Occult nodal metastases increase the risk of cancer recurrence, demoting prognosis and quality of life of patients. While targeted drug delivery by using systemically administered nanocarriers can ...potentially control metastatic disease, lymph node metastases have been mainly dealt by locally injecting nanocarriers, which may not always be applicable. Herein, we demonstrated that sub-50 nm polymeric micelles incorporating platinum anticancer drugs could target lymph node metastases in a syngeneic melanoma model after systemic injection, even after removing the primary tumors, limiting the growth of the metastases. By comparing these micelles with clinically used doxorubicin-loaded liposomes (Doxil) having 80 nm, as well as a 70 nm version of the micelles, we found that the targeting efficiency of the nanocarriers against lymph node metastases was associated with their size-regulated abilities to extravasate from the blood vasculature in metastases and to penetrate within the metastatic mass. These findings indicate the potential of sub-50 nm polymeric micelles for developing effective conservative treatments against lymph node metastasis capable of reducing relapse and improving survival.
Small interfering ribonucleic acid (siRNA) cancer therapies administered by intravenous injection require a delivery system for transport from the bloodstream into the cytoplasm of diseased cells to ...perform the function of gene silencing. Here we describe nanosized polymeric micelles that deliver siRNA to solid tumors and elicit a therapeutic effect. Stable multifunctional micelle structures on the order of 45 nm in size formed by spontaneous self-assembly of block copolymers with siRNA. Block copolymers used for micelle formation were designed and synthesized to contain three main features: a siRNA binding segment containing thiols, a hydrophilic nonbinding segment, and a cell-surface binding peptide. Specifically, poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLL) comprising lysine amines modified with 2-iminothiolane (2IT) and the cyclo-Arg-Gly-Asp (cRGD) peptide on the PEG terminus was used. Modification of PEG-b-PLL with 2IT led to improved control of micelle formation and also increased stability in the blood compartment, while installation of the cRGD peptide improved biological activity. Incorporation of siRNA into stable micelle structures containing the cRGD peptide resulted in increased gene silencing ability, improved cell uptake, and broader subcellular distribution in vitro and also improved accumulation in both the tumor mass and tumor-associated blood vessels following intravenous injection into mice. Furthermore, stable and targeted micelles inhibited the growth of subcutaneous HeLa tumor models and demonstrated gene silencing in the tumor mass following treatment with antiangiogenic siRNAs. This new micellar nanomedicine could potentially expand the utility of siRNA-based therapies for cancer treatments that require intravenous injection.
Cancer cells have high iron requirements due to their rapid growth and proliferation. Iron depletion using iron chelators has a potential in cancer treatment. Previous studies have demonstrated that ...deferoxamine (DFO) specifically chelates Fe(III) and exhibited antitumor activity in clinical studies. However, its poor pharmacokinetics has limited the therapeutic potential and practical application. Although polymeric iron chelators have been developed to increase the blood retention, none of previous studies has demonstrated their potential in iron chelation cancer therapy. Here, we developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)‐poly(aspartic acid) (PEG‐PAsp) block copolymers. The polymeric DFO exhibited iron‐chelating ability comparable with free DFO, thereby arresting cell cycle and inducing apoptosis and antiproliferative activity. After intravenous administration, the polymeric DFO showed marked increase in blood retention and tumor accumulation in subcutaneous tumor models. Consequently, polymeric DFO showed significant suppression of the tumor growth compared with free DFO. This study reveals the first success of the design of polymeric DFO for enhancing iron chelation cancer therapy.
Deferoxamine (DFO) is a unique iron chelator that exhibits antiproliferative activity on cancer cells by regulating the amount of iron in cells; however, its poor pharmacokinetics has limited the therapeutic potential and practical application. To realize effective iron chelation cancer therapy, we synthesized a simple biocompatible polymeric DFO (a polymer‐DFO conjugate) offering prolonged retention in blood and augmented tumor accumulation through the enhanced permeability and retention effect. Our polymeric DFO exhibited significant suppression of the tumor growth compared with free DFO, and was consistent with the pharmacokinetics and pharmacodynamics.
In boron neutron capture therapy (BNCT), boron drugs should accumulate selectively within a tumor and be quickly cleared from blood and normal organs. However, it is usually challenging to achieve ...the efficient tumor accumulation and the quick clearance simultaneously. Here we report the complex composed of a fructose-modified poly(ethylene glycol)-poly(l-lysine) block copolymer and p-boronophenylalanine, termed PEG-PLys/Lys(fructose)-BPA, as a boron delivery system permitting selective accumulation within the target tumor with quick clearance from normal organs as well as blood. Our PEG-PLys/Lys(fructose)-BPA could be internalized into tumor cells through LAT1 amino acid transporter-mediated endocytosis and retain in the targeted cells, thereby accomplishing more efficient accumulation and retention in a subcutaneous tumor than clinically used fructose-BPA complexes. Importantly, the moderately cationic property of the polymer facilitated renal clearance and PEG-PLys/Lys(fructose)-BPA exhibited high accumulation contrast between the target tumor and the blood/normal organ. Finally, upon thermal neutron irradiation, PEG-PLys/Lys(fructose)-BPA significantly inhibited the tumor growth in mice. PEG-PLys/Lys(fructose)-BPA may be a promising boron delivery system for BNCT.
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Tannic acid (TA) can form stable complexes with proteins, attracting significant attention as protein delivery systems. However, its systemic application has been limited due to nonspecific ...interaction. Here, we report a simple technique to prepare systemically applicable protein delivery systems using sequential self-assembly of a protein, TA, and phenylboronic acid-conjugated PEG-poly(amino acid) block copolymers in aqueous solution. Mixing the protein and TA in aqueous solution led to covering of the protein with TA, and subsequent addition of the copolymer resulted in the formation of boronate esters between TA and copolymers, constructing the core–shell-type ternary complex. The ternary complex covered with PEG exhibited a small hydrodynamic diameter of ∼10–20 nm and prevented an unfavorable interaction with serum components, thereby accomplishing significantly prolonged blood circulation and enhanced tumor accumulation in a subcutaneous tumor model. The technique utilizing supramolecular self-assembly may serve as a novel approach for designing protein delivery systems.
We developed a new perovskite film forming process based on solvent bathing method. The preheating of substrate before spin-coating of precursor solution drastically changed the quality of the ...obtained perovskite films. The perovskite films formed by modified solvent bathing method were much dense with large grains. The improvement of open circuit voltage implied that the modification succeeded to form the better interface between TiO2 and perovskite layer and to grow the higher quality perovskite layer. Finally, we obtained the best conversion efficiency of 12.6%. Although the conversion efficiency of this work is not sufficient compared with other reports, our modified solvent bathing method has a wider process window comparing to the commonly used anti-solvent dipping methods. We expect that our modified method can also applied to monolithic tandem solar cells.
•The solvent bathing method with preheating of substrate was developed.•Obtained perovskite films were much dense with large grains.•The improvement of open circuit voltage due to a better interface between TiO2 and perovskite layers.•The modified solvent bathing method has a wider process window.
Polyzwitterions are employed as coating polymers for biomaterials to induce an antifouling property on the surface. Fine‐tuning the betaine structure switches the antifouling property to be ...interactive with anionic tissue constituents in response to a tumorous pH gradient. The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the di‐protonation process around tumorous pH (6.5). The net charge of the developed polyzwitterion (PGlu(DET‐Car)) was thus neutral at pH 7.4 for antifouling, but was cationic at pH 6.5 for interaction with anionic constituents. Quantum dots coated with PGlu(DET‐Car) exhibited comparable stealth and enhanced tumor accumulation relative to the PEG system. The present study provides a novel design of smart switchable polyzwitterion based on a precise control of the net charge.
The unique protonation behavior of an ethylenediamine‐based carboxybetaine generates a smart polyzwitterion, which switches its antifouling property to become tissue‐interactive by the recognition of the small pH window between physiological and tumorous conditions. Nanomaterials coated with the polyzwitterion achieved similar blood circulation, and enhanced tumor accumulation, relative to a conventional antifouling system.
Organic–inorganic hybrid nanoparticles with calcium phosphate (CaP) core and PEGylated shell were developed to incorporate magnetic resonance imaging (MRI) contrast agent ...diethylenetriaminepentaacetic acid gadolinium (III) (Gd-DTPA) for noninvasive diagnosis of solid tumors. A two-step preparation method was applied to elaborate hybrid nanoparticles with a z-average hydrodynamic diameter about 80nm, neutral surface ξ-potential and high colloidal stability in physiological environments by self-assembly of poly(ethylene glycol)-b-poly(aspartic acid) block copolymer, Gd-DTPA, and CaP in aqueous solution, followed with hydrothermal treatment. Incorporation into the hybrid nanoparticles allowed Gd-DTPA to show significant enhanced retention ratio in blood circulation, leading to high accumulation in tumor positions due to enhanced permeability and retention (EPR) effect. Moreover, Gd-DTPA revealed above 6 times increase of relaxivity in the nanoparticle system compared to free form, and eventually, selective and elevated contrast enhancements in the tumor positions were observed. These results indicate the high potential of Gd-DTPA-loaded PEGylated CaP nanoparticles as a novel contrast agent for noninvasive cancer diagnosis.
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Abstract Both efficiency and safety profiles are crucial for promotion of gene delivery systems towards practical applications. A promising template system was previously developed based on block ...catiomer of poly(ethylene glycol) (PEG)- b -poly{N′- N -(2-aminoethyl)-2-aminoehtylaspartamide}-cholesteryl PEG-PAsp(DET)-cholesteryl with strategies of ligand conjugation at the α-terminus for specific affinity to the targeted cells and cholesteryl conjugation at the ω-terminus for structural stabilization to obtain systemic retention. Aiming for advocating this formulation towards practical applications, in the current study, the binding profile of this polymer to plasmid DNA (pDNA) was carefully studied to address an issue of toxicity origin. Quantification of free polymer composition confirmed that the toxicity mainly results from unbound polymer and polyplex micelle itself has negligible toxicity. This evaluation allowed for identifying an optimal condition to prepare safe polyplex micelles for systemic application that possess maximal polymer-binding but exclude free polymers. The identified polyplex micelles then faced a drawback of limited transfection efficiency due to the absence of free polymer, which is an acknowledged tendency found in various synthetic gene carriers. Thus, series of functional components was strategically compiled to improve the transfection efficiency such as attachment of cyclic (Arg-Gly-Asp) (cRGD) peptide as a ligand onto the polyplex micelles to facilitate cellular uptake, use of endosome membrane disruptive catiomer of PAsp(DET) for facilitating endosome escape along with use of the conjugated cholesteryl group to amplify the effect of PAsp(DET) on membrane disruption, so as to obtain efficient transfection. The mechanistic investigation respecting the appreciated pH dependent protonation behavior of PAsp(DET) permitted to depict an intriguing scenario how the block catiomers manage to escape from the endosome entrapment in response to the pH gradient. Subsequent systemic application to the pancreatic tumor demonstrated a capability of vascular targeting mediated by the cRGD ligand, which was directly confirmed based on in situ confocal laser scanning microscopy observation. Encouraging this result, the vascular targeting to transfect a secretable anti-angiogenic gene was attempted to treat the intractable pancreatic tumor with anticipation that the strategy could circumvent the intrinsic physiological barriers derived from hypovascular and fibrotic characters. The obtained therapeutic efficiency demonstrates promising utilities of the proposed formulation as a safe systemic gene delivery carrier in practical use.
The enhanced permeability and retention (EPR) effect is fundamental to tumor-targeted drug delivery using nanoparticles. However, recent studies reported heterogeneity of the EPR effect, and ...companion diagnostics are considered to be key to predicting and optimizing the benefits of the EPR effect. Here, as a new material to simply endow the function of companion diagnostics to nanoparticles, we designed a poly(ethylene glycol) (PEG) derivative conjugated with low molecular fluorescent dye through synthetic substrate linker that can be cleaved in response to MMP-2, which is overexpressed in tumor extracellular matrix. Upon tumor accumulation, the low molecular fluorescent dye is released from the PEG and quickly excreted to urine, thereby reporting its tumor accumulation level as a fluorescent signal in the urine. In this study, this urinary reporter was conjugated with albumin, and the functionalized albumin exhibited efficient accumulation in various tumors. Importantly, the functionalized albumin exhibited significantly higher excretion of the fluorescent dye in the urine in mice with tumors compared with those without tumors. The PEG derivatives proposed in this study may be a promising tool to predict the EPR effect in individual cancer patients.
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•PEG derivatives permitted potential urinary monitoring of the EPR effect.•Urinary monitoring suggested dynamics of the EPR effect.•Considerable intra-/extravasation could be observed in various tumor models.
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