Efficacy and toxicity of the DPCPX nanoconjugate drug study for the treatment of spinal cord injury in rats.

Effects of the Adenosine A1 blockade using 8-cyclopentyl-1,3-diprophyxanthine (DPCPX) nanoconjugate on inducing recovery of the hemidiaphragm paralyzed by hemisection have been thoroughly examined previously; however, the toxicology of DPCPX nanoconjugate remains unknown. This research study investigates the therapeutic efficacy and toxicology of the nanoconjugate DPCPX in the cervical spinal cord injury (SCI) rat model. We hypothesized that a single injection of nanoconjugate DPCPX in the paralyzed left hemidiaphragm (LDH) of hemisected rats at the 2nd cervical segment (C2Hx) would lead to the long-term recovery of LDH while showing minimal toxicity. Adult male rats underwent left C2Hx surgery and the diaphragms' baseline electromyography (EMG). Subsequently, rats were randomized into a control group and four treated subgroups. Three subgroups received a single intradiaphragmatic dose of either 0.09, 0.15, or 0.27 µg/kg, and one subgroup received 0.1 mg/kg of native DPCPX two times per day intravenously (i.v.) for 3 days (total 0.6 mg/kg). Rats were monitored for a total of 56 days. Compared with control, the treatment with nanoconjugate DPCPX at 0.09 µg/kg, 0.15 µg/kg, and 0.27 µg/kg doses elicited significant recovery of paralyzed LDH (i.e., 67% recovery at 8 wk) (P < 0.05). DPCPX nanoconjugate-treated rats had significant weight loss for first 2 wk but recovered significantly by day 56 (P < 0.05). The levels of gold in the blood and body tissues were below the recommended levels. No sign of weakness, histology of tissue damage, or organ abnormality was observed. A dose of DPCPX nanoconjugate can induce long-term diaphragm recovery after SCI without observed toxicity.NEW & NOTEWORTHY The intradiaphragmatic administration of nanoconjugate is safe and has the promise to significantly reduce the therapeutic dosage for the treatment and achieve long-term and possibly permanent recovery in respiratory muscle dysfunction after SCI. No toxicity of nanoconjugate was found in any of the experimental animals.

N-acetylcysteine-PLGA nano-conjugate: effects on cellular toxicity and uptake of gadopentate dimeglumine.

Gadolinium as a contrast agent in MRI technique combined with DTPA causes contrast induced nephropathy (CIN) and nephrogenic systemic fibrosis (NSF) which can reduce by usage of antioxidants such as N-acetyl cysteine by increasing the membrane's permeability leads to lower cytotoxicity. In this study, N-acetyl cysteine-PLGA Nano-conjugate was synthesized according to stoichiometric rules of molar ratios andafter assessment by FTIR, NMR spectroscopy and Atomic Force Microscopy (AFM) imaging was combined with Magnevist® (gadopentetate dimeglumine) and its effects on the renal cells were evaluated. MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] and cellular uptake assays have indicated relatively significant toxicity of magnevist (P < 0.05) on three cell lines including HEK293, MCF7 and L929 compared to other synthesized ligands that shown no toxicity. Moreover, systemic evaluation has shown no notable changes of blood urea nitrogen (BUN) and creatinine in kidney of mice. In consequence, antioxidant effect was increased as well as the renal toxicity of the contrast agent reduced at the cell level. As a result, PLGA-NAC nano-conjugate can be a promising choice for decreasing the magnevist toxicity for treatment and prevention of CIN and will be able to open a new horizon to research on reduction of toxicity of contrast agents by using nanoparticles.

Polydopamine -aminoglycoside nanoconjugates: Synthesis, characterization, antimicrobial evaluation and cytocompatibility.

Development of nanoparticle- and self-assembled nanomaterial-based therapeutics has become a rapidly growing area in the field of nanotechnology. One of the natural compounds, dopamine, presents as a neurotransmitter in the human brain serving as a messenger and deals with the behavioural responses, has provided an ideal platform through self-polymerization under aerobic conditions leading to the formation of a beneficial organic biopolymer, polydopamine (PDA). This polymer provides sufficient reactive functionalities, which can further be use to attach amine- or thiol-containing ligands to obtain conjugates. In the present study, self-polymerized polydopamine nanoparticles have been synthesized and tethered to aminoglycosides (AGs: Gentamicin, Kanamycin and Neomycin) through amino moieties to obtain PDA-AG nanoconjugates. These nanoconjugates are characterized by physicochemical techniques and evaluated for their antimicrobial potency against various bacterial strains including resistant ones. Simultaneously, cytocompatibility was also assessed for PDA-AG nanoconjugates. Of these three nanoconjugates (PDA-Gentamicin, PDA-Kanamycin and PDA-Neomycin), PDA-Kanamycin (PDA-K) nanoconjugate exhibited the highest activity against potent pathogens, least toxicity in human embryonic kidney (HEK 293) cells and intense toxic effects on human glioblastoma (U87) cells. Together, these results advocate the promising potential of these nanoconjugates to be used as potent antimicrobials in future applications.

Light-activated drug release from a hyaluronic acid targeted nanoconjugate for cancer therapy.

Hyaluronic acid (HA)-based nanocarriers are of great interest in the drug delivery field due to the tumor targetability via CD44-mediated recognition and endocytosis. However, sufficient tumor-specific release of encapsulated cargoes with steady controllability is necessary to optimize their outcome for cancer therapy. In this study, we constructed a light-activated nanocarrier TKHCENPDOX to enable on-demand drug release at the desired site (tumor). Particularly, TKHCENPDOX encapsulating doxorubicin (DOX) was self-assembled from a HA-photosensitizer conjugate (HA-TK-Ce6) containing reactive oxygen species (ROS)-sensitive thioketal (TK) linkers. Following i.v. injection, TKHCENPDOX was accumulated in the MDA-MB-231 breast tumor xenograft more efficiently through preventing drug leakage in the bloodstream and the HA-mediated targeting effect. Upon internalization into tumoral cells, 660 nm laser irradiation generated ROS during a photodynamic (PDT) process to cleave the TK linker next to Ce6, resulting in light-induced TKHCENPDOX dissociation and selective DOX release in the tumor area. Consequently, TKHCENPDOX showed a remarkable therapeutic effect and minimized toxicity in vivo. This strategy might provide new insight for designing cancer-selective nanoplatforms with active targeting and locoregional drug release simultaneously.

ß-cyclodextrin based dual-responsive multifunctional nanotheranostics for cancer cell targeting and dual drug delivery.

Multifunctional nanoconjugates possessing an assortment of key functionalities such as magnetism, florescence, cell-targeting, pH and thermo-responsive features were developed for dual drug delivery. The novelty lies in careful conjugation of each of the functionality with magnetic Fe3O4 nanoparticles by virtue of urethane linkages instead of silica in a simple one pot synthesis. Further ß-cyclodextrin (CD) was utilized to carry hydrophobic as well as hydrophilic drug. Superlative release of DOX could be obtained under acidic pH conditions and elevated temperature, which coincides with the tumor microenvironment. Mathematical modelling studies revealed that the drug release kinetics followed diffusion mechanism for both hydrophobic drug and hydrophilic drug. A number of fluorophores onto a single nanoparticle produced a strong fluorescence signal to optically track the nanoconjugates. Enhanced internalization due to folate specificity could be observed by fluorescence imaging. Further their accumulation driven by magnet near tumor site led to magnetic hyperthermia. in vitro studies confirmed the nontoxicity and hemocompatibility of the nanoconjugates. Remarkable cell death was observed with drug-loaded nanoconjugates at very low concentrations in cancer cells. The internalization and cellular uptake of poor bioavailable anticancer agent curcumin were found to be remarkably enhanced on dosing the drug loaded nanoconjugates as compared to free curcumin. Site specific drug delivery due to folate conjugation and subsequent significant suppression in tumor growth was demonstrated by in vivo studies.

ATP-Responsive Low-Molecular-Weight Polyethylenimine-Based Supramolecular Assembly via Host-Guest Interaction for Gene Delivery.

In this work, we report on an ATP-responsive low-molecular-weight polyethylenimine (LMW-PEI)-based supramolecular assembly. It formed via host-guest interaction between PEI (MW = 1.8 kDa)-α-cyclodextrin (α-CD) conjugates and PEI1.8k-phenylboronic acid (PBA) conjugates. The host-guest interaction between PEI1.8k-α-CD and PEI1.8k-PBA was confirmed by the 2D-NOESY chromatogram experiment and competition test. The ATP-responsive property of the supramolecular assembly was evaluated by a series of ATP-triggered degradation and siRNA release studies in terms of fluorescence resonance energy transfer, agarose gel electrophoresis assay, and the time course monitoring of the particle size and morphology. Confocal laser scanning microscopy confirmed the intracellular disassembly of the supramolecular polymer and the release of siRNA. The supramolecular assembly showed high buffering capability and was capable of protecting siRNA from RNase degradation. It had high cytocompatibility according to in vitro cytotoxicity and hemolysis assays. LMW-PEI-based supramolecular assembly facilitated cellular entry of siRNA via energy-dependent endocytosis. Moreover, the assembly/SR-A siRNA polyplexes at N/P ratio of 30 was most effective in knocking down SR-A mRNA and inhibiting uptake of modified LDL. Taken together, this work shows that ATP-responsive LMW-PEI-based supramolecular assembly is a promising gene vector and has potential application in treating atherosclerosis.

Ultrasensitive "FRET-SEF" Probe for Sensing and Imaging MicroRNAs in Living Cells Based on Gold Nanoconjugates.

MicroRNAs (miRNAs), a kind of single-stranded small RNA molecule, play significant roles in the physiological and pathological processes of human beings. Currently, miRNAs have been demonstrated as important biomarkers critically related to many diseases and life nature, including several cancers and cell senescence. It is valuable to establish sensitive assays for monitoring the levels of intracellular up-regulated/down-regulated miRNA expression, which would contribute to the early prediction of the tumor risk and cardiovascular disease. Here, an oriented gold nanocross (AuNC)-decorated gold nanorod (AuNR) probe with "OFF-enhanced ON" fluorescence switching was developed based on fluorescence resonance energy transfer and surface enhanced fluorescence (FRET-SEF) principle. The nanoprobe was used to specifically detect miRNA in vitro, which gave two linear responses represented by the equation F = 1830.32 log C + 6349.27, R2 = 0.9901, and F = 244.41 log C + 1916.10, R2 = 0.9984, respectively, along with a detection limit of 0.5 aM and 0.03 fM, respectively. Furthermore, our nanoprobe was used to dynamically monitor the expression of intracellular up-regulated miRNA-34a from the HepG2 and H9C2 cells stimulated by AFB1 and TGF-ß1, and the experimental results showed that the new probe not only could be used to quantitively evaluate miRNA oncogene in vitro, but also enabled tracking and imaging of miRNAs in living cells.

Selective uptake of epidermal growth factor-conjugated gold nanoparticle (EGF-GNP) facilitates non-thermal plasma (NTP)-mediated cell death.

Non-thermal atmospheric pressure plasma (NTP) has been shown to induce cell death in various mammalian cancer cells. Accumulated evidence also shows that NTP could be clinically used in cancer therapy. However, the current NTP-based applications lack target specificity. Here, a novel method in NTP-mediated cancer therapeutics was described with enhanced target specificity by treating EGF (epidermal growth factor)-conjugated GNP (gold nanoparticle). The treatment with EGF-conjugated GNP complex, followed by NTP irradiation showed selective apoptosis of cells having receptor-mediated endocytosis. NTP triggered γ-H2AX elevation which is a typical response elicited by DNA damage. These results suggest that EGF-conjugated GNP functions as an important adjuvant which gives target specificity in applications of conventional plasma therapy.

Surface biofunctionalized CdS and ZnS quantum dot nanoconjugates for nanomedicine and oncology: to be or not to be nanotoxic?

Herein, for the first time, we demonstrated that novel biofunctionalized semiconductor nanomaterials made of Cd-containing fluorescent quantum dot nanoconjugates with the surface capped by an aminopolysaccharide are not biologically safe for clinical applications. Conversely, the ZnS-based nanoconjugates proved to be noncytotoxic, considering all the parameters investigated. The results of in vitro cytotoxicity were remarkably dependent on the chemical composition of quantum dot (CdS or ZnS), the nature of the cell (human cancerous and embryonic types), and the concentration and time period of exposure to these nanomaterials, caused by the effects of Cd2+ on the complex nanotoxicity pathways involved in cellular uptake. Unexpectedly, no decisive evidence of nanotoxicity of CdS and ZnS conjugates was observed in vivo using intravenous injections in BALB/c mice for 30 days, with minor localized fluorescence detected in liver tissue specimens. Therefore, these results proved that CdS nanoconjugates could pose an excessive threat for clinical applications due to unpredicted and uncorrelated in vitro and in vivo responses caused by highly toxic cadmium ions at biointerfaces. On the contrary, ZnS nanoconjugates proved that the "safe by design" concept used in this research (ie, biocompatible core-shell nanostructures) could benefit a plethora of applications in nanomedicine and oncology.

Effect of poly-glutamate on uptake efficiency and cytotoxicity of cell penetrating peptides.

Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various molecules. An ideal CPP-peptide should not display any toxicity against cancer cells as well as healthy cells and efficiently enter into the cell. Because of the cationic nature and the intrinsic vector capabilities, these peptides can cause cytotoxicity. One of the possible reasons for toxicity of CPPs is direct translocation and consequently, pore formation on the plasma membrane. In this study it was demonstrated that interaction of poly-glutamate with CPP considerably reduced their cytotoxicity in A549 cell. This strategy could be useful for efficient drug delivery mediated by CPP.

Nanoparticles based on phenylalanine ethyl ester-alginate conjugate as vitamin B2 delivery system.

Phenylalanine ethyl ester (PAE)-alginate (Alg) conjugate (PAE-Alg, PEA) was synthesized and formation of an amide bond between PAE and Alg was confirmed by Fourier transformed-infrared and (1)H nuclear magnetic resonance spectroscopy. The degree of PAE substitution was 3.5-4.7 (PAE group per hundred sugar residues of Alg) which was determined by elemental analysis. The critical aggregation concentration values determined for PEA conjugates PEA1, PEA2, and PEA3 were 0.20, 0.12, and 0.10 mg/ml, respectively. The particle size of PEA nanoparticles (PEA-NPs) decreased from 425 nm to 226 nm with the increasing degree of PAE substitution. Vitamin B2 (VB2), as a model nutrient, was encapsulated into the nanoparticles. The drug-loading content increased with increasing degree of PAE substitution. The maximum VB2 loading capacity and loading efficiency of PEA3 nanoparticles were 3.53 ± 0.03% and 91.48 ± 0.80%, respectively. The in vitro release behavior of VB2 from the PEA-NPs showed a biphasic release profile with an initial burst release of about 40-50% of VB2 in the first 10 h followed by a steady and continuous release phase for the following 50 h in PBS, pH 7.4. The human colorectal carcinoma cell line was used to investigate the cytotoxicity of PEA-NPs. Our results showed that various concentrations of nanoparticles did not cause significant cytotoxicity against cell lines at normal concentrations.

Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy.

An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin-polylactide (Doxo-PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt-functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis.

Preparation of poly(ß-L-malic acid)-based charge-conversional nanoconjugates for tumor-specific uptake and cellular delivery.

In this study, a multifunctional poly(ß-L-malic acid)-based nanoconjugate with a pH-dependent charge conversional characteristic was developed for tumor-specific drug delivery. The short branched polyethylenimine-modified poly(ß-L-malic acid) (PEPM) was first synthesized. Then, the fragment HAb18 F(ab')2 and 2,3-dimethylmaleic anhydride were covalently attached to the PEPM to form the nanoconjugate, HDPEPM. In this nanoconjugate, the 2,3-dimethylmaleic anhydride, the shielding group, could shield the positive charge of the conjugate at pH 7.4, while it was selectively hydrolyzed in the tumor extracellular space (pH 6.8) to expose the previously-shielded positive charge. To study the anticancer activity, the anticancer drug, doxorubicin, was covalently attached to the nanoconjugate. The doxorubicin-loaded HDPEPM nanoconjugate was able to efficiently undergo a quick charge conversion from -11.62 mV to 9.04 mV in response to the tumor extracellular pH. The electrostatic interaction between the positively charged HDPEPM nanoconjugates and the negatively charged cell membrane significantly enhanced their cellular uptake, resulting in the enhanced anticancer activity. Also, the tumor targetability of the nanoconjugates could be further improved via the fragment HAb18 F(ab')2 ligand-receptor-mediated tumor cell-specific endocytosis.

Mechanism of multivalent nanoparticle encounter with HIV-1 for potency enhancement of peptide triazole virus inactivation.

Entry of HIV-1 into host cells remains a compelling yet elusive target for developing agents to prevent infection. A peptide triazole (PT) class of entry inhibitor has previously been shown to bind to HIV-1 gp120, suppress interactions of the Env protein at host cell receptor binding sites, inhibit cell infection, and cause envelope spike protein breakdown, including gp120 shedding and, for some variants, virus membrane lysis. We found that gold nanoparticle-conjugated forms of peptide triazoles (AuNP-PT) exhibit substantially more potent antiviral effects against HIV-1 than corresponding peptide triazoles alone. Here, we sought to reveal the mechanism of potency enhancement underlying nanoparticle conjugate function. We found that altering the physical properties of the nanoparticle conjugate, by increasing the AuNP diameter and/or the density of PT conjugated on the AuNP surface, enhanced potency of infection inhibition to impressive picomolar levels. Further, compared with unconjugated PT, AuNP-PT was less susceptible to reduction of antiviral potency when the density of PT-competent Env spikes on the virus was reduced by incorporating a peptide-resistant mutant gp120. We conclude that potency enhancement of virolytic activity and corresponding irreversible HIV-1 inactivation of PTs upon AuNP conjugation derives from multivalent contact between the nanoconjugates and metastable Env spikes on the HIV-1 virus. The findings reveal that multispike engagement can exploit the metastability built into virus the envelope to irreversibly inactivate HIV-1 and provide a conceptual platform to design nanoparticle-based antiviral agents for HIV-1 specifically and putatively for metastable enveloped viruses generally.

Covalent IR820-PEG-diamine nanoconjugates for theranostic applications in cancer.

Near-infrared dyes can be used as theranostic agents in cancer management, based on their optical imaging and localized hyperthermia capabilities. However, their clinical translatability is limited by issues such as photobleaching, short circulation times, and nonspecific biodistribution. Nanoconjugate formulations of cyanine dyes, such as IR820, may be able to overcome some of these limitations. We covalently conjugated IR820 with 6 kDa polyethylene glycol (PEG)-diamine to create a nanoconjugate (IRPDcov) with potential for in vivo applications. The conjugation process resulted in nearly spherical, uniformly distributed nanoparticles of approximately 150 nm diameter and zeta potential -0.4±0.3 mV. The IRPDcov formulation retained the ability to fluoresce and to cause hyperthermia-mediated cell-growth inhibition, with enhanced internalization and significantly enhanced cytotoxic hyperthermia effects in cancer cells compared with free dye. Additionally, IRPDcov demonstrated a significantly longer (P<0.05) plasma half-life, elimination half-life, and area under the curve (AUC) value compared with IR820, indicating larger overall exposure to the theranostic agent in mice. The IRPDcov conjugate had different organ localization than did free IR820, with potential reduced accumulation in the kidneys and significantly lower (P<0.05) accumulation in the lungs. Some potential advantages of IR820-PEG-diamine nanoconjugates may include passive targeting of tumor tissue through the enhanced permeability and retention effect, prolonged circulation times resulting in increased windows for combined diagnosis and therapy, and further opportunities for functionalization, targeting, and customization. The conjugation of PEG-diamine with a near-infrared dye provides a multifunctional delivery vector whose localization can be monitored with noninvasive techniques and that may also serve for guided hyperthermia cancer treatments.

Surface coating-dependent cytotoxicity and degradation of graphene derivatives: towards the design of non-toxic, degradable nano-graphene.

With the increasing interests of using graphene and its derivatives in the area of biomedicine, the systematic evaluation of their potential risks and impacts to biological systems is becoming critically important. In this work, we carefully study how surface coatings affect the cytotoxicity and extracellular biodegradation behaviors of graphene oxide (GO) and its derivatives. Although naked GO could induce significant toxicity to macrophages, coating those two-dimensional nanomaterials with biocompatible macromolecules such as polyethylene glycol (PEG) or bovine serum albumin (BSA) could greatly attenuate their toxicity, as independently evidenced by several different assay approaches. On the other hand, although GO can be gradually degraded through enzyme induced oxidization by horseradish peroxidase (HRP), both PEG and BSA coated GO or reduced GO (RGO) are rather resistant to HRP-induced biodegradation. In order to obtain biocompatible functionalized GO that can still undergo enzymatic degradation, we conjugate PEG to GO via a cleavable disulfide bond, obtaining GO-SS-PEG with negligible toxicity and considerable degradability, promising for further biomedical applications.

Hyaluronan-cisplatin conjugate nanoparticles embedded in Eudragit S100-coated pectin/alginate microbeads for colon drug delivery.

Hyaluronan-cisplatin conjugate nanoparticles (HCNPs) were chosen as colon-targeting drug-delivery carriers due to the observation that a variety of malignant tumors overexpress hyaluronan receptors. HCNPs were prepared by mixing cisplatin with a hyaluronan solution, followed by dialysis to remove trace elements. The cells treated with HCNPs showed significantly lower viability than those treated with cisplatin alone. HCNPs were entrapped in Eudragit S100-coated pectinate/alginate microbeads (PAMs) by using an electrospray method and a polyelectrolyte multilayer-coating technique in aqueous solution. The release profile of HCNPs from Eudragit S100-coated HCNP-PAMs was pH-dependent. The percentage of 24-hour drug release was approximately 25.1% and 39.7% in pH 1.2 and pH 4.5 media, respectively. However, the percentage of drug released quickly rose to 75.6% at pH 7.4. Moreover, the result of an in vivo nephrotoxicity study demonstrated that Eudragit S100-coated HCNP-PAMs treatment could mitigate the nephrotoxicity that resulted from cisplatin. From these results, it can be concluded that Eudragit S100-coated HCNP-PAMs are promising carriers for colon-specific drug delivery.

Enzyme-activated nanoconjugates for tunable release of doxorubicin in hepatic cancer cells.

We report the synthesis of a series of aromatic azo-linkers (L1-L4), which are selectively recognized and cleaved by azoreductase enzymes present in the cytoplasm of hepatic cancer cells via a NADPH-dependent mechanism. We utilized L1-L4 azo-linkers to conjugate doxorubicin to generation 5 (G5) of poly(amidoamine) dendrimers to prepare G5-L(x)-DOX nanoconjugates. We incorporated electron-donating oxygen (O) or nitrogen (N) groups in the para and ortho positions of L1-L4 azo-linkers to control the electronegativity of G5-L(x)-DOX conjugates and investigated their cleavage by azoreductase enzymes and the associated release of loaded DOX molecules. Hammett σ values of G5-L(x)-DOX conjugates ranged from -0.44 to -1.27, which is below the reported σ threshold (-0.37) required for binding to azoreductase enzymes. Results show that incubation of G5-L1-DOX (σ = -0.44), G5-L2-DOX (σ = -0.71), G5-L3-DOX (σ = -1.00), and G5-L4-DOX (σ = -1.27) conjugates with human liver microsomal (HLM) enzymes and the S9 fraction isolated from HepG2 hepatic cancer cells results in release of 4%-8%, 17%, 60%, and 100% of the conjugated DOX molecules, respectively. These results show that increasing the electronegativity (i.e. lower σ value) of L1-L4 azo-linkers increases their susceptibility to cleavage by azoreductase enzymes. Intracellular cleavage of G5-L(x)-DOX nanoconjugates, release of conjugated DOX molecules, and cytotoxicity correlated with conjugate's electronegativity (σ value) was investigated, with G5-L4-DOX conjugate exhibiting the highest toxicity towards hepatic cancer cells with an IC50 of 13 nm ± 5 nm in HepG2 cells. Cleavage of G5-L(x)-DOX conjugates was specific to hepatic cancer cells as shown by low non-specific DOX release upon incubation with non-enzymatic insect proteins and the S9 fraction isolated from rat cardiomyocytes. These enzyme-activated G5-L(x)-DOX conjugates represent a drug delivery platform that can achieve tunable and cell-specific release of the loaded cargo in hepatic cancer cells.

Separately doped upconversion-C60 nanoplatform for NIR imaging-guided photodynamic therapy of cancer cells.

A highly efficient upconversion-C60 nanoplatform was demonstrated for NIR imaging-guided photodynamic therapy of cancer.

Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer's disease.

Alzheimer's disease is a growing concern in the modern world. As the currently available medications are not very promising, there is an increased need for the fabrication of newer drugs. Curcumin is a plant derived compound which has potential activities beneficial for the treatment of Alzheimer's disease. Anti-amyloid activity and anti-oxidant activity of curcumin is highly beneficial for the treatment of Alzheimer's disease. The insolubility of curcumin in water restricts its use to a great extend, which can be overcome by the synthesis of curcumin nanoparticles. In our work, we have successfully synthesized water-soluble PLGA coated- curcumin nanoparticles and characterized it using different techniques. As drug targeting to diseases of cerebral origin are difficult due to the stringency of blood-brain barrier, we have coupled the nanoparticle with Tet-1 peptide, which has the affinity to neurons and possess retrograde transportation properties. Our results suggest that curcumin encapsulated-PLGA nanoparticles are able to destroy amyloid aggregates, exhibit anti-oxidative property and are non-cytotoxic. The encapsulation of the curcumin in PLGA does not destroy its inherent properties and so, the PLGA-curcumin nanoparticles can be used as a drug with multiple functions in treating Alzheimer's disease proving it to be a potential therapeutic tool against this dreaded disease.