Impact of nanotechnology in cancer: emphasis on nanochemoprevention

Imtiaz A Siddiqui, Vaqar M Adhami, Jean Christopher Chamcheu, Hasan MukhtarDepartment of Dermatology, University of Wisconsin, Madison, WI, USAAbstract: Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and treatment of the disease. Utilization of nanotechnology has enabled the development of devices in nanometer (nm) sizes which could be designed to encapsulate useful agents that have shown excellent results but otherwise are generally toxic due to the doses intended for extended use. In addition, examples are also available where these devices are easily conjugated with several purposeful moieties for better localization and targeted delivery. We introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention. This idea, which we termed as "nanochemoprevention," was subsequently exploited by several laboratories worldwide and has now become an advancing field in chemoprevention research. This review examines some of the up and coming applications of nanotechnology for cancer detection, imaging, treatment, and prevention. Further, we detail the current and future utilization of nanochemoprevention for prevention and treatment of cancer.Keywords: nanochemoprevention, cancer, nanotechnolog

Nanoencapsulation of natural triterpenoid celastrol for prostate cancer treatment

Vanna Sanna,1,2 Jean Christopher Chamcheu,3 Nicolino Pala,1 Hasan Mukhtar,3 Mario Sechi,1,2 Imtiaz Ahmad Siddiqui3 1Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy; 2Laboratory of Nanomedicine, University of Sassari, Sassari, Italy; 3Department of Dermatology, University of Wisconsin, Madison, WI, USA Abstract: Celastrol (CL), a triterpenoid extracted from the Chinese herb Tripterygium wilfordii, has recently attracted interest for its potential antitumor effects. However, unfavorable physicochemical and pharmacokinetics properties such as low solubility, poor bioavailability, and systemic toxicity, are limiting its therapeutic application. In this context, the development of innovative nanocarriers can be useful to overcome these issues, and nanoencapsulation would represent a powerful strategy. In this study, we developed novel CL-loaded poly(ε-caprolactone) nanoparticles (NPs), and investigated their antiproliferative efficacy on prostate cancer cells. CL-NPs were prepared using a nanoprecipitation method and fully characterized by physicochemical techniques. The antiproliferative effects on LNCaP, DU-145, and PC3 cell lines of CL-NPs, compared to those of free CL at different concentrations (0.5, 1.0, and 2.0 µM), were investigated. Moreover, fluorescence microscopy was utilized to examine the cellular uptake of the nanosystems. Furthermore, to elucidate impact of nanoencapsulation on the mechanism of action, Western analyses were conducted to explore apoptosis, migration, proliferation, and angiogenesis alteration of prostate cancer cells. The results confirmed that CL-NPs inhibit proliferation dose dependently in all prostate cancer cells, with inhibitory concentration50 less than 2 µM. In particular, the NPs significantly increased cytotoxicity at lower/medium dose (0.5 and 1.0 µM) on DU145 and PC3 cell lines with respect to free CL, with modulation of apoptotic and cell cycle machinery proteins. To date, this represents the first report on the development of biocompatible polymeric NPs encapsulating CL. Our findings offer new perspectives for the exploitation of developed CL-NPs as suitable prototypes for prostate cancer treatment. Keywords: celastrol, tripterine, nanoparticles, poly(ε-caprolactone), prostate cance

Chitosan-based nanoformulated (–)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis

Jean Christopher Chamcheu,1,2,* Imtiaz A Siddiqui,1,* Vaqar M Adhami,1,* Stephane Esnault,3 Dhruba J Bharali,4 Abiola S Babatunde,1,5 Stephanie Adame,1 Randall J Massey,6 Gary S Wood,1 B Jack Longley,1 Shaker A Mousa,4 Hasan Mukhtar11Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, and the Middleton VA Medical Center, Madison, WI, USA; 2Department of Basic Pharmaceutical Sciences, School of Pharmacy, College of Health and Pharmaceutic Sciences, University of Louisiana at Monroe, Monroe, LA, USA; 3Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, The University of Wisconsin–Madison School of Medicine and Public Health, Madison, WI, USA; 4The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; 5Department of Hematology, University of Ilorin, Ilorin, Nigeria; 6Electron Microscope Facility, Medical School Research Support Progs, School of Medicine and Public Health, University of Wisconsin, and the Middleton VAMedical Center, Madison, WI, USA *These authors contributed equally to this work Background: Psoriasis is a chronic and currently incurable inflammatory skin disease characterized by hyperproliferation, aberrant differentiation, and inflammation, leading to disrupted skin barrier function. The use of natural agents that can abrogate these effects could be useful for the treatment of psoriasis. Earlier studies have shown that treatment of keratinocytes and mouse skin with the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) mitigated inflammation and increased the expression of caspase-14 while promoting epidermal differentiation and cornification. However, bioavailability issues have restricted the development of EGCG for the treatment of psoriasis.Materials and methods: To overcome these limitations, we employed a chitosan-based polymeric nanoparticle formulation of EGCG (CHI-EGCG-NPs, hereafter termed nanoEGCG) suitable for topical delivery for treating psoriasis. We investigated and compared the efficacy of nanoEGCG versus native or free EGCG in vitro and in an in vivo imiquimod (IMQ)-induced murine psoriasis-like dermatitis model. The in vivo relevance and efficacy of nanoEGCG formulation (48 µg/mouse) were assessed in an IMQ-induced mouse psoriasis-like skin lesion model compared to free EGCG (1 mg/mouse).Results: Like free EGCG, nanoEGCG treatment induced differentiation, and decreased proliferation and inflammatory responses in cultured keratinocytes, but with a 4-fold dose advantage. Topically applied nanoEGCG elicited a significant (p<0.01) amelioration of psoriasiform pathological markers in IMQ-induced mouse skin lesions, including reductions in ear and skin thickness, erythema and scales, proliferation (Ki-67), infiltratory immune cells (mast cells, neutrophils, macrophages, and CD4+ T cells), and angiogenesis (CD31). We also observed increases in the protein expression of caspase-14, early (keratin-10) and late (filaggrin and loricrin) markers of differentiation, and the activator protein-1 factor (JunB). Importantly, a significant modulation of several psoriasis-related inflammatory cytokines and chemokines was observed compared to the high dose of free EGCG (p<0.05). Taken together, topically applied nanoEGCG displayed a >20-fold dose advantage over free EGCG.Conclusion: Based on these observations, our nanoEGCG formulation represents a promising drug-delivery strategy for treating psoriasis and possibly other inflammatory skin diseases. Keywords: chitosan nanoparticles, topical delivery of chitosan nanoformulated EGCG, psoriasis-like skin inflammation, phytochemical treatment of psoriasis, normal human epidermal keratinocytes, differentiation, anti-inflammatory actio

Chitosan-Based Nanoformulated (–)-Epigallocatechin-3-Gallate (EGCG) Modulates Human Keratinocyte-Induced Responses and Alleviates Imiquimod-Induced Murine Psoriasiform Dermatitis [Erratum]

Chamcheu JC, Siddiqui IA, Adhami VM, et al. Int J Nanomedicine. 2018;13:4189–4206. An error during the preparation of Figures 1 and 5 for publishing led to the inadvertent creation of duplicate regions in images from these figures on pages 4194 and 4199, respectively. The journal wishes to apologise for this error. The correct versions of Figures 1 and 5 are as follows: Figure 1 Size characterization and encapsulation and loading efficiencies of chitosan-based nanoEGCG. (A) Size measurement and distribution of nanoEGCGusing dynamic light scattering. (B) Zeta potential measurement of nanoEGCG. (C) Representative transmission electron microscopy photomicrographs showing the relative homogeneous size and morphology of (i) diluted nanoEGCGand (ii) undiluted nanoEGCG, and (iii) CHI-Void-NPs. Scale bar=200 nm; the insets represent higher magnification. (D) Encapsulation and loading efficiency of EGCG on to chitosan nanoparticles as monitored with UV-vis spectra for free EGCG (not encapsulated) and total EGCG (encapsulated + free). (E) UV-vis spectra used to construct the standard curve, with EGCGconcentrations of 25, 12.5, 6.25, 3.12, and 1.6 μg/mL.Abbreviations: EGCG, (–)-epigallocatechin-3-gallate; nanoEGCG, CHI-EGCG-NPs, chitosan-based polymeric nanoparticle formulation of EGCG; CHI-Void-NPs, chitosan-based void (without EGCG) nanoparticles; UV-vis, ultraviolet–visible. Figure 5 Effect of topically applied free EGCG and nanoEGCG on infiltrating immune cells and expression of differentiation markers in IMQ-treated mouse skin lesions: Mice were treated in 4 groups as described in the legends to Figure 4 and Figure S5. (A–D, F–I, K–N, P–S) Photomicrographs showing immunohistological features of: (A–D) mast cells (toluidine blue staining); (F–I) epidermis/dermis (NE, brown staining), and microabscesses (arrow); (K–N) macrophages (F4/80, red staining); and (P–S) double immunofluorescence staining for loricrin (green) and T-lymphocytes (CD4+, red staining). Nuclei were counterstained blue with DAPI. Magnification for all panels ×200. (E, J, O, T, U) Quantitative analyses of changes in immune cells: (E) mast cells; (J) NE+ cells; (O) F4/80+ cells; and (U) loricrin in the 4 treatment groups. Each data point represents the mean±SD of 4 random fields/mouse from 5 mice/group. *p, 0.05, **p, 0.01, ***p, 0.001, and ****p, 0.0001 for the indicated 2-way comparisons.Abbreviations: EGCG, (–)-epigallocatechin-3-gallate; nanoEGCG, chitosan-based polymeric nanoparticle formulation of EGCG; IMQ, imiquimod; NE, neutrophil elastase; LPV, low-power view