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1.  Theranostic quantum dots for crossing blood–brain barrier in vitro and providing therapy of HIV-associated encephalopathy 
The blood–brain barrier (BBB) is a complex physiological checkpoint that restricts the free diffusion of circulating molecules from the blood into the central nervous system. Delivering of drugs and other active agents across the BBB is one of the major technical challenges faced by scientists and medical practitioners. Therefore, development of novel methodologies to address this challenge holds the key for both the diagnosis and treatment of brain diseases, such as HIV-associated encephalopathy. Bioconjugated quantum dots (QDs) are excellent fluorescent probes and nano-vectors, being designed to transverse across the BBB and visualize drug delivery inside the brain. This paper discusses the use of functionalized QDs for crossing the blood–brain barrier and treating brain disease. We highlight the guidelines for using in vitro BBB models for brain disease studies. The theranostic QDs offers a strategy to significantly improve the effective dosages of drugs to transverse across the BBB and orientate to the targets inside the brain.
PMCID: PMC3828669  PMID: 24298256
theranostic quantum dots; HIV-associated encephalopathy; in vitro blood–brain barrier model; nanomedicine; drug delivery
2.  Near infrared phosphorescent polymeric nanomicelles: efficient optical probes for tumor imaging and detection 
ACS applied materials & interfaces  2009;1(7):1474-1481.
We report a formulation of near infrared (NIR) phosphorescent polymeric nanomicelles and their use for in vivo high contrast optical imaging, targeting and detection of tumors in small animals. NIR phosphorescent molecules of Pt(II)-tetraphenyltetranaphthoporphyrin [Pt(TPNP)] were found to maintain their NIR phosphorescence properties when encapsulated into phospholipid nanomicelles. The prepared phosphorescent micelles are of ~100 nm size and are highly stable in aqueous suspensions. A large spectral separation between Pt(TPNP) absorption, peaked at ~700 nm, and its phosphorescence emission, with peak at ~ 900 nm, allows a dramatic decrease in the level of background autofluorescence and scattered excitation light in the NIR spectral range, where the signal from phosphorescent probe is observed. In vivo animal imaging with subcutaneously xenograted tumor-bearing mice has resulted in high contrast optical images, indicating highly specific accumulation of the phosphorescent micelles into tumors. Using optical imaging with NIR phosphorescent nanomicelles, detection of smaller, visually undetectable tumors has also been demonstrated.
PMCID: PMC3681954  PMID: 20355951
Optical imaging; Near Infra Red (NIR); Phosphorescence; nanomicelles
3.  Synthesis of Luminescent Near-Infrared AgInS2 Nanocrystals as Optical Probes for In Vivo Applications 
Theranostics  2013;3(2):109-115.
Near infrared quantum dots have been receiving great attention as fluorescent optical probes for in vivo imaging applications. In this contribution, we report the synthesis and surface functionalization of cadmium free ternary AgInS2 nanocrystals emitting in the near infrared range for successful in vitro and in vivo bioimaging applications. The FDA approved triblock copolymer Pluronic F127 was used to encapsulate the nanocrystals and made them dispersible in aqueous solution. By employing a whole body small animal optical imaging setup, we were able to use the AgInS2 nanocrystals formulation for passive targeted delivery to the tumor site. The ultra-small crystal size, near-infrared emitting luminescence, and high quantum yield make the AgInS2 nanocrystals an attractive candidate as a biological contrast agent for cancer sensing and imaging.
PMCID: PMC3575591  PMID: 23422953
Near infrared quantum dots; Bioimaging; Surface functionalization; Targeted delivery; Nanotoxicity.
4.  Anti-HIV-1 nanotherapeutics: promises and challenges for the future 
The advent of highly active antiretroviral therapy (HAART) has significantly improved the prognosis for human immunodeficiency virus (HIV)-infected patients, however the adverse side effects associated with prolonged HAART therapy use continue. Although systemic viral load can be undetectable, the virus remains sequestered in anatomically privileged sites within the body. Nanotechnology-based delivery systems are being developed to target the virus within different tissue compartments and are being evaluated for their safety and efficacy. The current review outlines the various nanomaterials that are becoming increasingly used in biomedical applications by virtue of their robustness, safety, multimodality, and multifunctionality. Nanotechnology can revolutionize the field of HIV medicine by not only improving diagnosis, but also by improving delivery of antiretrovirals to targeted regions in the body and by significantly enhancing the efficacy of the currently available antiretroviral medications.
PMCID: PMC3468275  PMID: 23055735
nanotherapeutics; HAART; HIV; nano; nanomedicine; drug delivery
5.  Preparation of Quantum Dot/Drug Nanoparticle Formulations for Traceable Targeted Delivery and Therapy 
Theranostics  2012;2(7):681-694.
Quantum dots (QDs) are luminescent nanocrystals with rich surface chemistry and unique optical properties that make them useful as probes or carriers for traceable targeted delivery and therapy applications. QDs can be functionalized to target specific cells or tissues by conjugating them with targeting ligands. Recent advancement in making biocompatible QD formulations has made these nanocrystals suitable for in vivo applications. This review provides an overview of the preparation of QDs and their use as probes or carriers for traceable, targeted therapy of diseases in vitro and in vivo. More specifically, recent advances in the integration of QDs with drug formulations for therapy and their potential toxicity in vitro and in vivo are highlighted. The current findings and challenges for optimizing QD/drug formulations with respect to optimal size and stability, short-term and long-term toxicity, and in vivo applications are described. Lastly, we attempt to predict key trends in QD/drug formulation development over the next few years and highlight areas of therapy where their use may provide breakthrough results in the near future.
PMCID: PMC3418929  PMID: 22896770
Quantum dots; Drug Nanoparticle Formulations; Targeted Delivery
6.  Bioconjugated Pluronic Triblock-Copolymer Micelle-Encapsulated Quantum Dots for Targeted Imaging of Cancer: In Vitro and In Vivo Studies 
Theranostics  2012;2(7):705-713.
Early in this study, CdTe/ZnS core/shell quantum dots (QDs) were encapsulated in carboxylated Pluronic F127 triblock polymeric micelle, to preserve the optical and colloidal stability of QDs in biological fluids. Folic acid (FA) was then conjugated to the surface of QDs for the targeted delivery of the QD formulation to the tumor site, by exploiting the overexpressed FA receptors (FARs) on the tumor cells. Cytotoxicity study demonstrated that the QD formulation has negligible in vitro toxicity. The in vitro study showed that the bioconjugated micelle-encapsulated QDs, but not the unconjugated QDs, were able to efficiently label Panc-1 cancer cells. In vivo imaging study showed that bioconjugated QDs were able to target tumor site after intravenous injection of the formulation in tumor-bearing mice.
PMCID: PMC3418931  PMID: 22896772
Quantum dots; Targeted delivery; Bioimaging; Bioconjugation; Pluronics and Nanotoxicity.
7.  The Invasion and Reproductive Toxicity of QDs-Transferrin Bioconjugates on Preantral Follicle in vitro 
Theranostics  2012;2(7):734-745.
The toxicity of QD has been extensively studied over the past decade. However, the potential toxicity of QDs impedes its use for clinical research. In this work, we established a preantral follicle in vitro culture system to investigate the effects of QD-Transferrin (QDs-Tf) bioconjugates on follicle development and oocyte maturation. The preantral follicles were cultured and exposed to CdTe/ZnTe QDs-Tf bioconjugates with various concentrations and the reproductive toxicity was assessed at different time points post-treatment. The invasion of QDs-Tf for oocytes was verified by laser scanning confocal microscope. Steroid production was evaluated by immunoassay. C-band Giemsa staining was performed to observe the chromosome abnormality of oocytes. The results showed that the QDs-Tf bioconjugates could permeate into granulosa cells and theca cells, but not into oocyte. There are no obvious changes of oocyte diameter, the mucification of cumulus-oocyte-complexes and the occurrence of aneulpoidy as compared with the control group. However, delay in the antrum formation and decrease in the ratio of oocytes with first polar body were observed in QDs-Tf-treated groups. The matured oocytes with first polar body decreased significantly by ~16% (from 79.6±10 % to 63±2.9 %) when the concentration of QDs-Tf bioconjugates exceeded 2.89 nmol·L-1 (P < 0.05). Our results implied that the CdTe/ZnTe QDs-Tf bioconjugates were reproductive toxic for follicle development, and thus also revealed that this in vitro culture system of preantral follicle is a highly sensitive tool for study on the reproductive toxicity of nanoparticles.
PMCID: PMC3425092  PMID: 22916073
preantral follicle; invasion; reproductive toxicity; in vitro culture system; QDs-transferrin bioconjugate.
8.  Nano-delivery in Airway Diseases: Challenges and Therapeutic Applications 
We discuss here the challenges and therapeutic applications of nano-delivery systems for treatment of airway diseases. Therapeutic applications of nano-delivery in airway diseases involve targeted delivery of DNA, siRNA, drugs or peptides to hematopoietic progenitor cells and pulmonary epithelium to control chronic pathophysiology of obstructive and conformational disorders. The major challenges of nano-delivery involve physiological barriers like mucus and alveolar fluid for intranasal and reticuloendothelial (RES) system for systemic delivery. It is necessary that the nano-particles are biodegradable and capable of providing the sustained drug delivery to the selected cell type. Once inside the cell the nano-particle should be capable of escaping the endocytic degradation machinery. In addition, for effective gene-delivery nuclear entry and chromosomal integration are critical. We have also discussed the strategies to overcome these pathophysiological barriers as an attempt to synchronize the efforts of pulmonary biologists, chemists and clinicians to develop novel nano-delivery therapeutic(s) for airway diseases.
PMCID: PMC2847663  PMID: 19616124
Nano-delivery; Gene Therapy; Drug Delivery; Airway Diseases and Therapeutics
9.  Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein 
Molecular cancer therapeutics  2007;6(3):957-966.
Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemo-radiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists (“XAntag”; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags 1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC50 in the range of 2 to 5 μmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream “effector” caspases (caspase-3 and caspase-7) versus the upstream “initiator” caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation.
PMCID: PMC3062431  PMID: 17339366
10.  In vivo Biodistribution and Clearance Studies using Multimodal ORMOSIL Nanoparticles 
ACS nano  2010;4(2):699-708.
Successful translation of the use of nanoparticles from laboratories to clinics requires exhaustive and elaborate studies involving the biodistribution, clearance and biocompatibility of nanoparticles for in vivo biomedical applications. We report here the use of multimodal organically modified silica (ORMOSIL) nanoparticles for in vivo bioimaging, biodistribution, clearance and toxicity studies. We have synthesized ORMOSIL nanoparticles with diameters of 20-25 nm, conjugated with near infra-red (NIR) fluorophores and radiolabelled them with 124I, for optical and PET imaging in vivo. The biodistribution of the non targeted nanoparticles was studied in non-tumored nude mice by optical fluorescence imaging, as well by measuring the radioactivity from harvested organs. Biodistribution studies showed a greater accumulation of nanoparticles in liver, spleen and stomach than in kidney, heart and lungs. The clearance studies carried out over a period of 15 days indicated hepatobiliary excretion of the nanoparticles. Selected tissues were analyzed for any potential toxicity by histological analysis, which confirmed the absence of any adverse effect or any other abnormalities in the tissues. The results demonstrate that these multimodal nanoparticles have potentially ideal attributes for use as biocompatible probes for in vivo imaging.
PMCID: PMC2827663  PMID: 20088598
ORMOSIL Nanoparticles; optical and PET Imaging; NIR fluorophore; 124I radiolabeling; Biodistribution; clearance and toxicity
11.  Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis 
The mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in CF. The most common mutation, ΔF508-CFTR, is a temperature-sensitive, trafficking mutant with reduced chloride transport and exaggerated immune response. The ΔF508-CFTR is misfolded, ubiquitinated, and prematurely degraded by proteasome mediated- degradation. We recently demonstrated that selective inhibition of proteasomal pathway by the FDA approved drug PS-341 (pyrazylcarbonyl-Phe-Leuboronate, a.k.a. Velcade or bortezomib) ameliorates the inflammatory pathophysiology of CF cells. This proteasomal drug is an extremely potent, stable, reversible and selective inhibitor of chymotryptic threonine protease-activity. The apprehension in considering the proteasome as a therapeutic target is that proteasome inhibitors may affect proteostasis and consecutive processes. The affect on multiple processes can be mitigated by nanoparticle mediated PS-341 lung-delivery resulting in favorable outcome observed in this study.
To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEGPS-341) to provide controlled and sustained drug delivery. The in vitro release kinetics of drug from nanoparticle was quantified by proteasomal activity assay from days 1-7 that showed slow drug release from day 2-7 with maximum inhibition at day 7. For in vivo release kinetics and biodistribution, these drug-loaded nanoparticles were fluorescently labeled, and administered to C57BL6 mice by intranasal route. Whole-body optical imaging of the treated live animals demonstrates efficient delivery of particles to murine lungs, 24 hrs post treatment, followed by biodegradation and release over time, day 1-11. The efficacy of drug release in CF mice (Cftr-/-) lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease) and ability to rescue the Pseudomonas aeruginosa LPS (Pa-LPS) induced inflammation, which demonstrates the rescue of CF lung disease in murine model.
We have developed a novel drug delivery system to provide sustained delivery of CF "correctors" and "anti-inflammatories" to the lungs. Moreover, we demonstrate here the therapeutic efficacy of nano-based proteostasis-modulator to rescue Pa-LPS induced CF lung disease.
PMCID: PMC2954907  PMID: 20868490
12.  MMP-9 gene silencing by a Quantum Dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier 
Brain research  2009;1282:142-155.
The matrix-degrading metalloproteinases (MMPs), particularly MMP-9, are involved in the neuroinflammation processes leading to disrupting of the blood brain barrier (BBB), thereby exacerbating neurological diseases such as HIV-1 AIDS dementia and cerebral ischemia. Nanoparticles have been proposed to act as non-viral gene delivery vectors and have great potential for therapeutic applications in several disease states. In this study, we evaluated the specificity and efficiency of quantum dot (QD) complexed with MMP-9-siRNA (nanoplex) in downregulating the expression of MMP-9 gene in brain microvascular endothelial cells (BMVEC) that constitute the BBB. We hypothesize that silencing MMP-9 gene expression in BMVECs and other cells such as leukocytes may help prevent breakdown of the BBB and inhibit subsequent invasion of the central nervous system (CNS) by infected and inflammatory cells. Our results show that silencing of MMP-9 gene expression resulted in the upregulation of extracellular matrix (ECM) proteins like collagen I, IV, V and a decrease in endothelial permeability, as reflected by reduction of transendothelial resistance across the BBB in a well validated in-vitro BBB model. MMP-9 gene silencing also resulted in an increase in expression of the gene tissue inhibitor of metalloproteinase-1 (TIMP-1). This indicates the importance of a balance between the levels of MMP-9 and its natural inhibitor TIMP-1 in maintaining the basement membrane integrity. These studies promise the application of a novel nanoparticle based siRNA delivery system in modulating the MMP-9 activity in BMVECs and other MMP-9 producing cells. This will prevent neuroinflammation and maintain the integrity of the BBB.
PMCID: PMC2762384  PMID: 19477169
Nanotechnology; siRNA; Nanoplex; Blood Brain Barrier; Matrix metalloproteinases; MMP-9; Quantum Dot; CNS
13.  Enhancing the Delivery of Anti Retroviral Drug “Saquinavir” Across the Blood Brain Barrier Using Nanoparticles 
Current HIV research  2010;8(5):396-404.
Antiretroviral drugs are ineffective at treating viral infection in the brain because they cannot freely diffuse across the blood-brain barrier (BBB). Therefore, HIV-1 viral replication persists in the central nervous system (CNS) and continues to augment the neuropathogenesis process. Nanotechnology can play a pivotal role in HIV-1 therapeutics as it can increase drug solubility, enhance systemic bioavailability, and at the same time offer multifunctionality. Moreover, following conjugation with transferrin (Tf), these drug-loaded nanoformulations can permeate across biological barriers such as the blood brain barrier (BBB) via a receptor mediated transport mechanism. In the current study, we have stably incorporated the antiviral drug, Saquinavir, within Tf-conjugated quantum rods (QRs), which are novel nanoparticles with unique optical properties. We have evaluated the transversing ability of the QR-Tf-Saquinavir nanoformulation across an in vitro model of BBB. In addition, we have analyzed the subsequent antiviral efficacy of this targeted nanoformulation in HIV-1 infected peripheral blood mononuclear cells (PBMCs), which are cultured on the basolateral end of the in vitro BBB model. Our results show a significant uptake of QR-Tf-Saquinavir by brain microvascular endothelial cells (BMVECs), which constitute the BBB. In addition, we observed a significant enhancement in the transversing capability of QR-Tf-Saquinavir across the BBB, along with a marked decrease in HIV-1 viral replication in the PBMCs. These observations indicate that drug-loaded nanoparticles can deliver therapeutics across the BBB. These results highlight the potential of this nanoformulation in the treatment of Neuro-AIDS and other neurological disorders.
PMCID: PMC2904057  PMID: 20426757
HIV-1; antiretroviral drugs; saquinavir; protease inhibitor; quantum rods (QR); blood brain barrier; transferrin receptor; multimodal nanoparticles and bioconjugation
14.  Tumor Targeting and Imaging in Live Animals with Functionalized Semiconductor Quantum Rods 
In this contribution, we demonstrate that highly luminescent CdSe/CdS/ZnS quantum rods (QRs) coated with PEGylated phospholipids and conjugated with cyclic RGD-peptide can be successfully used for tumor targeting and imaging in live animals. The design of these targeted luminescent probes involves encapsulating hydrophobic CdSe/CdS/ZnS QRs with PEGylated phospholipids, followed by conjugation of these PEGylated phospholipids to ligands that specifically target the tumor vasculature. In vivo optical imaging studies in nude mice bearing pancreatic cancer xenografts, both subcutaneous and orthotopic, indicate that the QR probes accumulate at tumor sites via the cyclic RGD-peptides on the QR surface binding to theαVβ3 integrins overexpressed in the tumor vasculature, following systemic injection. In vivo tumor detection studies showed no adverse effects even at a dose roughly 6.5 times higher than has been reported for in vivo imaging studies using QDs. Cytotoxicity studies indicated absence of any toxic effect in the cellular and tissue levels arising from functionalized QRs. These results demonstrate the vast potential of QRs as bright, photostable, and biocompatible luminescent probes for the early diagnosis of cancer.
PMCID: PMC2768400  PMID: 20160901
15.  Imaging Pancreatic Cancer Using Bioconjugated InP Quantum Dots 
ACS nano  2009;3(3):502-510.
In this paper, we report the successful use of non-cadmium based quantum dots (QDs) as highly efficient and non-toxic optical probes for imaging live pancreatic cancer cells. Indium phosphide (core)-zinc sulphide (shell), or InP/ZnS, QDs with high quality and bright luminescence were prepared by a hot colloidal synthesis method in non-aqueous media. The surfaces of these QDs were then functionalized with mercaptosuccinic acid to make them highly dispersible in aqueous media. Further bioconjugation with pancreatic cancer specific monoclonal antibodies, such as anti-claudin 4 and anti-prostate stem cell antigen (anti-PSCA), to the functionalized InP/ZnS QDs, allowed specific in vitro targeting of pancreatic cancer cell lines (both immortalized and low passage ones). The receptor mediated delivery of the bioconjugates was further confirmed by the observation of poor in vitro targeting in non-pancreatic cancer based cell lines which are negative for the claudin-4-receptor. These observations suggest the immense potential of InP/ZnS QDs as non-cadmium based safe and efficient optical imaging nanoprobes in diagnostic imaging, particularly for early detection of cancer.
PMCID: PMC2762404  PMID: 19243145
Quantum dots; Bioconjugates; Bioimaging; Pancreatic Cancer; Targeted Delivery
16.  Multifunctional Nanoparticles as Biocompatible Targeted Probes for Human Cancer Diagnosis and Therapy 
Journal of materials chemistry  2009;19:4655-4672.
The use of nanoparticles in biological application has been rapidly advancing toward practical applications in human cancer diagnosis and therapy. Upon linking the nanoparticles with biomolecules, they can be used to locate cancerous area as well as for traceable drug delivery with high affinity and specificity. In this review, we discuss the engineering of multifunctional nanoparticle probes and their use in bioimaging and nanomedicine.
PMCID: PMC2841409  PMID: 20305738
17.  Metallic Nanostructures as Localized Plasmon Resonance Enhanced Scattering Probes for Multiplex Dark Field Targeted Imaging of Cancer Cells 
In this paper, we report the use of bioconjugated gold nanorods and silver nanoparticles as targeted localized surface plasmon resonance enhanced scattering probes for dark field multiplex and transmission electron microscopy (TEM) imaging of pancreatic cancer cells. We take advantage of the spectrally widely separated localized plasmon resonance of the gold nanorods and silver nanoparticles which produce wavelength selective plasmon resonance scattering to allow multiplex imaging with high contrast. By functionalizing the surfaces, aqueous dispersions of bioconjugated gold nanorods and silver nanoparticles are prepared. We demonstrate receptor-mediated delivery of bioconjugated gold nanorods and silver nanoparticles simultaneously into pancreatic cancer cells, using multiplexed dark field microscopy technique. We also show that the bioconjugated metallic nanostructures can be used for high contrast TEM imaging as well.
PMCID: PMC2717617  PMID: 20046993
18.  Zinc Oxide Nanocrystals for Non-resonant Nonlinear Optical Microscopy in Biology and Medicine 
In this paper we show that biocompatible zinc oxide (ZnO) nanocrystals (NCs) having non-centrosymmetric structure can be used as non-resonant nonlinear optical probes for targeting in bioimaging applications in vitro by use of the second order processes of second harmonic and sum frequency generation, as well as the third order process of four wave mixing. These non-resonant processes provide advantages above and beyond traditional two-photon bioimaging: (i) the probes do not photo-bleach; (ii) the input wavelength can be judiciously selected; and (iii) no heat is dissipated into the cells, ensuring longer cell viability and ultimately longer imaging times. ZnO NCs have been synthesized in organic media by using a non-hydrolytic sol-gel process, and subsequently dispersed in aqueous media using phospholipid micelles, and incorporated with the biotargeting molecule folic acid (FA). Sum Frequency, Second Harmonic and non-resonant four wave mixing non-linear signals from this stable dispersion of ZnO NCs, targeted to the live tumor (KB) cells were used for imaging. Robust intracellular accumulation of the targeted (FA incorporated) ZnO nanocrystals could be observed, without any indication of cytotoxicity.
PMCID: PMC2685283  PMID: 19633706
19.  Non-viral gene transfection nanoparticles: Function and applications in brain 
In vivo transfer and expression of foreign genes allows for the elucidation of functions of genes in living organisms and generation of disease models in animals that more closely resemble the etiology of human diseases. Gene therapy holds promise for the cure of a number of diseases at the fundamental level. Synthetic ‘non-viral’ materials are fast gaining popularity as safe and efficient vectors for delivering genes to target organs. Nanoparticles can not only function as efficient gene carriers, but also simultaneously carry diagnostic probes for direct ‘real-time’ visualization of gene transfer and downstream processes. This review has focused on the central nervous system (CNS) as the target for non-viral gene transfer, with special emphasis on organically modified silica nanoparticles (ORMOSIL) developed in our laboratory. These nanoparticles have shown robust gene transfer efficiency in brain cells in vivo and allowed to investigate mechanisms that control neurogenesis as well as neurodegenerative disorders.
PMCID: PMC2597487  PMID: 18313990
Gene therapy; Non-viral vectors; Nanoparticles; Central nervous system; ORMOSIL
20.  Biocompatible Luminescent Silicon Quantum Dots for Imaging of Cancer Cells 
ACS nano  2008;2(5):873-878.
Luminescent silicon quantum dots (Si QDs) have great potential for use in biological imaging and diagnostic applications. To exploit this potential, they must remain luminescent and stably dispersed in water and biological fluids over a wide range of pH and salt concentration. There have been many challenges in creating such stable water-dispersible Si QDs, including instability of photoluminescence due their fast oxidation in aqueous environments and the difficulty of attaching hydrophilic molecules to Si QD surfaces. In this paper, we report the preparation of highly stable aqueous suspensions of Si QDs using phospholipid micelles, in which the optical properties of Si nanocrystals are retained. These luminescent micelle-encapsulated Si QDs were used as luminescent labels for pancreatic cancer cells. This paves the way for silicon quantum dots to be a valuable optical probe in biomedical diagnostics.
PMCID: PMC2676166  PMID: 19206483
silicon; quantum dot; nanocrystal; micelle encapsulation; in vitro imaging
21.  A New Method for Delivering a Hydrophobic Drug for Photodynamic Therapy Using Pure Nanocrystal Form of the Drug 
Molecular pharmaceutics  2007;4(2):289-297.
A carrier free method for delivery of a hydrophobic drug in its pure form, using nanocrystals (nano sized crystals) is proposed. To demonstrate this technique, nanocrystals of a hydrophobic photosensitizing anticancer drug 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide (HPPH), have been synthesized using re-precipitation method. The resulting drug nanocrystals were monodispersed and stable in aqueous dispersion, without the necessity of an additional stabilizer (surfactant). As shown by confocal microscopy, these pure drug nanocrystals were taken-up by the cancer cells with high avidity. Though the fluorescence and photodynamic activity of the drug were substantially quenched in the form of nanocrystals in aqueous suspension, both these characteristics were recovered under in vitro and in vivo conditions. This recovery of drug activity and fluorescence is possibly due to the interaction of nanocrystals with serum albumin, resulting in conversion of the drug nanocrystals into the molecular form. This was confirmed by demonstrating similar recovery in presence of Fetal Bovine Serum (FBS) or Bovine Serum Albumin (BSA). Under similar treatment conditions, the HPPH in nanocrystal form or in 1% Tween 80/water formulation showed comparable in vitro and in vivo efficacy.
PMCID: PMC2667689  PMID: 17266331
nanocrystals; re-precipitation method; photosensitizers; photodynamic therapy; singlet oxygen; drug delivery
22.  Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer 
Bioorganic & medicinal chemistry  2008;16(6):2764-2768.
A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2 h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer.
PMCID: PMC2666345  PMID: 18249125
PSA; Cyclopamine; Prodrug; Hedgehog signaling; Peptides

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