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Poly (alkyl cyanoacrylate) (PACA) polymeric nanoparticles (NPs) are promising drug carriers in drug delivery. However, the selection of commercially available alkyl cyanoacrylate (ACA) monomers is limited, because most monomers were designed for use in medical and industrial glues and later repurposed for drug encapsulation. This study therefore aimed to seek out novel ACA materials for use in NP systems using a toxicity led screening approach. A multistep strategy, including cytotoxicity screening of alcohols as degradation products of PACA (44 alcohols), NPs (14 polymers), and a final in vivo study (2 polymers) gave poly (2-ethylhexyl cyanoacrylate) PEHCA as a promising novel PACA candidate. For the first time, this work presents cytotoxicity data on several novel ACAs, PEHCA in vivo toxicity data, and miniemulsion polymerisation-based encapsulation of the cabazitaxel and NR688 in novel PACA candidates. Furthermore, several of the ACA candidates were compatible with a wider selection of lipophilic active pharmaceutical ingredients (APIs) versus commercially available controls. Combined, this work demonstrates the potential benefits of expanding the array of available ACA materials in drug delivery. Novel ACAs have the potential to encapsulate a wider range of APIs in miniemulsion polymerisation processes and may also broaden PACA applicability in other fields.

We have investigated the biodistribution and tumor macrophage infiltration after intravenous injection of the poly(alkyl cyanoacrylate) nanoparticles (NPs): PEBCA (poly(2-ethyl-butyl cyanoacrylate), PBCA (poly(n-butyl cyanoacrylate), and POCA (poly(octyl cyanoacrylate), in mice. These NPs are structurally similar, have similar PEGylation, and have previously been shown to give large variations in cellular responses in vitro. The PEBCA NPs had the highest uptake both in the patient-derived breast cancer xenograft MAS98.12 and in lymph nodes, and therefore, they are the most promising of these NPs for delivery of cancer drugs. High-resolution magic angle spinning magnetic resonance (HR MAS MR) spectroscopy did not reveal any differences in the metabolic profiles of tumors following injection of the NPs, but the PEBCA NPs resulted in higher tumor infiltration of the anti-tumorigenic M1 macrophages than obtained with the two other NPs. The PEBCA NPs also increased the ratio of M1/M2 (anti-tumorigenic/pro-tumorigenic) macrophages in the tumors, suggesting that these NPs might be used both as a vehicle for drug delivery and to modulate the immune response in favor of enhanced therapeutic effects.

Abstract The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of free drug in the basal-like patient-derived xenograft and resulted in complete remission of 6 out of 8 tumors, whereas free drug gave complete remission only with 2 out of 9 tumors. To investigate the different efficacies obtained with nanoparticle-encapsulated versus free cabazitaxel, mass spectrometry quantification of cabazitaxel was performed in mice plasma and selected tissue samples. Nanoparticle-encapsulated drug had a longer circulation time in blood. There was approximately a three times higher drug concentration in tumor tissue 24 h after injection, and two times higher 96 h after injection of nanoparticles with drug compared to the free drug. The tissue biodistribution obtained after 24 h using mass spectrometry analyses correlates well with biodistribution data obtained using IVIS® Spectrum in vivo imaging of nanoparticles labeled with the fluorescent substance NR668, indicating that these data also are representative for the nanoparticle distribution. Furthermore, immunohistochemistry was used to estimate infiltration of macrophages into the tumor tissue following injection of nanoparticle-encapsulated and free cabazitaxel. The higher infiltration of anti-tumorigenic versus pro-tumorigenic macrophages in tumors treated with the nanoparticles might also contribute to the improved effect obtained with the nanoparticle-encapsulated drug. Tumor infiltration of pro-tumorigenic macrophages was four times lower when using nanoparticles containing cabazitaxel than when using particles without drug, and we speculate that the very good therapeutic efficacy obtained with our cabazitaxel-containing particles may be due to their ability to reduce the level of pro-tumorigenic macrophages in the tumor. In summary, encapsulation of cabazitaxel in poly(2-ethyl-butyl cyanoacrylate) nanoparticles seems promising for treatment of breast cancer. Graphical abstract Unlabelled Image Highlights • Efficient treatment of patient-derived basal-like breast cancer xenograft with NPs. • PEBCA NPs with cabazitaxel gave complete remission of 6 out of 8 tumors. • NPs induced higher infiltration in tumors of anti- than pro-tumorigenic macrophages. • Infiltration of pro-tumorigenic macrophages strongly reduced by drug-containing NPs. [ABSTRACT FROM AUTHOR]

The interaction of the promising drug carriers poly(alkyl cyanoacrylate) nanoparticles (PACA NPs) with lipid monolayers modeling the cell membrane and with RBE4 immortalized rat brain endothelial cells was compared to assess the relevance of lipid monolayer-based cell membrane models for PACA NP cellular uptake. NP properties such as size and charge of NPs and density of poly(ethylene glycol) coating (PEG) were kept in a narrow range to assess whether the type of PEG coating and the PACA monomer affected NP-monolayer and NP-cell interactions. The interaction with lipid monolayers was evaluated using surface pressure measurements and Brewster angle microscopy. NP association with and uptake by cells were assessed using flow cytometry and confocal laser scanning microscopy. The interaction between NPs and both lipid monolayers and the plasma membrane depended on the type of PEG. PEG density affected cellular uptake but not interaction with lipid monolayers. NP monomer, NPs size and charge had no effect on the interaction. This might be due to the fact that the size and charge distribution was kept rather narrow to study the effect of PACA monomer and PEG type. In conclusion, while modeling solely the passive aspect of NP-cell interactions, lipid monolayers nevertheless proved a valuable cell membrane model whose interaction with PACA NPs correlated well with NP-cell interaction. In addition, both NP-monolayer and NP-cell interactions were dependent on PEGylation type, which could be used in the design of NPs to either facilitate or hinder cellular uptake, depending on the intended purpose. [ABSTRACT FROM AUTHOR]

Poly (alkyl cyanoacrylate) (PACA) polymeric nanoparticles (NPs) are promising drug carriers in drug delivery. However, the selection of commercially available alkyl cyanoacrylate (ACA) monomers is limited, because most monomers were designed for use in medical and industrial glues and later repurposed for drug encapsulation. This study therefore aimed to seek out novel ACA materials for use in NP systems using a toxicity led screening approach. A multistep strategy, including cytotoxicity screening of alcohols as degradation products of PACA (44 alcohols), NPs (14 polymers), and a final in vivo study (2 polymers) gave poly (2-ethylhexyl cyanoacrylate) PEHCA as a promising novel PACA candidate. For the first time, this work presents cytotoxicity data on several novel ACAs, PEHCA in vivo toxicity data, and miniemulsion polymerisation-based encapsulation of the cabazitaxel and NR688 in novel PACA candidates. Furthermore, several of the ACA candidates were compatible with a wider selection of lipophilic active pharmaceutical ingredients (APIs) versus commercially available controls. Combined, this work demonstrates the potential benefits of expanding the array of available ACA materials in drug delivery. Novel ACAs have the potential to encapsulate a wider range of APIs in miniemulsion polymerisation processes and may also broaden PACA applicability in other fields., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter P. Molesworth reports financial support was provided by Research Council of Norway. Yrr Morch reports financial support was provided by Research Council of Norway. Sofie Snipstad reports financial support was provided by Research Council of Norway. Peter P. Molesworth has patent #Nanoparticles comprising copolymeric or homopolymeric compounds which comprise cyanoacrylate subunits (WO2020207655) pending to SINTEF TTO AS. Ruth Schmid has patent #Nanoparticles comprising copolymeric or homopolymeric compounds which comprise cyanoacrylate subunits (WO2020207655) pending to SINTEF TTO AS. Yrr Morch has patent #Nanoparticles comprising copolymeric or homopolymeric compounds which comprise cyanoacrylate subunits (WO2020207655) pending to SINTEF TTO AS., (© 2022 The Authors.)

Abstract: Alzheimer''s disease (AD) is a neurodegenerative disorder for which the research of new treatments is highly challenging. Since the fibrillogenesis of amyloid-β peptide 1–42 (Aβ1–42) peptide is considered as a major cause of neuronal degeneration, specific interest has been focused on aromatic molecules for targeting this peptide. In this paper, the synthesis of selegiline-functionalized and fluorescent poly(alkyl cyanoacrylate) nanoparticles (NPs) and their evaluation for the targeting of the Aβ1–42 peptide are reported. The synthetic strategy relied on the design of amphiphilic copolymers by tandem Knoevenagel–Michael addition of cyanoacetate derivatives, followed by their self-assembly in aqueous solutions to give the corresponding NPs. Different cyanoacetates were used: (i) hexadecyl cyanoacetate (HDCA) to form the hydrophobic core of the NPs; (ii) rhodamine B cyanoacetate (RCA) for fluorescent purposes; (iii) methoxypoly(ethylene glycol) cyanoacetate (MePEGCA) for stealth properties and (iv) selegiline-poly(ethylene glycol) cyanoacetate (SelPEGCA) to obtain the desired functionality. Two different amphiphilic copolymers were synthesized, a selegiline-containing copolymer, P(MePEGCA-co-SelPEGCA-co-HDCA), and a rhodamine-labelled counterpart, P(MePEGCA-co-RCA-co-HDCA), further blended at variable ratios to tune the amount of selegiline moieties displayed at the surface of the NPs. Optimal formulations involving the different amphiphilic copolymers were determined by the study of the NP colloidal characteristics. Interestingly, it was shown that the zeta potential value of the selegiline-functionalized nanoparticles dramatically decreased, thus emphasizing a significant modification in the surface charge of the nanoparticles. Capillary electrophoresis has then been used to test the ability of the selegiline-functionalized NPs to interact with the Aβ1–42 peptide. In comparison with non functionalized NPs, no increase of the interaction between these functionalized NPs and the monomeric form of the Aβ1–42 peptide was observed, thus highlighting the lack of availability of the ligand at the surface of the nanoparticles. A mechanism explaining this result has been proposed and was mainly based on the burial of the hydrophobic selegiline ligand within the nanoparticles core. [Copyright &y& Elsevier]

We have investigated the biodistribution and tumor macrophage infiltration after intravenous injection of the poly(alkyl cyanoacrylate) nanoparticles (NPs): PEBCA (poly(2-ethyl-butyl cyanoacrylate), PBCA (poly(n-butyl cyanoacrylate), and POCA (poly(octyl cyanoacrylate), in mice. These NPs are structurally similar, have similar PEGylation, and have previously been shown to give large variations in cellular responses in vitro. The PEBCA NPs had the highest uptake both in the patient-derived breast cancer xenograft MAS98.12 and in lymph nodes, and therefore, they are the most promising of these NPs for delivery of cancer drugs. High-resolution magic angle spinning magnetic resonance (HR MAS MR) spectroscopy did not reveal any differences in the metabolic profiles of tumors following injection of the NPs, but the PEBCA NPs resulted in higher tumor infiltration of the anti-tumorigenic M1 macrophages than obtained with the two other NPs. The PEBCA NPs also increased the ratio of M1/M2 (anti-tumorigenic/pro-tumorigenic) macrophages in the tumors, suggesting that these NPs might be used both as a vehicle for drug delivery and to modulate the immune response in favor of enhanced therapeutic effects. [ABSTRACT FROM AUTHOR]