Variants Of Nanoparticles Research Articles

Preclinical Efficacy of Cabazitaxel Loaded Poly(2-alkyl cyanoacrylate) Nanoparticle Variants.

Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect. Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry. In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment. We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response.

Can targeted nanoparticles distinguish cancer metastasis from inflammation?

Targeting ligands have been widely used to increase the intratumoral accumulation of nanoparticles and their uptake by cancer cells. However, these ligands aim at targets that are often also upregulated in inflamed tissues. Here, we assessed the ability of targeted nanoparticles to distinguish metastatic cancer from sites of inflammation. Using common targeting ligands and a 60-nm liposome as a representative nanoparticle, we generated three targeted nanoparticle (NP) variants that targeted either fibronectin, folate, or αvβ3 integrin, whose deposition was compared against that of standard untargeted NP. Using fluorescently labeled NPs and ex vivo fluorescence imaging of organs, we assessed the deposition of the NPs into the lungs of mice modeling 4 different biological landscapes, including healthy lungs, aggressive metastasis in lungs, dormant/latent metastasis in lungs, and lungs with general pulmonary inflammation. Among the four NP variants, fibronectin-targeting NP and untargeted NP exhibited the highest deposition in lungs harboring aggressive metastases. However, the deposition of all targeted NP variants in lungs with metastasis was similar to the deposition in lungs with inflammation. Only the untargeted NP was able to exhibit higher deposition in metastasis than inflammation. Moreover, flow-cytometry analysis showed all NP variants accumulated predominantly in immune cells rather than cancer cells. For example, the number of NP+ macrophages and dendritic cells was 16-fold greater than NP+ cancer cells in the case of fibronectin-targeting NP. Overall, targeted NPs were unable to distinguish cancer metastasis from general inflammation, which may have clinical implications to the nanoparticle-mediated delivery of cancer drugs.

Biodegradable polymeric nanoparticles administered in the cerebrospinal fluid: Brain biodistribution, preferential internalization in microglia and implications for cell-selective drug release

Cell-selective drug release in the central nervous system (CNS) holds great promise for the treatment of many CNS disorders but it is still challenging. We previously demonstrated that polymeric nanoparticles (NPs) injected intra-parenchyma in the CNS can be internalized specifically in microglia/macrophages surrounding the injection site. Here, we explored NPs administration in the cerebrospinal fluid (CSF) to achieve a wider spreading and increased cell targeting throughout the CNS; we generated new NPs variants and studied the effect of modifying size and surface charge on NPs biodistribution and cellular uptake. Intra-cerebroventricular administration resulted in prevalent localization of the NPs in proximity to stem-cell niches, such as around the lateral ventricles, the subventricular zone and the rostral migratory stream. NPs internalization occurred preferentially in brain myeloid cells/microglia. We demonstrated that brain biodistribution and extent of internalization in microglia are influenced by NPs dimensions and can be improved by applying a transient disruption of the blood-brain barrier with mannitol, leading to NPs internalization in up to 25% of brain myeloid/microglia cells. A fraction of the targeted cells was positive for markers of proliferation or stained positive for stemness/progenitor-cell markers such as Nestin, c-kit, or NG2. Interestingly, through these newly formulated NPs we obtained controlled and selective release of drugs otherwise difficult to formulate (such as busulfan and etoposide) to the target cells, preventing unwanted side effects and the toxicity obtained by direct brain delivery of the not encapsulated drugs. Overall, these data provide proof of concept of the applicability of these novel NP-based drug formulations for achieving internalization not only in mature microglia but also possibly in more immature myeloid cells in the brain and pave the way for brain-restricted microglia-targeted drug delivery regimens.

Synthesis variants of quaternary ammonium polyethyleneimine nanoparticles and their antibacterial efficacy in dental materials.

Resin-based dental materials allow bacterial growth on their surface and lack antibacterial activity, leading to functional and esthetic failure. Quaternary ammonium polyethyleneimine (QPEI) nanoparticles (NPs) incorporated in resin-based composite at 2% wt/wt have demonstrated prolonged and complete inhibition of bacterial growth. This study focused on optimization of QPEI NP synthesis to reduce the concentration required for bacterial growth inhibition. The objective here was to enhance antimicrobial efficacy by excess base neutralization, using phosphoric or hydrochloric acid, and by using surfactants. QPEI NP variants were prepared (i) under controlled neutralization of acid, using NaHCO3, (ii) under controlled carbonate ion neutralization with HCl or H3PO4 and (iii) by treatment with N-lauroylsarcosine or glycerol monostearate. NPs incorporated in the dental materials were examined for their antibacterial effect against Enterococcus faecalis. Controlled addition of NaHCO3 resulted in modified QPEI NPs with an increased ability to inhibit bacterial growth. Surface treatment with N-lauroylsarcosine resulted in enhanced antibacterial activity at 0.5% wt/wt concentration in acrylate and epoxy resin-based dental materials. The antimicrobial efficacy of QPEI NP may be improved significantly by controlling the addition of NaHCO3, neutralization of excess base and the surface-agent effect.

Development of polymeric and cyclodextrin nanoparticles for camptothecin delivery

Cell-selective drug release in the central nervous system (CNS) holds great promise for the treatment of many CNS disorders but it is still challenging. We previously demonstrated that polymeric nanoparticles (NPs) injected intra-parenchyma in the CNS can be internalized specifically in microglia/macrophages surrounding the injection site. Here, we explored NPs administration in the cerebrospinal fluid (CSF) to achieve a wider spreading and increased cell targeting throughout the CNS; we generated new NPs variants and studied the effect of modifying size and surface charge on NPs biodistribution and cellular uptake. Intra-cerebroventricular administration resulted in prevalent localization of the NPs in proximity to stem-cell niches, such as around the lateral ventricles, the subventricular zone and the rostral migratory stream. NPs internalization occurred preferentially in brain myeloid cells/microglia. We demonstrated that brain biodistribution and extent of internalization in microglia are influenced by NPs dimensions and can be improved by applying a transient disruption of the blood-brain barrier with mannitol, leading to NPs internalization in up to 25% of brain myeloid/microglia cells. A fraction of the targeted cells was positive for markers of proliferation or stained positive for stemness/progenitor-cell markers such as Nestin, c-kit, or NG2. Interestingly, through these newly formulated NPs we obtained controlled and selective release of drugs otherwise difficult to formulate (such as busulfan and etoposide) to the target cells, preventing unwanted side effects and the toxicity obtained by direct brain delivery of the not encapsulated drugs. Overall, these data provide proof of concept of the applicability of these novel NP-based drug formulations for achieving internalization not only in mature microglia but also possibly in more immature myeloid cells in the brain and pave the way for brain-restricted microglia-targeted drug delivery regimens.