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1.
Nanoscale Horiz ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32510090

RESUMO

Organ-specific cell-penetrating peptides (CPPs) are a class of molecules that can be highly effective at delivering therapeutic cargoes, and they are currently of great interest in cancer treatment strategies. Herein, we describe a new CPP (amino acid sequence serine-isoleucine-tyrosine-valine, or SIWV) that homes to glioblastoma multiforme (GBM) brain tumor tissues with remarkable specificity in vitro and in vivo. The SIWV sequence was identified from an isoform of annexin-A3 (AA3H), a membrane-interacting human protein. The mechanism of intracellular permeation is proposed to follow a caveolin-mediated endocytotic pathway, based on in vitro and in vivo receptor inhibition and genetic knockdown studies. Feasibility as a targeting agent for therapeutics is demonstrated in a GBM xenograft mouse model, where porous silicon nanoparticles (pSiNPs) containing the clinically relevant anticancer drug SN-38 are grafted with SIWV via a poly-(ethylene glycol) (PEG) linker. The formulation shows enhanced in vivo targeting ability relative to a formulation employing a scrambled control peptide, and significant (P < 0.05) therapeutic efficacy relative to free SN-38 in the GBM xenograft animal model.

2.
ACS Sens ; 5(5): 1247-1248, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32438814
3.
Drug Deliv ; 27(1): 703-711, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32393079

RESUMO

Mesoporous silica has attracted significant attention in the drug delivery area; however, impurities can be a source of toxicity. The current study used commercial microparticles produced at large scale in a well-controlled environment. Micrometer sized mesoporous silica particles were acquired through a commercial vendor and pore structures were characterized by SEM. The three silica particle formulations had a diameter of 15 micrometers and three different pore sizes of 10 nm, 30 nm, and 100 nm. The fourth formulation had particle size of 20-40 micrometers with 50 nm pores. Before in vivo tests, an in vitro cytotoxicity test was conducted with silicic acid, derived from the sol-gel particles, on EA.hy926 cells. Low concentration (2.5 µg/mL) of silicic acid showed no cytotoxicity; however, high concentration (25 µg/mL) was cytotoxic. In vivo intravitreal injection demonstrated that 15 um silica particles with 10 nm pore were safe in both rabbit and guinea pig eyes and the particles lasted in the vitreous for longer than two months. Formulations of with larger pores demonstrated variable localized vitreous cloudiness around the sol-gel particle depot and mild inflammatory cells in the aqueous humor. The incidence of reaction trended higher with larger pores (10 nm: 0%, 30 nm: 29%, 50 nm: 71%, 100 nm: 100%, p < .0001, Cochran Armitage Trend Test). Sol-gel mesoporous silica particles have uniform particle sizes and well-defined pores, which is an advantage for implantation via a fine needle. Selected formulations may be used as an intraocular drug delivery system with proper loading and encapsulation.

6.
Nanoscale ; 12(4): 2333-2339, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31930266

RESUMO

Synthetic DNA-based oligonucleotides are loaded into porous silicon nanoparticles (pSiNPs) and incorporated into nanofibers of poly(lactide-co-glycolide) (PLGA), poly-l-lactic acid (PLA), or polycaprolactone (PCL). The resulting hybrid nanofibers are characterized for their ability to release the functional oligonucleotide payload under physiologic conditions. Under temperature and pH conditions mimicking physiological values, the PLGA-based nanofibers release >80% of their DNA cargo within 5 days, whereas the PLA and PCL-based fibers require 15 days to release >80% of their cargo. The quantity of DNA released scales with the quantity of DNA-loaded pSiNPs embedded in the nanofibers; mass loadings of between 2.4 and 9.1% (based on mass of DNA-pSiNP construct relative to mass of polymer composite) are investigated. When a responsive DNA-based nanodevice (i.e. molecular beacon) is used as a payload, it retains its functionality during the release period, independent of the polymer used for the formation of the nanofibers.

7.
Nanoscale ; 11(46): 22248-22254, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31746913

RESUMO

Most current nanoparticle-based PET tracers are radiolabeled through metal chelators conjugated on the nanoparticle surface. Metal chelation usually requires sophisticated optimization and may impact the physical or chemical properties of nanoparticles, which leads to the changes in their distribution and pharmacokinetics in vivo. A chelator-free radiolabeling approach is thus highly desirable. Here, we report that zinc sulfide (ZnS) quantum dots (QDs) can be rapidly radiolabeled with 68Ga or 64Cu through cation exchange without chelators. The radiolabeling was accomplished in times as short as 5 min at 37 °C in aqueous solution, yielding a high labeling efficiency and radiochemical purity for both isotopes. Surface functionalization with targeting peptides was also readily achieved to enable or enhance the cellular uptake of QDs. In vivo PET imaging showed that 64Cu-labeled QDs had a much higher tumor uptake (7.3% ID g-1) than 64Cu-DOTA in a murine cancer model. Overall, this study presents a QD-based platform to achieve convenient and chelator-free radiolabeling, and improve PET imaging of solid tumors.


Assuntos
Quelantes/química , Pontos Quânticos/química , Compostos Radiofarmacêuticos/química , Animais , Linhagem Celular Tumoral , Radioisótopos de Cobre/química , Radioisótopos de Gálio/química , Meia-Vida , Humanos , Marcação por Isótopo , Camundongos , Neoplasias/diagnóstico , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Pontos Quânticos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Sulfetos/química , Transplante Heterólogo , Compostos de Zinco/química
9.
Adv Mater ; 31(49): e1903637, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31566258

RESUMO

With the recent FDA approval of the first siRNA-derived therapeutic, RNA interference (RNAi)-mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA-mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi , Animais , Edição de Genes/métodos , Humanos , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos
10.
Adv Mater ; 31(35): e1902952, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31267590

RESUMO

Despite the promise of ribonucleic acid interference therapeutics, the delivery of oligonucleotides selectively to diseased tissues in the body, and specifically to the cellular location in the tissues needed to provide optimal therapeutic outcome, remains a significant challenge. Here, key material properties and biological mechanisms for delivery of short interfering RNAs (siRNAs) to effectively silence target-specific cells in vivo are identified. Using porous silicon nanoparticles as the siRNA host, tumor-targeting peptides for selective tissue homing, and fusogenic lipid coatings to induce fusion with the plasma membrane, it is shown that the uptake mechanism can be engineered to be independent of common receptor-mediated endocytosis pathways. Two examples of the potential broad clinical applicability of this concept in a mouse xenograft model of ovarian cancer peritoneal carcinomatosis are provided: silencing the Rev3l subunit of polymerase Pol ζ to impair DNA repair in combination with cisplatin; and reprogramming tumor-associated macrophages into a proinflammatory state.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Endossomos/metabolismo , Nanopartículas/química , Peptídeos/metabolismo , RNA Interferente Pequeno/química , Silício/química , Animais , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Camundongos , Porosidade , RNA Interferente Pequeno/genética
11.
ACS Appl Mater Interfaces ; 11(30): 27162-27169, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31310495

RESUMO

The synthesis of microribbons based on the assembly of porous silicon nanoparticles (pSiNPs) in a silica matrix is reported. The formation of these structures is driven by dissolution and reprecipitation of silica derived from the NPs upon drying of an aqueous colloidal dispersion. The process generates composite films that fracture into filaments due to geometric stresses associated with drying of the film on a curved surface. By controlling NP concentration, solvent, and temperature during the evaporation process, well-defined microribbons with a rectangular cross section of ∼25 × 100 microns and lengths on the order of 1 cm are formed. Partial thermal oxidation of the ribbons generates luminescent Si-SiO2 core-shell composites, and complete oxidation generates porous SiO2 ribbons with retention of the mesoporous nanostructure. The pores can be infiltrated with daunorubicin as a model drug, and the resulting material shows sustained release of the chemotherapeutic for more than 70 days.

12.
ACS Appl Mater Interfaces ; 11(27): 23926-23937, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31251556

RESUMO

Silencing of aberrantly expressed microRNAs (miRNAs or miRs) has emerged as one of the strategies for molecular targeted cancer therapeutics. In particular, miR-21 is an oncogenic miRNA overexpressed in many tumors, including ovarian cancer. To achieve efficient administration of anti-miR therapeutics, delivery systems are needed that can ensure local accumulation in the tumor environment, low systemic toxicity, and reduced adverse side effects. In order to develop an improved anti-miR therapeutic agent for the treatment of ovarian cancer, a nanoformulation is engineered that leverages biodegradable porous silicon nanoparticles (pSiNPs) encapsulating an anti-miR-21 locked nucleic acid payload and displaying a tumor-homing peptide for targeted distribution. Targeting efficacy, miR-21 silencing, and anticancer activity are optimized in vitro on a panel of ovarian cancer cell lines, and a formulation of anti-miR-21 in a pSiNP displaying the targeting peptide CGKRK is identified for in vivo evaluation. When this nanoparticulate agent is delivered to mice bearing tumor xenografts, a substantial inhibition of tumor growth is achieved through silencing of miR-21. This study presents the first successful application of tumor-targeted anti-miR porous silicon nanoparticles for the treatment of ovarian cancer in a mouse xenograft model.


Assuntos
Portadores de Fármacos , MicroRNAs , Nanopartículas , Neoplasias Ovarianas , Silício , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , MicroRNAs/química , MicroRNAs/genética , MicroRNAs/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Porosidade , Silício/química , Silício/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Vis Exp ; (146)2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-31058889

RESUMO

With the advent of gene therapy, the development of an effective in vivo nucleotide-payload delivery system has become of parallel import. Fusogenic porous silicon nanoparticles (F-pSiNPs) have recently demonstrated high in vivo gene silencing efficacy due to its high oligonucleotide loading capacity and unique cellular uptake pathway that avoids endocytosis. The synthesis of F-pSiNPs is a multi-step process that includes: (1) loading and sealing of oligonucleotide payloads in the silicon pores; (2) simultaneous coating and sizing of fusogenic lipids around the porous silicon cores; and (3) conjugation of targeting peptides and washing to remove excess oligonucleotide, silicon debris, and peptide. The particle's size uniformity is characterized by dynamic light scattering, and its core-shell structure may be verified by transmission electron microscopy. The fusogenic uptake is validated by loading a lipophilic dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), into the fusogenic lipid bilayer and treating it to cells in vitro to observe for plasma membrane staining versus endocytic localizations. The targeting and in vivo gene silencing efficacies were previously quantified in a mouse model of Staphylococcus aureus pneumonia, in which the targeting peptide is expected to help the F-pSiNPs to home to the site of infection. Beyond its application in S. aureus infection, the F-pSiNP system may be used to deliver any oligonucleotide for gene therapy of a wide range of diseases, including viral infections, cancer, and autoimmune diseases.


Assuntos
Nanopartículas/química , Oligonucleotídeos/administração & dosagem , Silício/química , Animais , Inativação Gênica , Humanos , Camundongos , Tamanho da Partícula , Porosidade , Staphylococcus aureus/fisiologia
14.
Front Chem ; 7: 165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984738

RESUMO

We propose a rapid, one-pot method to generate photoluminescent (PL) mesoporous silicon nanoparticles (PSiNPs). Typically, mesoporous silicon (meso-PSi) films, obtained by electrochemical etching of monocrystalline silicon substrates, do not display strong PL because the silicon nanocrystals (nc-Si) in the skeleton are generally too large to display quantum confinement effects. Here we describe an improved approach to form photoluminescent PSiNPs from meso-PSi by partial oxidation in aqueous sodium borate (borax) solutions. The borax solution acts to simultaneously oxidize the nc-Si surface and to partially dissolve the oxide product. This results in reduction of the size of the nc-Si core into the quantum confinement regime, and formation of an insulating silicon dioxide (SiO2) shell. The shell serves to passivate the surface of the silicon nanocrystals more effectively localizing excitons and increasing PL intensity. We show that the oxidation/dissolution process can be terminated by addition of excess citric acid, which changes the pH of the solution from alkaline to acidic. The process is monitored in situ by measurement of the steady-state PL spectrum from the PSiNPs. The measured PL intensity increases by 1.5- to 2-fold upon addition of citric acid, which we attribute to passivation of non-radiative recombination centers in the oxide shell. The measured PL quantum yield of the final product is up to 20%, the PL activation procedure takes <20 min, and the resulting material remains stable in aqueous dispersion for at least 1 day. The proposed phenomenological model explaining the process takes into account both pH changes in the solution and the potential increase in solubility of silicic acid due to interaction with sodium cations.

15.
J Control Release ; 301: 42-53, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30871996

RESUMO

Macrophages play important and diverse roles during cancer progression. However, cancer therapies based on macrophage modulation are lacking in tools that can recognize and deliver therapeutic payloads to macrophages in a tumor-specific manner. As a result, treatments tend to interfere with normal macrophage functions in healthy organs. We previously identified a macrophage-binding peptide, termed CRV. Here, we show that upon systemic administration into tumor-bearing mice, CRV selectively homes to tumors, extravasates, and preferentially binds to macrophages within. CRV exhibits a higher affinity for tumor macrophages than for other cells in tumors or for other macrophage types elsewhere in the body. We further identified and validated retinoid X receptor beta (RXRB) as the CRV receptor. Intriguingly, although it is known as a nuclear receptor, RXRB shows a prominent cell surface localization that is largely restricted to tumor macrophages. Systemic administration of anti-RXRB antibodies also results in tumor-selective binding to macrophages similar to CRV. Lastly, we demonstrate the ability of CRV to improve the delivery of nano-carriers into solid tumors and macrophages within. In summary, we describe here a novel cell surface marker and targeting tools for tumor macrophages that may aid in future development of macrophage-modulatory cancer therapies.

16.
ACS Sens ; 4(2): 265-266, 2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30791689
18.
Adv Mater ; 30(35): e1802878, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30003620

RESUMO

A nanoparticle system for systemic delivery of therapeutics is described, which incorporates a means of tracking the fate of the nanocarrier and its residual drug payload in vivo by photoluminescence (PL). Porous silicon nanoparticles (PSiNPs) containing the proapoptotic antimicrobial peptide payload, D [KLAKLAK]2 , are monitored by measurement of the intrinsic PL intensity and the PL lifetime of the nanoparticles. The PL lifetime of the PSiNPs is on the order of microseconds, substantially longer than the nanosecond lifetimes typically exhibited by conventional fluorescent tags or by autofluorescence from cells and tissues; thus, emission from the nanoparticles is readily discerned in the time-resolved PL spectrum. It is found that the luminescence lifetime of the PSiNP host decreases as the nanoparticle dissolves in phosphate-buffered saline solution (37 °C), and this correlates with the extent of release of the peptide payload. The time-resolved PL measurement allows tracking of the in vivo fate of PSiNPs injected (via tail vein) into mice. Clearance of the nanoparticles through the liver, kidneys, and lungs of the animals is observed. The luminescence lifetime of the PSiNPs decreases with increasing residence time in the mice, providing a measure of half-life for degradation of the drug nanocarriers.


Assuntos
Nanopartículas , Animais , Luminescência , Camundongos , Peptídeos , Porosidade , Silício
19.
Drug Deliv ; 25(1): 1537-1545, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29996687

RESUMO

The number of blind and low vision persons in the US is projected to increase to 5.68 million by 2020. The eye diseases causing loss of vision are life-long, chronic, and often need protracted presence of therapeutics at the disease site to keep the disease in remission. In addition, multiple pathologies participate in the disease process and a single therapy seems insufficient to bring the disease under control and prevent vision loss. This study demonstrates the use of porous silicon (pSi) particles sequentially loaded with daunorubicin (DNR) and dexamethasone (DEX) to create a synergistic intravitreally injectable dual-drug delivery system. DEX targets chronic inflammation while DNR inhibits excessive cell proliferation as well as suppresses hypoxia-inducible factor 1 to reduce scarring. This pSi-based delivery system releases therapeutic concentrations of DNR for 100 days and DEX for over 165 days after a single dose. This intravitreal dual-drug delivery system is also well tolerated after injection into the rabbit eye model, attested by ocular biomicroscopy, ocular tonometry, electroretinography, and histology. This novel dual-drug delivery system opens an attractive modality for combination therapy to manage refractory chorioretinal diseases and further preclinical studies are warranted to evaluate its efficacy.


Assuntos
Daunorrubicina/administração & dosagem , Dexametasona/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Silício/administração & dosagem , Corpo Vítreo/efeitos dos fármacos , Animais , Anti-Inflamatórios , Antibióticos Antineoplásicos , Daunorrubicina/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/metabolismo , Dexametasona/metabolismo , Sinergismo Farmacológico , Feminino , Masculino , Microesferas , Tamanho da Partícula , Porosidade/efeitos dos fármacos , Coelhos , Silício/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Corpo Vítreo/metabolismo
20.
Nat Biomed Eng ; 2(2): 95-103, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29955439

RESUMO

Bacterial resistance to antibiotics has made it necessary to resort to antibiotics that have considerable toxicities. Here, we show that the cyclic 9-amino acid peptide CARGGLKSC (CARG), identified via phage display on Staphylococcus aureus (S. aureus) bacteria and through in vivo screening in mice with S. aureus-induced lung infections, increases the antibacterial activity of CARG-conjugated vancomycin-loaded nanoparticles in S. aureus-infected tissues and reduces the needed overall systemic dose, minimizing side effects. CARG binds specifically to S. aureus bacteria but not Pseudomonas bacteria in vitro, selectively accumulates in S. aureus-infected lungs and skin of mice but not in non-infected tissue and Pseudomonas-infected tissue, and significantly enhances the accumulation of intravenously injected vancomycin-loaded porous silicon nanoparticles bearing the peptide in S. aureus-infected mouse lung tissue. The targeted nanoparticles more effectively suppress staphylococcal infections in vivo relative to equivalent doses of untargeted vancomycin nanoparticles or of free vancomycin. The therapeutic delivery of antibiotic-carrying nanoparticles bearing peptides targeting infected tissue may help combat difficult-to-treat infections.

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