Virus-mimicking mesoporous organosilica nanocapsules with soft framework and rough surface for enhanced cellular uptake and tumor penetration.

An enveloped virus with soft and rough shells has strong penetration ability for cells. Inspired by the unique structure of virus, we successfully constructed virus-mimicking mesoporous organosilica nanocapsules (denoted as VMONs) for the first time by decorating small-sized silica nanoparticles on soft mesoporous organosilica hollow spheres. TEM and SEM images reveal that the prepared VMONs display uniform diameters (240 nm), a soft framework, a rough surface, and excellent dispersity. Quantitative nanomechanical mapping further demonstrates that the VMONs possess an extremely low Young's modulus (36 MPa) and a scraggly surface. In view of the successful construction of the virus-mimicking nanocapsules, the VMONs are further modified with human serum albumin (HSA) and Cy5.5-maleimide (Mal-Cy5.5) to investigate their cell penetration ability. Flow cytometry analysis reveals that the internalization of VMONs@HSA-Cy5.5 increases 2.74-fold compared to that of the conventional mesoporous nanosphere. Confocal laser scanning microscopy images show that the VMONs@HSA-Cy5.5 diffuses deeper for multicellular spheroids compared to both hard and soft mesoporous organosilica nanospheres. The penetration ability of the VMONs and SMONs increases 18.49 and 6.13-fold compared to that of MONs at the depth of 60 µm. Thanks to the excellent cellular penetration ability, the virus-mimicking VMONs@HSA-Cy5.5 can effectively deliver the anticancer drug doxorubicin (Dox) into drug-resistant MCF-7/ADR human breast cancer cells and significantly enhance the chemotherapeutic efficacy. Taken together, the constructed virus-mimicking organosilica nanocapsules with a soft framework and a rough surface possess strong cellular internalization and tumor penetration abilities, providing a unique and effective nanoplatform for biomedical applications.

Rapid One-Step 18F-Labeling of Peptides via Heteroaromatic Silicon-Fluoride Acceptors.

A new class of organosilicon-based radiosynthons, heteroaromatic silicon-fluoride acceptors, namely, HetSiFAs, that readily undergo isotope exchange with dry [18F]fluoride at room temperature in high radiochemical yield (up to 94%) with good molar activity is reported. Radiofluorination proceeds in a single step in 2 min without high-performance liquid chromatography purification to provide an operationally simple method for 18F-PET tracer production. This method was used to prepare an 18F-labeled commercial tetrapeptide, and positron emission tomography imaging confirmed in vivo stability.

Tetraphenylsilane-Cored Star-Shaped Polymer Micelles with pH/Redox Dual Response and Active Targeting Function for Drug-Controlled Release.

This paper presents the design and synthesis of star-shaped copolymers with two poly[2-(diethylamino)ethyl methacrylate] and poly(ethylene glycol) blocks linked via a disulfide bond and each end of the four arms capped by folic acid (FA), from which the prepared nanodrug carriers simultaneously possess pH/redox dual response and active targeting functions. The polymer micelles exhibit excellent stability as reflected by their low critical micelle concentration values of 1.03-2.51 mg/L. The doxorubicin (DOX)-loaded polymer micelles are in the range of 108 to 143 nm, and the DOX-loading capacities are found to be up to 32.3%. The sensitive pH and redox responses are demonstrated by examining the drug release behaviors under the varied acidic condition from pH 7.4 to 5.0 and the glutathione concentrations from 0 to 10 mM, respectively. Moreover, the observation of confocal laser scanning microscopy confirms that the functionalization of arm ends by FA indeed enhances the internalization of DOX-loaded micelle particles in HeLa cells. As a result, the DOX-loaded nanocarriers can deliver therapeutic drugs to target HeLa cells, and the viability of HeLa cells (10.1%) approaches the value of the pristine DOX (9.98%), showing promising application as drug delivery nanocarriers for safe and highly efficient cancer therapy.

Size effect of mesoporous organosilica nanoparticles on tumor penetration and accumulation.

The size effect of mesoporous organosilica nanoparticles (MONs) on tumor penetration and accumulation remains poorly understood, which strongly affects the tumor therapeutic efficacy. Herein, four different-sized thioether-bridged MONs (20, 40, 60, and 100 nm) are synthesized; all the MONs have a spherical morphology, excellent dispersity, similar surface charge, uniform mesopores (3.2-3.5 nm), and large surface areas (709-1353 m2·g-1). Hematology and histopathology analyses demonstrate that the four MONs do not cause pathological changes in mice even at a dose of 20 mg kg-1 for 30 d. The penetration depth of the MONs for multicellular spheroids (MCSs) decreases with increasing particle sizes, and the 20 nm MONs are uniformly distributed in the MCSs at a depth of 60 µm, while the larger MONs are mainly restricted to peripheral areas. In vivo experiments show that the 40 nm MONs possess the longest mean residence times, leading to their highest accumulation in blood and tumors. However, the 20 nm MONs reach the deepest penetration depth of 1230 µm for xenograft tumors. In contrast, the penetration depths of 40, 60, and 100 nm MONs are 783, 105, and 40 µm, respectively. Overall, this work provides an important guideline for the rational design of nanoplatforms for tumor treatment.

Pharmacokinetic modeling of the blood-stable camptothecin analog AR-67 in two different formulations.

AR-67 is a lipophilic camptothecin analog currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Cremophor, an alternative cyclodextrin (SBE-ß-CD) based formulation has been proposed. Pharmacokinetic (PK) studies were conducted in mice and the SBE-ß-CD based formulation was compared with the Cremophor EL formulation. PK studies were conducted following intravenous or oral administration of AR-67 in either Cremophor or SBE-ß-CD formulation in mice. Noncompartmental analysis was used to determine the plasma and tissue drug distribution. A non-linear mixed effects (population) PK model was developed to fit both the oral and intravenous data and to estimate key PK parameters. The effect of formulation was explored as a covariate in the PK model. AR-67 in the SBE-ß-CD formulation had similar plasma PK and biodistribution to that in the Cremophor EL formulation. The proposed two-compartment model described the plasma PK of AR-67 in both formulations adequately. AR-67 in the SBE-ß-CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate that SBE-ß-CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR-67.

Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells.

Ovarian cancer represents the seventh most commonly diagnosed cancer worldwide. Herein, we report on the development of a withaferin A (WA)-silyl ether library with 30 analogues reported for the first time. Cytotoxicity assays on human epithelial ovarian carcinoma cisplatin-sensitive and -resistant cell lines identified eight analogues displaying nanomolar potency (IC50 ranging from 1 to 32 nM), higher than that of the lead compound and reference drug. This cytotoxic potency is also coupled with a good selectivity index on a nontumoral cell line. Cell cycle analysis of two potent analogues revealed cell death by apoptosis without indication of cell cycle arrest in G0/G1 phase. The structure-activity relationship and in silico absorption, distribution, metabolism, and excretion studies demonstrated that the incorporation of silicon and a carbonyl group at C-4 in the WA framework enhances potency, selectivity, and drug likeness. These findings reveal analogues 22, 23, and 25 as potential candidates for clinical translation in patients with relapsed ovarian cancer.

Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors.

Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N = 26) were treated at nine dosage levels (1.2-12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics. Results A two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emax models showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose. Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.

Floating molecularly imprinted polymers based on liquid crystalline and polyhedral oligomeric silsesquioxanes for capecitabine sustained release.

Molecularly imprinted polymers (MIPs) have drawn extensive attention as carriers on drug delivery. However, most of MIPs suffer from insufficient drug loading capacity, burst release of drugs and/or low bioavailability. To solve the issues, this study designed an imprinted material with superior floating nature for oral drug delivery system of capecitabine (CAP) rationally. The MIPs was synthesized in the presence of 4-methylphenyl dicyclohexyl ethylene (liquid crystalline, LC) and polyhedral oligomeric silsesquioxanes (POSS) via polymerization reaction. The LC-POSS MIPs had extended release of the template molecules over 13.4 h with entrapment efficiency of 20.53%, diffusion coefficient of 2.83 × 10-11 cm2 s-1, and diffusion exponent of 0.84. Pharmacokinetic studies further revealed the prolong release and high relative bioavailability of CAP in vivo of rats, showing the effective floating effect of the LC-POSS MIPs. The in vivo images revealed visually that the gastroretentive time of the LC-POSS MIPs was longer than non-LC-POSS imprinted polymers. The physical characteristics of the polymers were also characterized by nitrogen adsorption experiment, scanning electron microscopy, thermogravimetric analysis and differential scanning calorimetry analysis. As a conclusion, the LC-POSS MIPs can be used as an eligible CAP carrier and might hold great potential in clinical applications for sustained release drug.

Chemodrug-Gated Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Multimodal Imaging-Guided Low-Temperature Photothermal Therapy/Chemotherapy of Cancer.

Noninvasive physical treatment with relatively low intensity stimulation and the development of highly efficient anticancer medical strategy are still desirable for cancer therapy. Herein a versatile, biodegradable, hollow mesoporous organosilica nanocapsule (HMONs) nanoplatform that is capped by the gemcitabine (Gem) molecule through a pH-sensitive acetal covalent bond is designed. The fabricated nanocapsule exhibits desirable small molecule release at the tumor tissues/cell sites and shows a reduced risk for drug accumulation. After loading indocyanine green (ICG), the heat-shock protein 90 (Hsp 90) inhibitor, and 17AAG and modification with polyethylene glycol (NH2-PEG), the resulting ICG-17AAG@HMONs-Gem-PEG exhibited a precisely controlled release of ICG and 17AAG and low-temperature photothermal therapy (PTT) (∼41 °C) with excellent tumor destruction efficacy. In addition, ICG loading conferred the nanoplatform with near-infrared fluorescence imaging (FL) and photoaccoustic (PA) imaging capability. In short, this work not only presents a smart drug self-controlled nanoplatform with pH-responsive payload release and theranostic performance but also provides an outstanding low-temperature PTT strategy, which is highly valid in the inhibition of cancer cells with minimal damage to the organism. Therefore, this research provides a paradigm that has a chemodrug-gated HMONs-based theranostic nanoplatform with intrinsic biodegradability, multimodal imaging capacity, high low-temperature PTT/chemotherapy efficacy, and reduced systemic toxicity.

Effect of multiple cyclic RGD peptides on tumor accumulation and intratumoral distribution of IRDye 700DX-conjugated polymers.

Strategic delivery of IRDye 700DX (photosensitizer) is a key for improving its effect in photodynamic therapy. In this study, we have synthesized IRDye 700DX-conjugated polymers containing multiple cyclic RGD peptides to deliver IRDye 700DX selectively to tumor cells and tumor-associated blood vessels overexpressing αvß3 integrin. Our polymer has a backbone of hydrophilic poly(ethylene glycol)-poly(L-glutamic acid) block copolymer, and cyclic RGD peptides are conjugated to side chains of the poly(L-glutamic acid) while IRDye 700DX is conjugated to the terminal of poly(ethylene glycol). The polymers exhibited selective accumulation to the target sites in a subcutaneous solid tumor, and the accumulation was augmented with the increased number of cyclic RGD peptides. More importantly, the polymer containing 15 cyclic RGD peptides in one construct revealed preferential accumulation on the tumor-associated blood vessels without compromising penetration to deep portions of the tumor, thereby drastically inhibiting tumor growth upon photoirradiation, while the polymer containing 5 cyclic RGD peptides showed moderate antitumor activity despite efficient accumulation in the tumor with almost homogenous intratumoral distribution. These results suggest that controlling the intratumoral distribution of IRDye 700DX is critical for successful PDT, and our polymer containing multiple cyclic RGD peptides may be a promising carrier for this spatial control.

TIPS pentacene loaded PEO-PDLLA core-shell nanoparticles have similar cellular uptake dynamics in M1 and M2 macrophages and in corresponding in vivo microenvironments.

Nanoparticle based drug delivery platforms have the potential to transform disease treatment paradigms and therapeutic strategies, especially in the context of pulmonary medicine. Once administered, nanoparticles disperse throughout the lung and many are phagocytosed by macrophages. However, there is a paucity of knowledge regarding cellular up-take dynamics of nanoparticles due largely to macrophage heterogeneity. To address this issue, we sought to better define nanoparticle up-take using polarized M1 and M2 macrophages and novel TIPS-pentacene loaded PEO-PDLLA nanoparticles. Our data reveal that primary macrophages polarized to either M1 or M2 phenotypes have similar levels of nanoparticle phagocytosis. Similarly, M1 and M2 polarized macrophages isolated from the lungs of mice following either acute (Th1) or allergic (Th2) airway inflammation also demonstrated equivalent levels of nanoparticle up-take. Together, these studies provide critical benchmark information pertaining to cellular up-take dynamics and biodistribution of nanoparticles in the context of clinically relevant inflammatory microenvironments.

Targeted iron-oxide nanoparticle for photodynamic therapy and imaging of head and neck cancer.

Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer therapies. PDT has been under development for decades, but light-associated toxicity limits its clinical applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp), which binds integrin ß1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than nonformulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than nontargeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.

Rapid (18)F-labeling and loading of PEGylated gold nanoparticles for in vivo applications.

Water-soluble 3 nm maleimide-terminated PEGylated gold nanoparticles (maleimide-AuNP) were synthesized in both partially hydrolyzed and nonhydrolyzed forms. Both of these maleimide-AuNPs, when reacted with the silicon-fluorine prosthetic group [(18)F]SiFA-SH, resulted in radiolabeled AuNPs. These NPs were readily purified with high radiochemical yields (RCY) of 60-80% via size exclusion chromatography. Preliminary small animal positron emission tomography (PET) measurements in healthy rats gives information about the pathway of excretion and the stability of the radioactive label in vivo. The partially hydrolyzed [(18)F]SiFA-maleimide-AuNPs shows uptake in the brain region of interest (ROI) (> 0.13%ID/g) which was confirmed by ex vivo examination of the thoroughly perfused rat brain. The multiple maleimide end groups on the AuNP surface also allows for the simultaneous incorporation of [(18)F]SiFA-SH and a bioactive peptide (cysteine-modified octreotate, cys-TATE, which can bind to somatostatin receptor subtypes 2 and 5) in a proof-of-concept study. The well-defined Michael addition reaction between various thiol containing molecules and the multifunctionalized maleimide-AuNPs thus offers an opportunity to develop a new bioconjugation platform for new diagnostics as well as therapeutics.

Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.

PURPOSE: Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment. METHODS: After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days. RESULTS: Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial. CONCLUSIONS: We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation.

Silicon-containing GABA derivatives, silagaba compounds, as orally effective agents for treating neuropathic pain without central-nervous-system-related side effects.

Neuropathic pain is a chronic condition resulting from neuronal damage. Pregabalin, the (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), is widely used to treat neuropathic pain, despite the occurrence of central nervous system (CNS)-related side effects such as dizziness and somnolence. Here we describe the pharmacology of novel GABA derivatives containing silicon-carbon bonds, silagaba compounds. Silagaba131, 132, and 161 showed pregabalin-like analgesic activities in animal models of neuropathic pain, but in contrast to pregabalin they did not impair neuromuscular coordination in rotarod tests. Pharmacokinetic studies showed that brain exposure to silagaba compounds was lower than that to pregabalin. Surprisingly, despite their potent analgesic action in vivo, silagaba compounds showed only weak binding to α2-δ protein. These compounds may be useful to study mechanisms of neuropathic pain. Our results also indicate that silagaba132 and 161 are candidates for orally effective treatment of neuropathic pain without CNS-related side effects.

Safety assessment of silylates and surface-modified siloxysilicates.

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate as used in cosmetics. These silylates and surface-modified siloxysilicates function in cosmetics as antifoaming agents, anticaking agents, bulking agents, binders, skin-conditioning agents--emollient, skin-conditioning agents-occlusive, slip modifiers, suspension agents--nonsurfactant, and viscosity increasing agents--nonaqueous. The Expert Panel reviewed the available animal and clinical data as well as information from a previous CIR safety assessment of amorphous silica. The CIR Expert Panel concluded that silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate are safe as used when formulated and delivered in the final product not to be irritating or sensitizing to the respiratory tract.

The effect of breast cancer resistance protein, multidrug resistant protein 1, and organic anion-transporting polypeptide 1B3 on the antitumor efficacy of the lipophilic camptothecin 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in vitro.

AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a lipophilic camptothecin analog, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, we investigated the interplay between the breast cancer resistance protein (BCRP), multidrug resistant protein 1 (MDR1), and organic anion-transporting polypeptide (OATP) 1B1/1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1- and SLCO1B3-transfected cell systems compared with the mock-transfected ones. Notably, both BCRP and MDR1 conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3-expressing cells had increased carboxylate uptake as compared with mock-transfected cells but were not sensitized because the intracellular amount of lactone was 50-fold higher than that of carboxylate and comparable between OATP1B3-expressing and OATP1B3-nonexpressing cells. In conclusion, BCRP- and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3-expressing tumor cells.

A cell-targeted photodynamic nanomedicine strategy for head and neck cancers.

Photodynamic therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intratumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise toward a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas.

A novel luminescent bifunctional POSS as a molecular platform for biomedical applications.

A novel luminescent polyhedral oligomeric silsesquioxane (POSS) containing in the structure a fluorescein derivative molecule and a carboxylic functionality, suitable to anchor different organic compounds (dyes, markers, drugs, contrast agents, …), was successfully synthesized and characterized in this manuscript by a multidisciplinary approach. An emission enhancement of the dye of ca. four times was found after reaction with POSS, rendering this new hybrid compound a promising contrast agent for optical imaging. In vitro tests on tumoral HeLa cells demonstrated that the luminescent POSS (namely POSS_F), here described, is able to be taken up in the cell cytosol by an efficient and selective process. Its high chemical versatility and peculiar properties could render this novel bifunctional POSS a molecular platform for biomedical applications.

Synergistic effects of cell-penetrating peptide Tat and fusogenic peptide HA2-enhanced cellular internalization and gene transduction of organosilica nanoparticles.

The nonviral gene delivery system is an attractive alternative to cancer therapy. A new kind of gelatin-silica nanoparticles (GSNPs) was developed through a two-step sol-gel procedure. To improve the transfection efficacy, GSNPs modified with different fusion peptides (Tat, HA2, R8, Tat/HA2, and Tat/R8) were prepared for particle size, zeta potential, cellular uptake, hemolysis activity at physiological pH (7.0) or acidic pH (5.0), and condensation of plasmid DNA. The results suggest that the sizes and zeta potentials of GS-peptide conjugates were 147 - 161 nm and 19 - 33 mV, respectively; GS-peptide conjugates exhibited low cytotoxicity; the plasmid DNA was readily entrapped at a GS-peptide/pDNA weight ratio of 50 - 200. The in vitro and in vivo studies demonstrated that the synergistic effects of cell-penetrating peptide Tat and fusogenic peptide HA2 could promote the efficient cellular internalization, endosome escape, and nucleus targeting, hence delivering the therapeutic nucleic acid efficiently.