Polyvalent Folate-Dendrimer-Coated Iron Oxide Theranostic Nanoparticles for Simultaneous Magnetic Resonance Imaging and Precise Cancer Cell Targeting.

The low therapeutic index of conventional chemotherapy and poor prognosis of patients diagnosed with metastatic cancers are prompting clinicians to adopt newer strategies to simultaneously detect cancer lesions at an early stage and to precisely deliver anticancer drugs to tumor sites. In this study, we employed a novel strategy to engineer a polyvalent theranostic nanocarrier consisting of superparamagnetic iron oxide nanoparticle core (SPIONs) decorated with folic acid-polyamidoamine dendrimers surface (FA-PAMAM). In addition, a highly potent hydrophobic anticancer agent 3,4-difluorobenzylidene-curcumin (CDF) was coloaded in the FA-PAMAM dendrimer to increase its solubility and assess its therapeutic potentials. The resulting targeted nanoparticles (SPIONs@FA-PAMAM-CDF) exhibited high MR contrast. When tested on folate receptor overexpressing ovarian (SKOV3) and cervical (HeLa) cancer cells, the CDF loaded targeted nanoformulations showed higher accumulation with a better anticancer activity as compared to the nontargeted counterparts, possibly due to multivalent folate receptor binding interaction with cells overexpressing the target. The results were corroborated by observation of a larger population of cells undergoing apoptosis due to upregulation of tumor suppressor phosphatase and tensis homologue (PTEN), caspase 3, and inhibition of NF-κB in groups treated with the targeted formulations, which further confirmed the ability of the multivalent theranostic nanoparticles for simultaneous imaging and therapy of cancers.

pH responsive biodegradable nanogels for sustained release of bleomycin.

Site specific drug delivery with desired therapeutic effect still remains challenging task due to suboptimal release, tissue toxicity, low selectivity and meager therapeutic efficacy in skin cancers. The aim of the current study was to fabricate pH responsive, self-assembled, chemically cross-linked biodegradable chitosan nanogel loaded with bleomycin to target the dermal area of the skin. The nanogel synthesized by ion gelation technique and was characterized for drug loading, swelling and thermal stability followed by in vitro analysis. HaCaT (Human Keratinocyte cell) and HDF (Human dermal fibroblast) cell line were used for the biocompatibility and cytocompatibility evaluation prior to the hemolysis assay and coagulation assessment. The nanogel had a size range of 150nm as determined by TEM and DLS. The nanogel possessed optimum thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). Biodegradation was confirmed by lysozyme enzyme degradation assays. The drug entrapment efficacy was about 55% in the swollen state. The In vitro drug release profile revealed sustained release pattern. The hemolysis of 2.39% and prothrombin time (PT) and activated partial thromboplastin time (APTT) of 12.9 and 31s revealed the biocompatibility of nanogels. The cell uptake and localization profile was validated by fluorescence and confocal microscopy using HDF and HaCaT cell lines. Finally, the MTT assay demonstrated the cytocompatibility of nanogels. In conclusion, the present findings suggest that biodegradable chitosan nanogels with stimuli responsive nature can release the anticancer drug cargo in a sustained and controlled manner and offer promising potentials for treating skin cancers. STATEMENT OF SIGNIFICANCE: Drug delivery to the targeted site is a major challenge in clinical medicine. The newly constructed pH responsive biodegradable nanogel consisting of bleomycin revealed pH triggered drug release in a sustained manner to the dermal area offering novel approach against skin cancer. The nanogel system is biodegradable in nature possessing high drug entrapment efficiency and offers patient compliance with biocompatible and cytocompatible characteristics. This nanogel system can thus be highly useful for delivery of anticancer drugs to the skin in a controlled and sustained manner.

In Vivo Antitumor Activity of Folate-Conjugated Cholic Acid-Polyethylenimine Micelles for the Codelivery of Doxorubicin and siRNA to Colorectal Adenocarcinomas.

Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 µM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.

Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer.

PURPOSE: Approaches for the synthesis of biomaterials to facilitate the delivery of "biologics" is a major area of research in cancer therapy. Here we designed and characterized a hyaluronic acid (HA) based self-assembling nanoparticles that can target CD44 receptors overexpressed on multidrug resistance (MDR) ovarian cancer. The nanoparticle system is composed of HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) designed to deliver MDR1 siRNA for the treatment of MDR in an ovarian cancer model. METHODS: HA-PEI/HA-PEG nanoparticles were synthesized and characterized, then the cellular uptake and knockdown efficiency of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles was further determined. A human xenograft MDR ovarian cancer model was established to evaluate the effects of the combination of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles and paclitaxel on MDR tumor growth. RESULTS: Our results demonstrated that HA-PEI/HA-PEG nanoparticles successfully targeted CD44 and delivered MDR1 siRNA into OVCAR8TR (established paclitaxel resistant) tumors. Additionally, HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and P-glycoprotein (Pgp), inhibited the functional activity of Pgp, and subsequently increased cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment inhibited tumor growth in MDR ovarian cancer mouse models. CONCLUSIONS: These findings suggest that this CD44 targeted HA-PEI/HA-PEG nanoparticle platform may be a clinicaly relevant gene delivery system for systemic siRNA-based anticancer therapeutics for the treatment of MDR cancers.

Lipid-functionalized dextran nanosystems to overcome multidrug resistance in cancer: a pilot study.

BACKGROUND: The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches. QUESTIONS/PURPOSES: We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR. METHODS: To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOS(R2) and SKOV-3(TR) in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells. RESULTS: Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOS(R2). CONCLUSIONS: Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs. CLINICAL RELEVANCE: Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.

Combinatorial-designed multifunctional polymeric nanosystems for tumor-targeted therapeutic delivery.

By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems. The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery.

Nanoparticles for Immune Cell Reprogramming and Reengineering of Tumor Microenvironment.

Nanoparticles in cancer therapy have garnered significant attention in the past few decades. Cancer immunotherapy, which is aptly called "the new-generation cancer therapy," is slowly making remarkable strides in the improvement of patient outcome and longevity. Taken together, nanoparticles in immune therapy have the potential to offer advantages of both nanoparticles and immune therapy on a single platform.

Discovering pH triggered charge rebound surface modulated topical nanotherapy against aggressive skin papilloma.

A modified facile biomimetic Temozolomide Chitosan nanogel (TCNL) was developed offering pH responsive, charge attracted and microenvironment dependent tumor targeting nanotherapy. USFDA approved chemotherapeutic TMZ (Temozolomide) was encapsulated in a cationic biocompatible chitosan nanogel subsequently surface modified with nonionic Transcutol by inotropic gelation method and evaluated for its combined anti-metastatic and antitumor efficiency. The in-vitro results authenticated that TMZ encapsulated TCNL was effectively uptake and distributed in HaCaT cell line inducing high apoptosis and necrosis of tumor cells prior to the electron microscopic (TEM & SEM) and thermal evaluations (DSC, DTA & TG) suggesting spherical and thermo-stable nanogel system. An accelerated sustained release pattern of TMZ from TCNL was displayed in mildly acidic conditions (pH 6) signifying ultra-sensitivity of TCNL. In-vivo evaluation over 16 week DMBA/croton oil tumor induced mice model showed noteworthy tumor targeting with down regulation of overexpressed COX-2, cytokines and nuclear factors on western blot analysis. Moreover, advanced gamma scintigraphy analysis displayed significant drug accommodation and expressing potent tumor accumulation, suppression and metastasis effect on carcinogenic mice. The TCNL outcomes displayed effective tumor targeting on transdermal delivery for operative nanotherapy against skin cancer.

Exploring siRNA Umpired Nanogels: A Tale of Barrier Combating Carrier.

Potential short interfering RNAs (siRNA) modulating gene expression have emerged as a novel therapeutic arsenal against a wide range of maladies and disorders containing cancer, viral infections, bacterial ailments and metabolic snags at the molecular level. Nanogel, in the current medicinal era, displayed a comprehensive range of significant drug delivery prospects. Biodegradation, swelling and de-swelling tendency, pHsensitive drug release and thermo-sensitivity are some of the renowned associated benefits of nanogel drug delivery system. Global researches have also showed that nanogel system significantly targets and delivers the biomolecules including DNAs, siRNA, protein, peptides and other biologically active molecules. Biomolecules delivery via nanogel system explored a wide range of pharmaceutical, biomedical engineering and agro-medicinal application. The siRNAs and DNAs delivery plays a vivacious role by addressing the hitches allied with chronic and contemporary therapeutic like generic possession and low constancy. They also incite release kinetics approach from slow-release while mingling to rapid release at the targets will be beneficial as interference RNAs delivery carriers. Therefore, in this research, we focused on the latest improvements in the delivery of siRNA loaded nanogels by enhancing the absorption, stability, sensitivity and combating the hindrances in cellular trafficking and release process.

Graphene Decorated Zinc Oxide and Curcumin to Disinfect the Methicillin-Resistant Staphylococcus aureus.

Sometimes, life-threatening infections are initiated by the biofilm formation facilitated at the infection site by the drug-resistant bacteria Staphylococcus aureus. The aggregation of the same type of bacteria leads to biofilm formation on the delicate tissue, dental plaque, and skin. In the present investigation, a Graphene (Gr)-based nano-formulation containing Curcumin (C.C.M.) and Zinc oxide nanoparticles (ZnO-NPs) showed a wide range of anti-microbial activity against Methicillin-resistant Staphylococcus aureus (MRSA) biofilm and demonstrated the anti-microbial mechanism of action. The anti-microbial effect of GrZnO nanocomposites, i.e., GrZnO-NCs, suggests that the integrated graphene-based nanocomposites effectively suppressed both sensitive as well as MRSA ATCC 43300 and BAA-1708 isolates. The S. aureus inhibitory effect of GrZnO-NCs improved >5-fold when combined with C.C.M., and demonstrated a M.I.C. of 31.25 µg/mL contrasting with the GrZnO-NCs or C.C.M. alone having M.I.C. value of 125 µg/mL each. The combination treatment of GrZnO-NCs or C.C.M. inhibited the M.R.S.A. topical dermatitis infection in a mice model with a significant decrease in the CFU count to ~64%. Interestingly, the combination of C.C.M. and GrZnO-NCs damaged the bacterial cell wall structure, resulting in cytoplasm spillage, thereby diminishing their metabolism. Thus, owing to the ease of synthesis and highly efficient anti-microbial properties, the present graphene-based curcumin nano-formulations can cater to a new treatment methodology against M.R.S.A.

Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma.

BACKGROUND: Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. METHODS: Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. RESULTS: Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. CONCLUSION: Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma.

Nano-engineered delivery systems for cancer imaging and therapy: Recent advances, future direction and patent evaluation.

Cancer is the second highest cause of death worldwide. Several therapeutic approaches, such as conventional chemotherapy, antibodies and small molecule inhibitors and nanotherapeutics have been employed in battling cancer. Amongst them, nanotheranostics is an example of successful personalized medicine bearing dual role of early diagnosis and therapy to cancer patients. In this review, we have focused on various types of theranostic polymer and metal nanoparticles for their role in cancer therapy and imaging concerning their limitation, future application such as dendritic cell cancer vaccination, gene delivery, T-cell activation and immune modulation. Also, some of the recorded patent applications and clinical trials have been illustrated. The impact of the biological microenvironment on the biodistribution and accumulation of nanoparticles have been discussed.

pH Responsive 5-Fluorouracil Loaded Biocompatible Nanogels For Topical Chemotherapy of Aggressive Melanoma.

Combating melanoma via topical route is a highly challenging task due to low selectivity, poor efficacy and impeding biological environment of the skin. In the present study, we engineered a chitosan based pH responsive biodegradable nanogel (FCNGL), encapsulated with 5-FU that was effective even at very low drug doses (0.2% w/v) against melanoma. The FCNGL was synthesized by ion gelation technique exhibited nano-size particle distribution and sustained drug release kinetics. Hemolysis and coagulation analysis revealed high safety whereas MTT and apoptosis assays exhibited the efficacy of FCNGL. DMBA-Croton oil Swiss albino mice model was employed for in vivo assessment followed by gamma scintigraphic screening. Tumor burden and pharmacokinetic antioxidant stress levels along with whole-body gamma scintigraphy imaging using 99 mTc labelled nanogel exhibited selective accumulation in melanoma tumor nodules. The pH responsive behaviour of the nanogels resulted in triggered release of 5-FU in slightly acidic microenvironment, resulting in selective drug accumulation at the melanoma site. Immunohistochemistry (IHC) analysis of tumor showed improvement of subcutaneous layer alignment and regeneration of the epithelial skin layer when compared with standard 5% 5-FU and control mice group. Overall our preclinical data using the FCNGL portends to be a promising platform for efficient and sustained delivery of 5-FU for topical chemotherapy that can result in high efficacy, patient compliance and safety in the clinical set up.

pH triggered and charge attracted nanogel for simultaneous evaluation of penetration and toxicity against skin cancer: In-vitro and ex-vivo study.

The current research is focused to develop and investigate the toxicity and penetration potential of biocompatible chitosan nanogel encapsulating capecitabine by ionic interaction mechanism exhibiting pH triggered transdermal targeting. The nanogel (CPNL) was synthesized by ion gelation mechanism using Pluronic F 127 and surface decoration by Transcutol as non-ionic penetration enhancer. The CPNL possesses fine morphology and nano size range when evaluated by TEM, SEM and DLS analysis with cationic charge and slightly acidic pH assayed by zeta potential and pH analysis. It showed pH responsive drug release characteristics mimicking the skin cancer micro-environment. The MTT assay and apoptotic index of CPNL on HaCaT cell line elaborated optimal cell toxicity and retention on 24h of exposure. The ex-vivo skin penetration analysis exhibited noteworthy diffusion and penetration caliber through concentration depth profile, steady state flux and fluorescent skin imaging on porcine tissue. Overall outcomes suggested CPNL as a potent alternative biocompatible, transdermal nanotherapy against skin cancer displaying significant penetration caliber with enhance toxicity on cancerous cell.

Oxystress inducing antitumor therapeutics via tumor-targeted delivery of PEG-conjugated D-amino acid oxidase.

We had developed a H(2)O(2) generating enzyme, polyethylene glycol conjugated D-amino acid oxidase (PEG-DAO), which exhibited potent antitumor activity by generating toxic reactive oxygen species, namely oxidation therapy, subsequently showed remarkable antitumor effect on murine Sarcoma 180 solid tumor, by taking advantage of the enhanced permeability and retention effect. Along this line, we report here the preparation of PEG-DAO by use of recombinant DAO and its antitumor activity by using various tumor cell lines and tumor models. Recombinant DAO (rDAO) was obtained from E. coli BL21 (DE3) carrying the porcine DAO expression vector with high yield (20 mg/l) and high enzyme activity (5.3 U/mg). Pegylated rDAO (PEG-rDAO) showed high stability against sonication, repeated freezing/thawing, lyophilization and exhibited superior in vivo pharmacokinetics. PEG-rDAO had a molecular size of 65 kDa and existed as nanoparticles in aqueous solution with mean particle diameter of 119 nm. In vitro experiments showed strong cytotoxicity of PEG-rDAO against various tumor cells, whereas less cytotoxicity was found against various normal cells. In vivo antitumor treatment was carried out using 2 mice tumor models, namely colon 38 tumor and Meth A tumor model. PEG-rDAO was administered i.v. and after an adequate lag time, D-proline (the substrate of DAO) was injected i.p. to the tumor-bearing mice. Consequently, preferential generation of H(2)O(2) in the tumor was successfully achieved, which resulted in remarkable suppression of tumor growth without any visible side effects. These findings suggest a potential of PEG-rDAO as a novel anticancer strategy toward clinical development.

High-loading nanosized micelles of copoly(styrene-maleic acid)-zinc protoporphyrin for targeted delivery of a potent heme oxygenase inhibitor.

Amphiphilic styrene-maleic acid (SMA) copolymer efficiently formed micelles with a potent heme oxygenase inhibitor-zinc protoporphyrin (ZnPP). The micelles were constructed by subtle pH adjustments to form non-covalent interaction between the hydrophobic ZnPP and amphiphilic SMA. The micelles (SMA-ZnPP) thus formed were nanoparticles with narrow size distribution in water (mean diameter 176.5nm), having tunable loading (from 15% to 60% w/w of ZnPP) with remarkable aqueous solubility. SMA-ZnPP had an average molecular size of 144kDa as determined by size-exclusion chromatography (SEC), this size is a marked increase from the molecular weight of free ZnPP (626.03Da), suggesting the formation of micellar structure. The micelles showed a constant ZnPP release rate of about 0.5%/day in vitro at neutral pH. SMA-ZnPP micelles inhibited splenic microsomal HO-1 activity, in a competitive and dose-dependent manner, with an apparent inhibitory constant (K(i)) of 0.12mum, comparable to free ZnPP and also exhibited marked cytotoxic effect on KYSE-510 human esophageal cancer cells. The unique features of SMA-ZnPP micelles are that they are nanoparticles in aqueous solution having high water solubility and loading, yet macromolecular in nature, which can be beneficial in targeted release of a potent HO-1 inhibitor.

Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generation.

Polymeric micelles of zinc protoporphyrin (ZnPP) with water soluble biocompatible and amphiphilic polymer, polyethylene glycol (PEG) demonstrated unique characteristics to target tumor tissues selectively based on the enhanced permeability and retention (EPR) effect. The micellar macromolecular drug of ZnPP (SMA-ZnPP and PEG-ZnPP) previously showed notable anticancer activity as a consequence of selective tumor targeting ability and its potent HO-1 inhibitory potential, resulting in suppressed biliverdin/bilirubin production in tumors thereby leading to oxystress induced tumor cell killing. Furthermore, recent findings also showed that ZnPP efficiently generated reactive singlet oxygen under illumination of visible light, laser, or xenon light source, which could augment its oxystress induced cell killing abilities. In the present paper, we report the synergistic effects of light induced photosensitizing capabilities and HO-1 inhibitory potentials of these unique micelles when tested in vitro and in vivo on tumor models under localized, mild illumination conditions using a tungsten-xenon light source. The results indicate that these water soluble polymeric micelles of ZnPP portend to be promising candidates for targeted chemotherapy as well as photodynamic therapy against superficial tumors as well as solid tumors located at light penetrable depths.

Assessment of penetration potential of pH responsive double walled biodegradable nanogels coated with eucalyptus oil for the controlled delivery of 5-fluorouracil: In vitro and ex vivo studies.

Penetration enhancers coated biodegradable polymeric nanogels loaded with cytotoxic drugs applied via the topical route, can be a promising strategy for improving the chemotherapeutic efficiency of skin cancers. The major objective of proposed research was to investigate the in vitro and ex vivo chemotherapeutic potential of double walled PLGA-chitosan biodegradable nanogel entrapped with 5-fluororuacil (5-FU) coated with eucalyptus oil, topically applied onto the skin. 5-FU was first entrapped in PLGA core by solvent evaporation technique followed by coating with cationic chitosan for ionic interaction with anionic skin cancer cell membrane. A surface coating of eucalyptus oil (1%) was employed to improve the penetration efficacy of the nanogel into stratum corneum. The surface modified biodegradable double walled nanogel was characterized for particle size, charge and thermal properties followed by pH dependent in vitro analysis. Human keratinocyte (HaCaT) cell line was employed for the bio- and cyto-compatibility testing prior to the hemolysis assay and coagulation assessment. A porcine skin ex vivo screening was performed for assessing the penetration potential of the nanogels. DLS and TEM revealed a particle size about 170nm for the double walled nanogels. The nanogels also exhibited high thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). The drug entrapment efficacy was about ~40%. The drug release showed sustained release pattern noted up to 24h. The low hemolysis of 2.39% with short prothrombin time (PT) and activated partial thromboplastin time (APTT) of 14.2 and 35.5s respectively, revealed high biocompatibility of the nanogels. The cellular uptake and localization was assessed by confocal microscopy. The cytotoxicity (MTT assay) on HaCaT cell line demonstrated high cytocompatibilty of the nanogels. An ex vivo evaluation using porcine skin displayed efficient and steady state flux of 5-FU from the biodegradable nanogles into the skin, while the histology of the porcine skin revealed enhanced penetration potential of eucalyptus oil coated PLGA-chitosan double walled nanogels. Taken together the in vivo and ex vivo results portend promising potential for the utility of the biodegradable nanogels for treating skin cancers.

Nanomedicine for cancer diagnosis and therapy: advancement, success and structure-activity relationship.

Multifunctional nanoparticles (NPs), composed of organic and inorganic materials, have been explored as promising drug-delivery vehicles for cancer diagnosis and therapy. The success of nanosystems has been attributed to its smaller size, biocompatibility, selective tumor accumulation and reduced toxicity. The relationship among numbers of molecules in payload, NP diameter and encapsulation efficacy have crucial role in clinical translation. Advancement of bioengineering, and systematic fine-tuning of functional components to NPs have diversified their optical and theranostic properties. In this review, we summarize wide varieties of NPs, such as ultrasmall polymer-lipid hybrid NPs, dendrimers, liposomes, quantum dots, carbon nanotubes, gold NPs and iron oxide NPs. We also discuss their tumor targetability, tissue penetration, pharmacokinetics, and therapeutic and diagnostic properties. [Formula: see text].

Recent advances in TPGS-based nanoparticles of docetaxel for improved chemotherapy.

Docetaxel (DTX) is one of the important antitumor drugs, being used in several common chemotherapies to control leading cancer types. Severe toxicities of the DTX are prominent due to sudden parenteral exposure of desired loading dose to maintain the therapeutic concentration. Field of nanotechnology is leading to resist sudden systemic exposure of DTX with more specific delivery to the site of cancer. Further nanometric size range of the formulation aid for prolonged circulation, thereby extensive exposure results better efficacy. In this article, we extensively reviewed the therapeutic benefit of incorporating d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS, or simply TPGS) in the nanoparticle (NP) formulation of DTX for improved delivery, tumor control and tolerability. TPGS is well accepted nonionic-ampiphilic polymer which has been identified in the role of emulsifier, stabilizer, penetration enhancer, solubilizer and in protection in micelle. Simultaneously, P-glycoprotein inhibitory activity of TPGS in the multidrug resistant (MDR) cancer cells along with its apoptotic potential are the added advantage of TPGS to be incorporated in nano-chemotherapeutics. Thus, it could be concluded that TPGS based nanoparticulate application is an advanced approach to improve therapeutic efficacy of chemotherapeutic agents by better internalization and sustained retention of the NPs.