Synthesis and characterization of a novel pH-responsive drug-releasing nanocomposite hydrogel for skin cancer therapy and wound healing.

Local skin cancer recurrence occurs in ∼12% of the patients post-surgery due to persistent growth of residual cancer cells. Wound infection is another significant complication following surgery. We report a novel in situ-forming nanocomposite hydrogel (NCH) containing PLGA-carboxymethyl chitosan nanoparticles (186 nm) for localized pH-responsive skin cancer therapy and wound healing. This injectable hydrogel, comprising of a citric acid-derived polymer backbone, gelled within 5 minutes, and demonstrated excellent swelling (283% of dry weight) and compressive strengths (∼5.34 MPa). Nanoparticle incorporation did not significantly affect hydrogel properties. The NCH effluents were cytocompatible with human dermal fibroblasts at 500 µg ml-1 concentration and demonstrated pH-dependent drug release and promising therapeutic efficacy against A431 and G361 skin cancer cells in vitro. Significant zones of inhibition were observed in S. aureus and E. coli cultures on NCH treatment, confirming its antibacterial properties. Our studies show that the pH-responsive NCH can be potentially used for adjuvant skin cancer treatment and wound healing.

Pulsed focused ultrasound lowers interstitial fluid pressure and increases nanoparticle delivery and penetration in head and neck squamous cell carcinoma xenograft tumors.

Nanocarriers offer a promising approach to significantly improve therapeutic delivery to solid tumors as well as limit the side effects associated with anti-cancer agents. However, their relatively large size can negatively affect their ability to efficiently penetrate into more interior tumor regions, ultimately reducing therapeutic efficacy. Poor penetration of large agents such as nanocarriers is attributed to factors in the tumor microenvironment such as elevated interstitial fluid pressure (IFP) and fibrillar collagen in the extracellular matrix. Our previous studies reported that pretreatment of solid tumor xenografts with nondestructive pulsed focused ultrasound (pFUS) can improve the delivery and subsequent therapy of a variety of therapeutic formulations in different tumor models, where the results were associated with expanded extracellular spaces (ECS), an increase in hydraulic conductivity, and decrease in tissue stiffness. Here, we demonstrate the inverse relationship between IFP and the penetration of systemically administered nanoparticle (NP) probes, where IFP increased from the tumor periphery to their center. Furthermore, we show that pretreatment with pFUS can safely reduce IFP and improve NP delivery; especially into the center of the tumors. These results coincide with effects generated in the fibrillar collagen network microstructure in the ECS as determined by quantitative polarized light microscopy. Whole tumor and histomorphometric analysis, however, did not show significant differences in collagen area fraction or collagen feature solidity, as well as tumor cross-sectional area and aspect ratio, as a result of the treatments. We present a biophysical model connecting the experimental results, where pFUS-mediated cytoarchitectural changes are associated with improved redistribution of the interstitial fluid and lower IFP. The resulting improvement in NP delivery supports our previous therapeutic studies and may have implications for clinical applications to improve therapeutic outcomes in cancer therapy.

Decreased nonspecific adhesivity, receptor-targeted therapeutic nanoparticles for primary and metastatic breast cancer.

Development of effective tumor cell-targeted nanodrug formulations has been quite challenging, as many nanocarriers and targeting moieties exhibit nonspecific binding to cellular, extracellular, and intravascular components. We have developed a therapeutic nanoparticle formulation approach that balances cell surface receptor-specific binding affinity while maintaining minimal interactions with blood and tumor tissue components (termed "DART" nanoparticles), thereby improving blood circulation time, biodistribution, and tumor cell-specific uptake. Here, we report that paclitaxel (PTX)-DART nanoparticles directed to the cell surface receptor fibroblast growth factor-inducible 14 (Fn14) outperformed both the corresponding PTX-loaded, nontargeted nanoparticles and Abraxane, an FDA-approved PTX nanoformulation, in both a primary triple-negative breast cancer (TNBC) model and an intracranial model reflecting TNBC growth following metastatic dissemination to the brain. These results provide new insights into methods for effective development of therapeutic nanoparticles as well as support the continued development of the DART platform for primary and metastatic tumors.

Thermo-responsive Fluorescent Nanoparticles for Multimodal Imaging and Treatment of Cancers.

Theranostic systems capable of delivering imaging and therapeutic agents at a specific target are the focus of intense research efforts in drug delivery. To overcome non-degradability and toxicity concerns of conventional theranostic systems, we formulated a novel thermo-responsive fluorescent polymer (TFP) and conjugated it on the surface of iron oxide magnetic nanoparticles (MNPs) for imaging and therapeutic applications in solid tumors. METHODS: TFP-MNPs were synthesized by copolymerizing poly(N-isopropylacrylamide), allylamine and a biodegradable photoluminescent polymer, and conjugating it on MNPs via a free radical polymerization reaction. Physicochemical properties of the nanoparticles were characterized using Fourier transform infrared spectroscopy, dynamic light scattering, and vibrational sample magnetometry. Nanoparticle cytocompatibility, cellular uptake and cytotoxicity were evaluated using in vitro cell assays. Finally, in vivo imaging and therapeutic efficacy studies were performed in subcutaneous tumor xenograft mouse models. RESULTS: TFP-MNPs of ~135 nm diameter and -31 mV ζ potential maintained colloidal stability and superparamagnetic properties. The TFP shell was thermo-responsive, fluorescent, degradable, and released doxorubicin in response to temperature changes. In vitro cell studies showed that TFP-MNPs were compatible to human dermal fibroblasts and prostate epithelial cells. These nanoparticles were also taken up by prostate and skin cancer cells in a dose-dependent manner and exhibited enhanced killing of tumor cells at 41°C. Preliminary in vivo studies showed theranostic capabilities of the nanoparticles with bright fluorescence, MRI signal, and therapeutic efficacy under magnetic targeting after systemic administration in tumor bearing mice. CONCLUSION: These results indicate the potential of TFP-MNPs as multifunctional theranostic nanoparticles for various biological applications, including solid cancer management.

Leveraging Surface Plasmon Resonance to Dissect the Interfacial Properties of Nanoparticles: Implications for Tissue Binding and Tumor Penetration.

Therapeutic efficacy of nanoparticle-drug formulations for cancer applications is significantly impacted by the extent of intra-tumoral accumulation and tumor tissue penetration. We advanced the application of surface plasmon resonance to examine interfacial properties of various clinical and emerging nanoparticles related to tumor tissue penetration. We observed that amine-terminated or positively-charged dendrimers and liposomes bound strongly to tumor extracellular matrix (ECM) proteins, whereas hydroxyl/carboxyl-terminated dendrimers and PEGylated/neutrally-charged liposomes did not bind. In addition, poly(lactic-co-glycolic acid) (PLGA) nanoparticles formulated with cholic acid or F127 surfactants bound strongly to tumor ECM proteins, whereas nanoparticles formulated with poly(vinyl alcohol) did not bind. Unexpectedly, following blood serum incubation, this binding increased and particle transport in ex vivo tumor tissues reduced markedly. Finally, we characterized the protein corona on PLGA nanoparticles using quantitative proteomics. Through these studies, we identified valuable criteria for particle surface characteristics that are likely to mediate their tissue binding and tumor penetration.

Engineering of L-Plastin Peptide-Loaded Biodegradable Nanoparticles for Sustained Delivery and Suppression of Osteoclast Function In Vitro.

We have recently demonstrated that a small molecular weight amino-terminal peptide of L-plastin (10 amino acids; "MARGSVSDEE") suppressed the phosphorylation of endogenous L-plastin. Therefore, the formation of nascent sealing zones (NSZs) and bone resorption are reduced. The aim of this study was to develop a biodegradable and biocompatible PLGA nanocarrier that could be loaded with the L-plastin peptide of interest and determine the efficacy in vitro in osteoclast cultures. L-plastin MARGSVSDEE (P1) and scrambled control (P3) peptide-loaded PLGA-PEG nanoparticles (NP1 and NP3, respectively) were synthesized by double emulsion technique. The biological effect of nanoparticles on osteoclasts was evaluated by immunoprecipitation, immunoblotting, rhodamine-phalloidin staining of actin filaments, and pit forming assays. Physical characterization of well-dispersed NP1 and NP3 demonstrated ~130-150 nm size, < 0.07 polydispersity index, ~-3 mV ζ-potential, and a sustained release of the peptide for three weeks. Biological characterization in osteoclast cultures demonstrated the following: NP1 significantly reduced (a) endogenous L-plastin phosphorylation; (b) formation of NSZs and sealing rings; (c) resorption. However, the assembly of podosomes which are critical for cell adhesion was not affected. L-plastin peptide-loaded PLGA-PEG nanocarriers have promising potential for the treatment of diseases associated with bone loss. Future studies will use this sustained release of peptide strategy to systematically suppress osteoclast bone resorption activity in vivo in mouse models demonstrating bone loss.

Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas.

The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, 'sticky' microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as 'DART' therapeutics. In this work, we applied this information toward the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor - an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors.

Tumor-targeted nanotherapeutics: overcoming treatment barriers for glioblastoma.

Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment of GBM including the tightly controlled interface between the bloodstream and central nervous system termed the 'neurovascular unit,' a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal of GBM therapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified as GBM targets include the transferrin receptor, low-density lipoprotein receptor-related protein, αv ß3 integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR), EGFR variant III, interleukin-13 receptor α chain variant 2, and fibroblast growth factor-inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (1) adhesive interactions with nontarget structures, (2) low density or prevalence of the target, (3) lack of target specificity, and (4) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the key GBM targets with the goal of advancing the understanding and development of targeted nanotherapeutics for GBM. WIREs Nanomed Nanobiotechnol 2017, 9:e1439. doi: 10.1002/wnan.1439 For further resources related to this article, please visit the WIREs website.

Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma.

Glioblastoma (GBM) is a fatal brain cancer for which new treatment options are sorely needed. Platinum-based drugs have been investigated extensively for GBM treatment but few have shown significant efficacy without major central nervous system (CNS) and systemic toxicities. The relative success of platinum drugs for treatment of non-CNS cancers indicates great therapeutic potential when effectively delivered to the tumor region(s). New insights into the broad anticancer effects of platinum drugs, particularly immunomodulatory effects, and innovative delivery strategies that can maximize these multi-modal effects and minimize toxicities may promote the re-purposing of this chemotherapeutic drug class for GBM treatment.

Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue.

Therapeutic nanoparticles (NPs) approved for clinical use in solid tumor therapy provide only modest improvements in patient survival, in part due to physiological barriers that limit delivery of the particles throughout the entire tumor. Here, we explore the thresholds for NP size and surface poly(ethylene glycol) (PEG) density for penetration within tumor tissue extracellular matrix (ECM). We found that NPs as large as 62nm, but less than 110nm in diameter, diffused rapidly within a tumor ECM preparation (Matrigel) and breast tumor xenograft slices ex vivo. Studies of PEG-density revealed that increasing PEG density enhanced NP diffusion and that PEG density below a critical value led to adhesion of NP to ECM. Non-specific binding of NPs to tumor ECM components was assessed by surface plasmon resonance (SPR), which revealed excellent correlation with the particle diffusion results. Intravital microscopy of NP spread in breast tumor tissue confirmed a significant difference in tumor tissue penetration between the 62 and 110nm PEG-coated NPs, as well as between PEG-coated and uncoated NPs. SPR assays also revealed that Abraxane, an FDA-approved non-PEGylated NP formulation used for cancer therapy, binds to tumor ECM. Our results establish limitations on the size and surface PEG density parameters required to achieve uniform and broad dispersion within tumor tissue and highlight the utility of SPR as a high throughput method to screen NPs for tumor penetration.

Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier.

The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

Sustained release of calcium hydroxide from poly(DL-lactide-co-glycolide) acid microspheres for apexification.

Calcium hydroxide (CH) loaded poly(DL-lactide-co-glycolide) acid (PLGA) microspheres (MS) might be used for apexification requiring a sustained release of Ca(2+). The aim of this study was to formulate and characterize CH-PLGA-MS. The CH-loaded MS were prepared by either oil-in-water (O/W) or water-in-oil/in-water (W/O/W) emulsion solvent evaporation technique. MS produced by the O/W technique exhibited a larger diameter (18.63 ± 7.23 µm) than the MS produced by the W/O/W technique (15.25 ± 7.37 µm) (Mann-Whitney U test P < 0.001). The CH encapsulation efficiency (E e) and Ca(2+) release were calculated from data obtained by absorption techniques. Ca(2+) release profile was evaluated for 30 days. To know the E e, the CH-loaded MS were dissolved in 1 M NaOH to release all its content and a Ca(2+) colorimetric marker was added to this solution. The reagent marked the Ca(2+) in blue color, which was then measured by a UV-Vis system (650 nm). The percentage of E e was calculated on the basis of the theoretical loading. The E e of the O/W-produced MS was higher (24 %) than the corresponding percentage of the W/O/W-produced MS (11 %). O/W- and W/O/W-produced MS released slower and lower Ca(2+) than a control CH paste with polyethylene glycol 400 (Kruskal-Wallis test). O/W-produced MS released higher Ca(2+) than W/O/W-produced MS (statistically significant differences; P < 0.05). In conclusion, the CH-PLGA-MS were successfully formulated; the technique of formulation influenced the size, encapsulation efficiency and release profile. The MS were better sustained release system than the CH paste.

Surface plasmon resonance as a high throughput method to evaluate specific and non-specific binding of nanotherapeutics.

Surface plasmon resonance (SPR) is a powerful analytical technique used to quantitatively examine the interactions between various biomolecules, such as proteins and nucleic acids. The technique has been particularly useful in screening and evaluating binding affinity of novel small molecule and biomolecule-derived therapeutics for various diseases and applications including lupus medications, thrombin inhibitors, HIV protease inhibitors, DNA gyrase inhibitors and many others. Recently, there has been increasing interest in nanotherapeutics (nanoRx), due to their unique properties and potential for controlled release of encapsulated drugs and structure-specific targeting to diseased tissues. NanoRx offer the potential to solve many drug delivery challenges by enabling, specific interactions between molecules on the surface of the nanoparticle and molecules in the diseased tissue, while minimizing off-target interactions toward non-diseased tissues. These properties are largely dependent upon careful control and balance of nanoRx interactions and binding properties with tissues in vivo. Given the great promise of nanoRx with regard to engineering specific molecular interactions, SPR can rapidly quantify small aliquots of nanoRx formulations for desired and undesired molecular interactions. Moving forward, we believe that utilization of SPR in the screening and design of nanoRx has the potential to greatly improve the development of targeted nanoRx formulations and eventually lead to improved therapeutic efficacy. In this review, we discuss (1) the fundamental principles of SPR and basic quantitative analysis of SPR data, (2) previous applications of SPR in the study of non-particulate therapeutics and nanoRx, and (3) future opportunities for the use of SPR in the evaluation of nanoRx.

Design of antimicrobial peptides conjugated biodegradable citric acid derived hydrogels for wound healing.

Wound healing is usually facilitated by the use of a wound dressing that can be easily applied to cover the wound bed, maintain moisture, and avoid bacterial infection. In order to meet all of these requirements, we developed an in situ forming biodegradable hydrogel (iFBH) system composed of a newly developed combination of biodegradable poly(ethylene glycol) maleate citrate (PEGMC) and poly(ethylene glycol) diacrylate (PEGDA). The in situ forming hydrogel systems are able to conform to the wound shape in order to cover the wound completely and prevent bacterial invasion. A 2(k) factorial analysis was performed to examine the effects of polymer composition on specific properties, including the curing time, Young's modulus, swelling ratio, and degradation rate. An optimized iFBH formulation was achieved from the systematic factorial analysis. Further, in vitro biocompatibility studies using adult human dermal fibroblasts (HDFs) confirmed that the hydrogels and degradation products are not cytotoxic. The iFBH wound dressing was conjugated and functionalized with antimicrobial peptides as well. Evaluation against bacteria both in vitro and in vivo in rats demonstrated that the peptide-incorporated iFBH wound dressing offered excellent bacteria inhibition and promoted wound healing. These studies indicated that our in situ forming antimicrobial biodegradable hydrogel system is a promising candidate for wound treatment.

In vitro cytotoxicity evaluation of four vital pulp therapy materials on l929 fibroblasts.

The aim of this study was to evaluate cytotoxicity of direct pulp capping materials such as Dycal, Life, ProRoot MTA, and Super-Bond C&B on L929 fibroblasts. Freshly mixed or set materials were prepared and eluted by incubation with cell culture medium for working time period (fresh) or for 6 hours (set). The cells were exposed to media containing elutes for 24 hours, after which the cell survival was evaluated by MTS assays. In freshly mixed materials, average ± standard deviation % cell viabilities were 40.2 ± 14.0%, 43.7 ± 16.0%, 72.9 ± 12.7%, and 66.0 ± 13.6% for Dycal, Life, ProRoot MTA, and Super-Bond C&B, respectively. There was no statistical difference in cell viabilities among material groups, whereas in set materials, the cell viabilities were 48.7 ± 14.8%, 37.2 ± 10.6%, 46.7 ± 15.2%, and 100 ± 21.9% for Dycal, Life, ProRoot MTA, and Super-Bond C&B, respectively. Super-Bond C&B showed more cell viabilities than the other three material groups (P < 0.05). The four vital pulp therapy materials had similar cytotoxicity when the materials were fresh. Super-Bond C&B was less cytotoxic than Dycal, Life, and ProRoot MTA after the materials were set, which suggests the use of SB-C&B in future in vivo clinical investigations.

Dual-responsive polymer-coated iron oxide nanoparticles for drug delivery and imaging applications.

We reported the synthesis and characterization of dual-responsive poly(N-isopropylacrylamide-acrylamide-chitosan) (PAC)-coated magnetic nanoparticles (MNPs) for controlled and targeted drug delivery and imaging applications. The PAC-MNPs size was about 150nm with 70% iron mass content and excellent superparamagnetic properties. PAC-MNPs loaded with anti-cancer drug doxorubicin showed dual-responsive drug release characteristics with the maximum release of drugs at 40°C (∼78%) than at 37°C (∼33%) and at pH of 6 (∼55%) than at pH of 7.4 (∼28%) after 21 days. Further, the conjugation of prostate cancer-specific R11 peptides increased the uptake of PAC-MNPs by prostate cancer PC3 cells. The dose-dependent cellular uptake of the nanoparticles was also significantly increased with the presence of 1.3T magnetic field. The nanoparticles demonstrated cytocompatibility up to concentrations of 500µg/ml when incubated over a period of 24h with human dermal fibroblasts and normal prostate epithelial cells. Finally, pharmacokinetic studies indicated that doxorubicin-loaded PAC-MNPs caused significant prostate cancer cell death at 40°C than at 37°C, thereby confirming the temperature-dependent drug release kinetics and in vitro therapeutic efficacy. Future evaluation of in vivo therapeutic efficacy of targeted image-guided cancer therapy using R11-PAC-MNPs will reinforce a significant impact of the multifunctional PAC-MNPs on the future drug delivery systems.

Magnetic-based multi-layer microparticles for endothelial progenitor cell isolation, enrichment, and detachment.

Although endothelial progenitor cells (EPCs) are useful in many applications including cell-based therapies, their use is still limited due to issues associated with cell culture techniques like a low isolation efficiency, use of harmful proteolytic enzymes in cell cultures, and difficulty in ex vivo expansion. Here, we report a tool to simultaneously isolate, enrich, and detach EPCs without the use of harmful chemicals. In particular, we developed magnetic-based multi-layer microparticles (MLMPs) that (1) magnetically isolate EPCs via anti-CD34 antibodies to avoid the use of Ficoll and harsh shear forces; (2) provide a 3D surface for cell attachment and growth; (3) produce sequential releases of growth factors (GFs) to enrich ex vivo expansion of cells; and (4) detach cells without using trypsin. MLMPs were successful in isolating EPCs from a cell suspension and provided a sequential release of GFs for EPC proliferation and differentiation. The cell enrichment profiles indicated steady cell growth on MLMPs in comparison to commercial Cytodex3 microbeads. Further, the cells were detached from MLMPs by lowering the temperature below 32 °C. Results indicate that the MLMPs have potential to be an effective tool towards efficient cell isolation, fast expansion, and non-chemical detachment.

Design and Application of Magnetic-based Theranostic Nanoparticle Systems.

Recently, magnetic-based theranostic nanoparticle (MBTN) systems have been studied, researched, and applied extensively to detect and treat various diseases including cancer. Theranostic nanoparticles are advantageous in that the diagnosis and treatment of a disease can be performed in a single setting using combinational strategies of targeting, imaging, and/or therapy. Of these theranostic strategies, magnetic-based systems containing magnetic nanoparticles (MNPs) have gained popularity because of their unique ability to be used in magnetic resonance imaging, magnetic targeting, hyperthermia, and controlled drug release. To increase their effectiveness, MNPs have been decorated with a wide variety of materials to improve their biocompatibility, carry therapeutic payloads, encapsulate/bind imaging agents, and provide functional groups for conjugation of biomolecules that provide receptor-mediated targeting of the disease. This review summarizes recent patents involving various polymer coatings, imaging agents, therapeutic agents, targeting mechanisms, and applications along with the major requirements and challenges faced in using MBTN for disease management.

Prostate cancer-specific thermo-responsive polymer-coated iron oxide nanoparticles.

Thermo-responsive poly(N-isopropylacrylamide-acrylamide-allylamine)-coated magnetic nanoparticles (PMNPs) were developed and conjugated with prostate cancer-specific R11 peptides for active targeting and imaging of prostate cancer. The stable nanoparticles with an average diameter of 100 nm and surface charge of -27.0 mV, had a lower critical solution temperature of 40 °C. Magnetic characterization showed that the nanoparticles can be recruited using a magnetic field and possess superparamagnetic behavior even after R11 conjugation. In vitro cell studies demonstrated that R11-conjugated PMNPs (R11-PMNPs) were compatible with human dermal fibroblasts and normal prostate epithelial cells to all tested concentrations up to 500 µg/ml after 24 h of incubation. Moreover, the nanoparticles were taken up by prostate cancer cells (PC3 and LNCaP) in a dose-dependent manner, which was higher in case of R11-PMNPs than PMNPs. Further, in vivo biodistribution of the nanoparticles showed significantly more R11-PMNPs accumulation in tumors than other vital organs unlike PMNPs without R11 conjugation. Moreover, R11-PMNPs decreased 30% magnetic resonance T2 signal intensity in tumors in vivo compared to 0% decrease with PMNPs. These results indicate great potential of R11-PMPs as platform technology to target and monitor prostate cancers for diagnostic and therapeutic applications.

Deep vein thrombosis: current status and nanotechnology advances.

Deep vein thrombosis (DVT) affects up to 2 million people in the United States, and worldwide incidence is 70 to 113 cases per 100,000 per year. Mortality from DVT is often due to subsequent pulmonary embolism (PE). Precise diagnosis and treatment is thereby essential for the management of DVT. DVT is diagnosed by a thorough history and physical examination followed by laboratory and diagnostic tests. The choice of laboratory and diagnostic test is dependent on clinical pretest probability. Available laboratory and diagnostic techniques mainly involve D-dimer test, ultrasound, venography, and magnetic resonance imaging. The latter two diagnostic tools require high doses of contrast agents including either radioactive or toxic materials. The available treatment options include lifestyle modifications, mechanical compression, anticoagulant therapy, inferior vena cava filter, and thrombolysis/thrombolectomy. All of these medical and surgical treatments have serious side effects including improper clot clearance and increased risk of hemorrhage occurrence. Therefore, research in this field has recently focused on the development of non-invasive and accurate diagnostics, such as ultrasound enhanced techniques and molecular imaging methods, to assess thrombus location and its treatment course. The frontier of nanomedicine also shows high prospects in tackling DVT with efficient targeted drug delivery. This review describes the pathology of DVT along with successive medical problems such as PE and features a detailed listing of various diagnostic and therapeutic modalities that have been in use and are under development.