) complex, 1, [Cu2(L-)2(OAc)](OAc) of imidazole-based ligand LH {LH = 2-(bis(2-ethyl-5-methyl-1H-imidazol-4-yl)methyl)phenol} was synthesized and characterized spectroscopically and structurally. Addition of an equivalent amount of nitric oxide (NO) by a gastight syringe to the acetonitrile:methanol (5:1, v/v) solution of complex 1 at room temperature resulted in the reduction of Cu(II) center to Cu(I) with concomitant C-nitrosation of the ligand. Spectroscopic characterization of the resulting Cu(I) complex (1a) of the C-nitrosylated ligand, L' {L' = 2-(bis(2-ethyl-5-methyl-1H-imidazol-4-yl)methyl)-4-nitroso-phenol} has been done. The Cu(I) complex, 1a, further reacted with NO to result in the corresponding N-nitrosohydroxylaminato complex, 2, [Cu2(L-ONNO)2](OAc)2 through the formation of a Cu(I)-nitrosyl intermediate. A small fraction of the nitrosyl intermediate decomposed to the corresponding Cu(II) complex 3, [Cu(L')2], and N2O in a parallel reaction.

Reaction of a Co(III)-Peroxo Complex and NO: Formation of a Putative Peroxynitrite Intermediate.

A Co(II) complex, [Co(L)2]Cl2, 1 of the ligand L (L = bis(2-ethyl-4-methylimidazol-5-yl)methane) upon reaction with H2O2 in methanol solution at -40 °C resulted in the formation of the corresponding Co(III)-peroxo complex [Co(L)2(O2)]+ (2). The addition of NO gas to the freshly generated solution of the complex 2 led to the formation of the Co(II)-nitrato complex 3 through the putative formation of a Co(II)-peroxynitrite intermediate, 2a. The intermediate 2a was found to mediate the nitration of the externally added phenol resembling the nitration of tyrosine in biological systems.

Dioxygenation Reaction of a Cobalt-Nitrosyl: Putative Formation of a Cobalt-Peroxynitrite via a {CoIII(NO)(O2-)} Intermediate.

A cobalt-nitrosyl complex, [(BPI)Co(NO)(OAc)], 1 {BPI = 1,3-bis(2'-pyridylimino)isoindol} was prepared and characterized. Structural characterization revealed that the cobalt center has a distorted square pyramidal geometry with the NO group coordinated from the apical position in a bent fashion. The addition of dioxygen (O2) to the dichloromethane solution of complex 1 resulted in the formation of nitro complex, [(BPI)Co(NO2)(OAc)], 2. It was characterized structurally. Kinetic studies suggested the involvement of an associative mechanism. FT-IR spectroscopic studies suggested the formation of the intermediate 1a [(BPI)CoIII(NO)(O2-)(OAc)] in the reaction. The intermediate 1a decomposed to complex 2 via a presumed peroxynitrite intermediate which was implicated by its characteristic phenol ring nitration reaction.

Reaction of a Nitrosyl Complex of Cobalt Porphyrin with Hydrogen Peroxide: Putative Formation of Peroxynitrite Intermediate.

The cobalt porphyrin complex [(Cl4TPP)Co], 1, {Cl4TPP = 5,10,15,20-tetrakis(4'-chlorophenyl)porphyrinate dianion} in dichloromethane solution was subjected to react with nitric oxide (NO) gas and resulted in the formation of the corresponding nitrosyl complex [(Cl4TPP)Co(NO)], 2, having {CoNO}8 description. It was characterized by spectroscopic studies and single-crystal X-ray structure determination. It did not react with dioxygen. However, in CH2Cl2/CH3CN solution, it reacted with H2O2 to result in the Co-nitrito complex [(Cl4TPP)Co(NO2)], 3, with the simultaneous release of O2. It induced ring nitration to the added phenol in an appreciable yield. The reaction presumably proceeds through the formation of corresponding Co-peroxynitrite intermediate.

Persistence of acetamiprid in paddy and soil under West Bengal agro-climatic conditions.

Acetamiprid insecticide has been widely used to control paddy insects. In order to find out the dissipation of acetamiprid residues in paddy (variety: Satabdi), field studies were conducted in Nadia, West Bengal. Acetamiprid (20% SP) was applied twice at 10 g (T1), 20 g (T2) and 40 g (T3) a.i. ha-1 with three replications along with untreated control (T4). Residue analysis of acetamiprid in paddy (leaf, grain, husk and straw) and soil was conducted utilizing high-pressure liquid chromatograph (HPLC) with UV detector at LOQ of 0.05 mg kg-1. The recoveries of acetamiprid from fortified paddy sample were obtained in the range of 81.8 to 93.1% (for leaf, grain, husk and straw), and for soil, it was 87.2 to 94.3% at the LOQ level and upper two levels of LOQ. The initial residue of acetamiprid (0.11-0.99 mg kg-1) dissipated following the first-order reaction kinetics with the half-life of 1.5 to 1.8 days in paddy leaf and 1.3 to 1.4 days in soil. In harvested samples of paddy straw, grain and soil, the residue was found below LOQ. Because of the rapid dissipation, acetamiprid may be considered to have low risk to the ecosystem. Therefore, the use of acetamiprid for plant protection in paddy may be considered safe for food and environmental health.

Cu-Based Nanocomposites as Multifunctional Catalysts.

Herein, we report the synthesis of Cu/Cu2 O nanocomposites by a one-step hydrothermal process at 180 °C, for which the resulting morphology is dependent on the hydrothermal reaction time (24, 72, and 120 h). With a longer reaction time of 120 h, a rod-shape morphology is obtained, whereas at 72 and 24 h assemblies of nanoparticles are obtained. The rod-shaped (120 h) particles of the Cu/Cu2 O nanocomposites show a much higher efficiency (6.3 times) than the agglomerates and 2.5 times more than the assemblies of nanoparticles for the hydrogen-evolution reaction. During the oxygen-evolution reaction, the nanorods produce a current that is 5.2 and 3.7 times higher than that produced by the agglomerated and assembled nanoparticles, respectively. The electrocatalysts are shown to be highly stable for over 50 cycles. As catalysts for organic synthesis, a 100 % yield is achieved in the Sonogashira cross-coupling reaction with the nanorods, which is higher than with the other nanocomposite particles. This result demonstrates the significant enhancement of yield obtained with the nanorods for cross-coupling reactions.

Systemic Codelivery of a Homoserine Derived Ceramide Analogue and Curcumin to Tumor Vasculature Inhibits Mouse Tumor Growth.

Prior studies reported significant anticancer activities of ceramides. However, anticancer activities of homoserine based ceramides have not been tested. With a view to compare the anticancer activity of ceramides and homoceramides, in the present study, we have synthesized four serine based and four homoserine based C8-ceramide analogues. Since many cancer cells have shown resistance to ceramides, curcumin is now being used in combination with ceramides because of its ability to reverse multidrug resistance. Aimed at targeting curcumin-ceramide combination to tumor endothelial cells, herein we have used a tumor vasculature targeting liposomes of a newly synthesized pegylated RGDGWK-lipopeptide. Importantly, the liposomal formulations of the homoserine based C8-ceramide analogue containing oleyl chain showed more promising antineoplastic activities under both in vitro and systemic settings than the liposomal formulations of commercially available C8-ceramide. Findings in the mouse tumor growth inhibition study revealed synergistic therapeutic benefit from simultaneous delivery of curcumin and a homoserine based ceramide containing oleyl chain to tumor vasculature. Results in RT-PCR and Western blot experiments suggest that inhibition of solid tumor growth is mediated via inhibition of PI3K-Akt signaling pathway. The present structure-activity study is the first report to demonstrate therapeutic promise of curcumin-homoserine based ceramide combination in antiangiogenic cancer therapy.

Identification and validation of a new male sex-specific ISSR marker in pointed gourd (Trichosanthes dioica Roxb.).

The aim of the present study was to develop a genetic sex marker for the pointed gourd (Trichosanthes dioica Roxb.) to allow gender determination at any stage in the life cycle. Screening of genomic DNA with intersimple sequence repeat (ISSR) primers was used to discover sex-specific touch-down polymerase chain reaction (Td-PCR) amplification products. Using pooled DNA from male and female genotypes and 42 ISSR primers, a putative male specific marker (~550 bp) was identified. DNA marker specific to male is an indication of existence of nonepigenetic factors involved in gender development in pointed gourd. The ISSR technique has proved to be a reliable technique in gender determination of pointed gourd genotypes at the seedling phenophase. The sex marker developed here could also be used as a starting material towards sequence characterization of sex linked genes for better understanding the developmental as well as evolutionary pathways in sexual dimorphism.

Hardness potential derivatives and their relation to Fukui indices.

A simple as well as easy to compute formalism of hardness potential (originally defined by Parr and Gazquez, J. Phys. Chem., 1993, 97, 3939) is presented. Use of hardness potential formally resolves the N-dependence problem of local hardness. However, the hardness potential cannot describe the intra as well as intermolecular reactivity sequence satisfactorily of some chemical systems. The corresponding electrophilic [Δ(+)h(k)] and nucleophilic [Δ(-)h(k)] variants of the hardness potential are also developed, which measure the reactivity toward a nucleophilic (i.e., Nu(-)) and an electrophilic (i.e., El(+)) reagent, respectively. Interestingly, these two variants of the hardness potential lead to the right and left derivatives of Fukui potential. The proposed reactivity descriptors correctly predict the expected reactivity trends in the chosen systems. It has also been illustrated that the values of the variants of hardness potential (or Fukui potential) at the atomic nucleus have the ability to explain the intramolecular reactivity of biologically active indole derivatives. The future scope of applications as well as limitations of the proposed descriptors is also highlighted.

In vivo targeting of a tumor-antigen encoded DNA vaccine to dendritic cells in combination with tumor-selective chemotherapy eradicates established mouse melanoma.

Despite remarkable progress during the past decade, eradication of established tumors by targeted cancer therapy and cancer immunotherapy remains an uphill task. Herein, we report on a combination approach for eradicating established mouse melanoma. Our approach employs the use of tumor selective chemotherapy in combination with in vivo dendritic cell (DC) targeted DNA vaccination. Liposomes of a newly synthesized lipopeptide containing a previously reported tumor-targeting CGKRK-ligand covalently grafted in its polar head-group region were used for tumor selective delivery of cancer therapeutics. Liposomally co-loaded STAT3siRNA and WP1066 (a commercially available inhibitor of the JAK2/STAT3 pathway) were used as cancer therapeutics. In vivo targeting of a melanoma antigen (MART-1) encoded DNA vaccine (p-CMV-MART1) to dendritic cells was accomplished by complexing it with a previously reported mannose-receptor selective in vivo DC-targeting liposome. Liposomes of the CGKRK-lipopeptide containing encapsulated FITC-labeled siRNA, upon intravenous administration in B16F10 melanoma bearing mice, showed remarkably higher accumulation in tumors 24 h post i.v. treatment, compared to their degree of accumulation in other body tissues including the lungs, liver, kidneys, spleen and heart. Importantly, the findings in tumor growth inhibition studies revealed that only in vivo DC-targeted genetic immunization or only tumor-selective chemotherapy using the presently described systems failed to eradicate the established mouse melanoma. The presently described combination approach is expected to find future applications in combating various malignancies (with well-defined surface antigens).