Tuning Polyamidoamine Design To Increase Uptake and Efficacy of Ruthenium Complexes for Photodynamic Therapy

Mascheroni, Luca; Dozzi, Maria Vittoria; Ranucci, Elisabetta; Ferruti, Paolo; Francia, Valentina; Salvati, Anna; Maggioni, Daniela

doi:10.1021/acs.inorgchem.9b02245

Cited by 20 publications

(32 citation statements)

References 71 publications

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“…We have recently reported on the synthesis as well as the chemical and photophysical characterization of a linear polycationic PAA complexed with a luminescent tris-phenanthroline Ru complex, called Ru–PhenAN ( Chart 1 ), which is at the basis of this investigation. 36 …”

Section: Results and Discussionmentioning

confidence: 99%

“…Reactions with longer times at lower temperature allow producing smaller polymers (by SEC analysis M n = 11,912, M w = 13,577, polydispersity index = 1.14), with respect to the one obtained previously. 36 The polymer is characterized by two mean p K a values (p K a1 = 3.35, p K a2 = 7.40) that make the polymer cationic below a pH value of 7.40, and instead only slightly positive (about 25% of the repeating units) at physiological pH. 36 Polycationic polymers have been shown to promote endosomal escape and it is known that their overall charge and buffering capacity are at the basis of endosomal escape mechanisms promoted by the so-called proton sponge effect, 38 even though other theories and mechanisms of escape by cationic species have been proposed in the literature.…”

Section: Results and Discussionmentioning

confidence: 99%

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Light-Triggered Trafficking to the Cell Nucleus of a Cationic Polyamidoamine Functionalized with Ruthenium Complexes

Mascheroni

Francia

Rossotti

et al. 2020

ACS Appl. Mater. Interfaces

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Strategies for endosomal escape and access to the cell nucleus are highly sought for nanocarriers to deliver their load efficiently following endocytosis. In this work, we have studied the uptake and intracellular trafficking of a polycationic polyamidoamine (PAA) endowed with a luminescent Ru complex, Ru–PhenAN, that shows unique trafficking to the cell nucleus. Live cell imaging confirmed the capacity of this polymer to access the nucleus, excluding artifacts due to cell fixation, and clarified that the mechanism of escape is light-triggered and relies on the presence of the Ru complexes and their capacity to absorb light and act as photosensitizers for singlet oxygen production. These results open up the possibility to use PAA–ruthenium complexes for targeted light-triggered delivery of genetic material or drugs to the cytosol and nucleus.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Light-Triggered Trafficking to the Cell Nucleus of a Cationic Polyamidoamine Functionalized with Ruthenium Complexes

Mascheroni

Francia

Rossotti

et al. 2020

ACS Appl. Mater. Interfaces

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“…They then decided to vary the structure of PAMAM by synthesizing Ru8‐PhenAN with a M n value of 34 600, M w / M n of 1.38 and 2% of Ru‐containing repeating units that could self‐assemble into ≈10 nm nanoparticles. [ 36 ] The PDT efficiency of Ru8‐PhenAN was evaluated in HeLa cells and compared to that of Ru8‐PhenISA and [Ru(phen) 2 (BAP)](OTf) 2 ( Ru9 ), a complex used as a model of the photoactive units. Ru8‐PhenAN was found to be more cytotoxic than Ru8‐PhenISA and Ru9 in HeLa cells with an EC 50 of 0.7 × 10 −6 m as opposed to 9 × 10 −6 m for the free complex upon visible light irradiation (40 min, 23.7 mW cm −2 ).…”

Section: Organic Nanoparticlesmentioning

confidence: 99%

Incorporation of Ru(II) Polypyridyl Complexes into Nanomaterials for Cancer Therapy and Diagnosis

2020

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Ru(II) metal center. [2] They absorb light and emit wavelength within the red and the near infrared (NIR) spectral regions and possess large Stokes shift, long luminescence lifetime, and potential twophoton (2P) absorption properties. These characteristics have made them highly desirable across numerous research fields such as catalysis, [3] solar energy, [4] sensors [5] and now across the biomedical field either in diagnostics as cellular imaging tools, luminescent probes of DNA structures or in therapy as new classes of anticancer drugs for chemotherapy and photosensitizers (PSs) for photodynamic therapy (PDT) or photoactivated chemotherapy (PACT). [6-11] Worthy of note, a Ru(II) polypyridyl compound (TLD1433) has recently entered phase II clinical trials in Canada for the treatment of nonmuscle invasive bladder cancer as a PS for PDT. [12] However, these complexes still suffer from some drawbacks such as poor water solubility, lack of targeting capability, nonspecific distribution, systemic toxicity and hence, low therapeutic index hampering their translation into the clinic. One strategy to address those medical challenges is to use nanomedicine. Nanomedicine is the application of sub-micron particles (i.e., nanoparticles) in the field of medicine. The materials used for the synthesis and/ or formulation of nanoparticles are extremely diverse, ranging from organic to inorganic molecules (Figure 1). [13] The unique features of nanoparticles including small size, high surface area, surface chemistry, water solubility and multifunctionality make them highly interesting for drug delivery purposes. [14,15] Owing to their size, nanoparticles can passively accumulate to solid tumors while sparing healthy cells thanks to the enhanced permeation and retention (EPR) effect. [16] The EPR effect exploits the abnormalities of tumor vasculature, namely hypervascularity, atypical vascular architecture, leaky vasculature, and lack of lymphatic drainage. This results in the efficient extravasation of nanoparticles from the tumor vasculature and their retention in the tumor interstitium. Therefore, drug incorporation into nanoparticles provides significant improvements in pharmacokinetics, solubility, toxicity, and biodistribution when compared to freely administered molecules, reducing adverse side effects observed with conventional medicine. However, to take full advantage of the EPR effect, nanoparticles must remain in circulation long enough for tumor accumulation. PEGylation, which refers to modification with poly(ethylene glycol) (PEG) chains or PEG copolymers (e.g., Jeffamine), is the most common strategy for imparting stealth properties to nanoparticles. [17] The presence of PEG enables steric stabilization Ru(II) polypyridyl complexes are compounds of great interest in cancer therapy due to their unique photophysical, photochemical, and biological properties. For effective treatment, they must be able to penetrate tumor cells effectively and selectively. The development of nanoscale carriers capable of delivering Ru(I...

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“…62 As examples, selenium [63][64][65] , silver 66 , gold [67][68][69] and silicon [70][71][72][73][74] nanoparticles as well as upconverting nanoparticles [75][76][77] were successfully loaded with Ru(II) polypyridine complexes, forming a drug delivery vehicle. Further, the physical encapsulation of Ru(II) polypyridine complexes into polymeric partciles [78][79][80][81][82][83][84][85][86] , micelles [87][88][89] , dendrimers 90 or liposomes [91][92] was reported. Recent studies have also shown the conjugation of Ru(II) polypyridine complexes to carbon nanotubes [93][94][95] as well as metal-organic frameworks 96-97 as a delivery system.…”

Section: Introductionmentioning

confidence: 99%

Polymeric Encapsulation of a Ruthenium Polypyridine Complex for Tumor Targeted 1- and 2-Photon Photodynamic Therapy

Karges¹,

Li²,

Zeng³

et al. 2020

Preprint

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Photodynamic therapy is a medical technique, which is gaining increasing attention to treat various types of cancer. Among the investigated classes of photosensitizers, the use of Ru(II) polypyridine complexes is gaining momentum. However, the currently investigated compounds generally show poor cancer cell selectivity. As a consequence, high drug doses are needed, which can cause side effects. To overcome this limitation, there is a need for the development of a suitable drug delivery system to increase the amount of PS delivered to the tumor. Herein, we report on the encapsulation of a promising Ru(II) polypyridyl complex into polymeric nanoparticles with terminal biotin groups. Thanks to this design, the particles showed much higher selectivity for cancer cells in comparison to non-cancerous cells in a 2D monolayer and 3D multicellular tumor spheroid model. As a highlight, upon intravenous injection of an identical amount of the Ru(II) polypyridine complex, an improved accumulation inside an adenocarcinomic human alveolar basal epithelial tumor of a mouse by a factor of 8.7 compared to the Ru complex itself was determined. The nanoparticles were found to have a high phototoxic effect upon 1-photon (500 nm) or 2-photon (800 nm) excitation with an eradication of an adenocarcinomic human alveolar basal epithelial tumor inside a mouse. Overall, this work describes, to the best of our knowledge, the first <i>in vivo</i> study demonstrating the cancer cell selectivity of a very promising Ru(II)-based PDT photosensitizer encapsulated into polymeric nanoparticles with terminal biotin groups.

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Tuning Polyamidoamine Design To Increase Uptake and Efficacy of Ruthenium Complexes for Photodynamic Therapy

Cited by 20 publications

References 71 publications

Light-Triggered Trafficking to the Cell Nucleus of a Cationic Polyamidoamine Functionalized with Ruthenium Complexes

Light-Triggered Trafficking to the Cell Nucleus of a Cationic Polyamidoamine Functionalized with Ruthenium Complexes

Incorporation of Ru(II) Polypyridyl Complexes into Nanomaterials for Cancer Therapy and Diagnosis

Polymeric Encapsulation of a Ruthenium Polypyridine Complex for Tumor Targeted 1- and 2-Photon Photodynamic Therapy

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