In photodynamic therapy (PDT), the inherent physicochemical properties of a photosensitizer (PS) critically affect its biodistribution and therapeutic outcome as well as side effect. Here, we ...developed a PS-polymer conjugate displaying isothermal hydrophilic-to-hydrophobic phase transition in response to tumorous acidic pH. The polymer backbone was poly(N-isopropylacrylamide (NIPAAm)/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)), which shows lower critical solution temperature (LCST) of 30 °C. The amine groups in its side chains were converted to hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amides, forming poly(NIPAAm/AIPAAm-PMM). The conjugation of PMM moieties drastically increased the LCST of the polymer to 40 °C and displayed hydrophilic character to minimalize unspecific interaction of PS-P(NIPAAm/AIPAAm-PMM) in bloodstream, diminishing potential photosensitivity. The detachment of PMM at tumorous pH lowered the LCST to that of original P(NIPAAm/AIPAAm), permitting hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C). This pH-responsive isothermal phase transition facilitated interaction with the cultured cancer cells, accomplishing 8.1 times-enhanced cellular uptake and strong phototoxicity in a tumorous pH-selective manner. Even in subcutaneous tumor models, our polymer conjugates exhibited efficient tumor accumulation and significantly augmented PDT effect without inducing unfavorable photochemical toxicity to the skin. This study offers a novel concept of PS delivery systems targeting tumorous pH by the use of isothermal phase transition.
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•pH-responsive isothermal phase transition potentiates photosensitizer delivery.•The polymer could target mild acidic extracellular pH in a tumor.•Hydrophilicity prevented unfavorable interaction with serum components.•Hydrophobicity facilitated cellular uptake and augmented therapeutic effect.
Intravenously injected high-dose vitamin C (VC) induces extracellular H2O2, which can penetrate into the tumor cells and suppress tumor growth. However, extracellular labile iron ions in the tumor ...decompose H2O2 via the Fenton reaction, limiting the therapeutic effect. In this regard, we recently developed a polymeric iron chelator that can inactivate the intratumoral labile iron ions. Here, we examined the effect of our polymeric iron chelator on the high-dose VC therapy in in vitro and in vivo. In the in vitro study, the polymeric iron chelator could inactivate the extracellular labile iron ions and prevent the unfavorable decomposition of VC-induced H2O2, augmenting pro-oxidative damage to DNA and inducing apoptosis in cultured cancer cells. Even in the in vivo study, the polymeric iron chelator significantly improved the antitumor effect of VC in subcutaneous DLD-1 and CT26 tumors in mice, while conventional iron chelators could not. This work indicates the importance of modulating tumor-associated iron ions in the high-dose VC therapy and should contribute to a better understanding of its mechanism.
A system that permits the delivery of cargoes to the lung endothelium would be extraordinarily useful in terms of curing a wide variety of lung-related diseases. This study describes the development ...of a multifunctional envelope-type nanodevice (MEND) that targets the lung endothelium, delivers its encapsulated siRNA to the cytoplasm, and eradicates lung metastasis. The key to the success can be attributed to the presence of a surface-modified GALA peptide that has dual functions: targeting the sialic acid-terminated sugar chains on the pulmonary endothelium and subsequently delivering the encapsulated cargoes to the cytosol via endosomal membrane fusion, analogous to the influenza virus. The active targeting of MENDs without the formation of large aggregates was verified by intravital real-time confocal laser scanning microscopy in living lung tissue. The GALA-modified MEND is a promising carrier that opens a new generation of therapeutic approaches for satisfying unmet medical needs in curing lung diseases.
Various cancer cells overexpress L-type amino acid transporter 1 (LAT1) to take up a large number of neutral amino acids such as phenylalanine and methionine, and LAT1 transporter should be a ...promising target for cancer diagnosis and therapy. However, only a few studies reported drug delivery systems targeting LAT1 probably due to limited knowledge about the interaction between LAT1 and its substrate. Here, we developed polymers having methionine (Met)- or cysteine (Cys)-like structures on their side chains to examine their affinity with LAT1. While both the Met- and Cys-modified polymers exhibited efficient cellular uptake selectively in cancer cells, the Met-modified polymers exhibited higher cellular uptake efficiency in an LAT1-selective manner than the Cys-modified polymers. In the in vivo study, the intraperitoneally injected Met-modified polymers showed appreciable tumor-selective accumulation in the peritoneal dissemination model, and importantly, Met-modified polymers conjugated with photosensitizers exhibited significant therapeutic effects upon photoirradiation with reduced photochemical damage to normal organs. Our results may provide important knowledge about the polymer-LAT1 interaction, and the Met-modified polymers should offer a new concept for designing LAT1-targeting drug delivery systems.
Surface modification using poly(ethylene glycol) (PEG) is a widely used strategy to improve the biocompatibility of cationic polymer-based nonviral gene vectors (polyplexes). A novel method based on ...intravital real-time confocal laser scanning microscopy (IVRTCLSM) was applied to quantify the dynamic states of polyplexes in the bloodstream, thereby demonstrating the efficacy of PEGylation to prevent their agglomeration. Blood flow in the earlobe blood vessels of experimental animals was monitored in a noninvasive manner to directly observe polyplexes in the circulation. Polyplexes formed distinct aggregates immediately after intravenous injection, followed by interaction with platelets. To quantify aggregate formation and platelet interaction, the coefficient of variation and Pearson's correlation coefficient were adopted. In contrast, polyplex micelles prepared through self-assembly of plasmid DNA with PEG-based block catiomers had dense PEG palisades, revealing no formation of aggregates without visible interaction with platelets during circulation. This is the first report of
in situ monitoring and quantification of the availability of PEGylation to prevent polyplexes from agglomeration over time in the blood circulation. This shows the high utility of IVRTCLSM in drug and gene delivery research.
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The construction of enzyme delivery systems, which can control enzymatic activity at a target site, is important for efficient enzyme–prodrug therapy/diagnosis. Herein we report a facile technique to ...construct a systemically applicable β-galactosidase (β-Gal)-loaded ternary complex comprising tannic acid (TA) and phenylboronic acid-conjugated polymers through sequential self-assembly in aqueous solution. At physiological conditions, the ternary complex exhibited a hydrodynamic diameter of ∼40 nm and protected the loaded β-Gal from unfavorable degradation by proteinase. Upon cellular internalization, the ternary complex recovered β-Gal activity by releasing the loaded β-Gal. The intravenously injected ternary complex thereby delivered β-Gal to the target tumor in a subcutaneous tumor model and exerted enhanced and selective enzymatic activity at the tumor site. Sequential self-assembly with TA and phenylboronic acid-conjugated polymers may offer a novel approach for enzyme–prodrug theragnosis.
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Triangular Au nanoplates (TrAuNPls) possessing strong plasmonic properties can be used as photothermal agents in cancer therapy. However, the controlled preparation of such ...morphologies typically requires harsh synthetic conditions. Biomolecules offer an alternative route to developing biocompatible synthetic protocols. In particular, peptides offer a novel route for inorganic synthesis under ambient conditions. Herein, using the previously isolated peptide, ASHQWAWKWE, for Au nanoparticle (AuNP) synthesis, the conditions for preparing TrAuNPls via a one-pot synthetic process of mixing HAuCl4 and peptides at room temperature were investigated to effectively obtain particles possessing near-infrared absorbance for non-invasive optical diagnosis and phototherapy. By adjusting the peptide concentration, the size and property of TrAuNPls were controlled under neutral pH conditions. The synthesised particles showed potential as photothermal therapeutic agents in vitro. In addition, peptide characterisation using B3 derivatives revealed the importance of the third amino acid histidine in morphological regulation and potential circular Au nanoplates (AuNPl) synthesis with ASEQWAWKWE and ASAQWAWKWE peptides. These findings provide not only an easy and green synthetic method for TrAuNPls and circular AuNPls, but also some insight to help elucidate the regulation of peptide-based nanoparticle synthesis for use in cancer therapy.
Biological molecules have received increasing attention as a vehicle to synthesise inorganic materials with specific properties under ambient conditions; particularly, short peptides have the potential to control the synthesis of nanoscale materials with tailored functions. Here, the application of a previously isolated peptide was assessed in synthesising Au nanoparticles containing decahedral and triangular nanoplates with near-infrared absorbance. The size and absorbance peaks of the triangular nanoplates observed were peptide concentration-dependent. In addition, these fine-tuned triangular nanoplates exhibited potential as a phototherapeutic agent. Moreover, the peptide derivatives indicated the possibility of synthesising circular nanoplates. These findings may offer insight into development of new techniques for synthesising functional nanoparticles having biological applications using non-toxic molecules under mild conditions stituted in the original B3 peptide is underlined.
Ultrasound facilitates the penetration of macromolecular compounds through the skin and offers a promising non-invasive technique for transdermal delivery. However, technical difficulties in ...quantifying ultrasound-related parameters have restricted further analysis of the sonophoresis mechanism. In this study, we devise a bolt-clamped Langevin transducer-based sonophoresis device that enables us to measure with a thin lead zirconate titanate (PZT) sensor. One-dimensional acoustic theory accounting for wave interaction at the skin interface indicates that the acoustic pressure and cavitation onset on the skin during sonophoresis are sensitive to the subcutaneous support, meaning that there is a strong need to perform the pressure measurement in an experimental environment replacing the human body. From a series of the experiments with our new device, the transdermal penetration of polystyrene, silica and gold nanoparticles is found to depend on the size and material of the particles, as well as the hardness of the subcutaneous support material. We speculate from the acoustic pressure measurement that the particles' penetration results from the mechanical action of cavitation.
The Enhanced Permeability and Retention (EPR) effect is a golden strategy for the nanoparticle (NP)-based targeting of solid tumors, and the surface property of NPs might be a determinant on their ...targeting efficiency. Poly(ethylene glycol) (PEG) is commonly used as a shell material; however, it has been pointed out that PEG-coated NPs may exhibit accumulation near tumor vasculature rather than having homogenous intratumor distribution. The PEG shell plays a pivotal role on prolonged blood circulation of NPs but potentially impairs the intratumor retention of NPs. In this study, we report on a shell material to enhance tumor-targeted delivery of NPs by maximizing the EPR effect: polyzwitterion based on ethylenediamine-based carboxybetaine PGlu(DET-Car), which shows the changeable net charge responding to surrounding pH. The net charge of PGlu(DET-Car), is neutral at physiological pH 7.4, allowing it to exhibit a stealth property during the blood circulation; however, it becomes cationic for tissue-interactive performance under tumorous acidic conditions owing to the stepwise protonation behavior of ethylenediamine. Indeed, the PGlu(DET-Car)-coated NPs (i.e., gold NPs in the present study) exhibited prolonged blood circulation and remarkably enhanced tumor accumulation and retention than PEG-coated NPs, achieving 32.1% of injected dose/g of tissue, which was 4.2 times larger relative to PEG-coated NPs. Interestingly, a considerable portion of PGlu(DET-Car)-coated NPs clearly penetrated into deeper tumor sites and realized the effective accumulation in hypoxic regions, probably because the cationic net charge of PGlu(DET-Car) is augmented in more acidic hypoxic regions. This study suggests that the changeable net charge on the NP surface in response to tumorous acidic conditions is a promising strategy for tumor-targeted delivery based on the EPR effect.
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•Nanoparticles can enter tumor tissues through EPR effect.•PGlu(DET-Car) is a polyzwitterion which becomes cationic at tumorous pH.•PGlu(DET-Car)-coated nanoparticles achieves the effective tumor delivery.•Such pH-responsive design has comparable (or higher) stealthiness relative to PEG.•The coated nanoparticle penetrates into deeper tumor sites such as hypoxic areas.
The polymerization of N-isopropylacrylamide (NIPAAm) with ionizable monomers results in pH-responsive lower critical solution temperature (LCST) polymer which works in an ionization-dependent manner. ...However, gradual ionization of the comonomer occurs at a broad pH range due to the electrostatic field generated by the polymers, limiting the extent of LCST shift in response to pH change. Furthermore, excess introduction of comonomer may dull phase transition behavior. Here, we report the development of an ionization-independent LCST polymer that exerts a sharp isothermal hydrophilic-to-hydrophobic phase transition in response to slight pH change. Our polymer has a poly(NIPAAm/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)) backbone that retains the continuous structural similarity of N-alkyl groups for preserving phase transition sensitivity, and primary amine for forming hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amide linkage. The PMM moiety improves the polymer’s hydrophilicity and drastically increases the LCST. Detachment of the PMM moiety in response to mild acidic condition (pH < 6.8) lowers the LCST to that of original P(NIPAAm/AIPAAm), permitting isothermal pH-responsive phase transition. Utilizing this mechanism, P(NIPAAm/AIPAAm) modified with PMM amide linkage exhibits a sharp hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C) and, strikingly, facilitates interaction with cultured cells. Most importantly, our polymer showed significantly higher accumulation within a solid tumor after systemic injection compared to conventional PNIPAAm, which may be due to its phase transition responding to slightly acidic tumor microenvironment. Thus, this study provides a novel polymer that offers delicate control of LCST and pH-responsiveness suitable for use in even fuzzy biological environments.
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