Search

Background: Cabazitaxel (CBZ) is a second-generation taxane that has the potential to overcome taxane-resistance due to the low affinity for the P-glycoprotein efflux pump. However, with the high systemic toxicity such as neutropenia and hypersensitivity, the clinical use is restricted to patients with metastatic castration-resistant prostate cancer who show progression after docetaxel-based chemotherapy. MPB-1734 is a CBZ nanoformulation which is currently being evaluated as monotherapy in patients with advanced solid tumors in a Phase 1/2a trial (NCT04643418). It is developed to overcome the limitations associated with CBZ application and as potential therapeutic agent for chemo-resistant cancers. This work outlines the results of preclinical studies that support the tumor targeting ability, improved safety profiles, significant therapeutic effect, and synergistic benefit in combination with immune checkpoint inhibitor. Methodology: A series of nonclinical studies of MPB-1734 were conducted including toxicology evaluations in two species and the antitumor activity evaluations in a range of xenograft mice models as cervical cancer (KB), ovarian cancer (OVCAR3) and platinum-resistant human ovarian cancer patient-derived-xenograft (PDX) model (OV0276). The antitumor activity of MPB1734 combined with anti-PD-1 antibody were also evaluated in the syngenetic 4T1 breast cancer mice model. Results: Toxicology evaluations of MPB-1734 demonstrated the safety profiles of CBZ were significantly improved, and the tolerated doses of MPB-1734 are at least 2 folds higher than commercial formulation. An in-vivo tumor targeting study showed that MPB1734 mainly accumulated in the tumor sites, rather than in the vital organs. MPB1734 exhibited a better efficacy compared to commercial formulation in KB and OVCAR3 models. For platinum-resistant PDX model, MPB-1734 demonstrated significant anti-tumor efficacy (TGI:100%, p compared to anti-PD-1 antibody monotherapy (TGI: 2.8%) and MPB-1734 monotherapy (TGI: 52.9%). This synergistic benefit may result from increased CD8+ T cells in tumor region after MPB-1734 treatment. Conclusion: MPB-1734 can reduce the major dose-limiting side effect (neutropenia) of CBZ and increase the tolerated dose. With tumor targeting ability, superior antitumor effects were demonstrated as compared with commercial formulation in a range of cancer models. MPB-1734 combined with anti-PD-1 antibody showed synergistic benefit in tumor inhibition. These preclinical results support the potential use of MPB-1734 as therapeutic agent for chemo-resistant cancer with monotherapy or combination therapy with immuno-oncology agents. Citation Format: Yuan Hung Hsu, Chih-Lung Chen, Jhih-Yun Jian, Ming-Cheng Wei, Wen-Yuan Hsieh, Chia-Wen Huang, Yung-Chu Chen, Tzu-Hsin Liao, Shian-Jy Wang. Preclinical studies of the cabazitaxel nanoformulation MPB-1734 support therapeutic application in chemo-resistant solid tumors and synergistic benefit in combination with immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 818.

In order to enhance visualization of soft tissues, a dual-imaging diagnostic polymersome system featured with highly hydrated multilamellar wall structure capable of simultaneously embedding a hydrophobic near-infrared fluorophore, Cy5.5, and a paramagnetic probe, gadolinium (Gd(III)) cations was developed. The polymersomes were obtained from the self-assembly of lipid-containing copolymer, poly(acrylic acid-co-distearin acrylate), in aqueous solution. The Cy5.5 and Gd(III) species were loaded into polymersomes via hydrophobic association (loading efficiency of Cy5.5 ca 74%) and electrostatic complexation (Gd(III) 83%), respectively. The Cy5.5/Gd(III)-loaded polymersomes (CGLPs) have shown excellent payload confinement, reduced dilution effect on assembly dissociation and decreased protein/salt-induced colloidal aggregation. Owing to the highly hydrated structure of vesicular membrane, the superior contrast enhancement of CGLPs in magnetic resonance (MR) imaging was obtained as a result of prolonged rotational correlation time of Gd(III) cations and fast water exchange from Gd(III) to bulk solution. The CGLPs exhibit a 15-fold higher longitudinal relaxivity value ( ca 60 mM −1 s −1 ) than that (4 mM −1 s −1 ) of the commercial contrast agent, Magnevist, in phosphate buffered saline. The in vivo characterization demonstrates that CGLPs exhibit a signal-to-noise ratio in T 1 -weighted MR image contrast similar to that of Magnevist, yet with a Gd dose 5-fold lower. An excellent contrast in NIR imaging at tumor site was attained following the intravenous injection of GGLPs into Tramp-C1 tumor-bearing mice (C57BL/6). Along with their non-toxicity at the dose used, these results demonstrate the great potential of the CGLPs as an advanced diagnostic nanodevice.

Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m-THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate-conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC-loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT.

Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2-diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen and kidney by 20.4%, 42.5% and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively.

Dextran hydrogels were obtained by radical copolymerization of methacrylated dextran (MA-dextran) with acrylic acid (AAc) using ammonium peroxydisulfate (APS) and N,N,N′,N′-tetramethylethylenediamine (TMEDA) as an initiation system in an aqueous solution. The AAc content in hydrogels was determined by FTIR. Copolymerization of MA-dextran with AAc increased the cross-linking density of hydrogels by the bridging effect of AAc and, to a certain extent, facilitated the formation of hydrogels from MA-dextran with a low degree of MA substitution (DS). For hydrogels with a low DS (5.9), the swelling at pH 7.4 initially decreased and then increased with increasing AAc. The swelling of hydrogels with high DS (11.4 and 22.4) increased gradually with AAc. This discrepancy was explained by the differences in the chemical potentials of water outside and inside of the hydrogels as a function of AAc. Further increases of AAc, however, led to a reduction in polymerization conversion and even incomplete formation of hydrogel. The reduction in polymerization yield was primarily a consequence of the pH reduction and salt formation of AAc with TMEDA.

Graft copolymer comprising acrylic acid (AAc) units as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts undergoes phase transition and supramolecular assembly into colloidal particles in water upon the thermally induced hydrophobic association. The structural characteristics of the polymeric assemblies made from the graft copolymer in water are strongly dependent on the copolymer concentration and the way that the copolymer solution is subjected to heating from 25 degrees C to the phase transition region (occurring in the range 30 approximately 35 degrees C). The resultant assemblies are characterized by forming hydrophobic PNIPAAm regions with the multicore architecture and intercore connections. Interesting enough, these colloidal systems obtained from the copolymer solutions at different concentrations (10.0 and 1.0 mg/mL) and heating methods (fast and slow heating) exhibit very different structural responses when subjected to further temperature increase (from 30 approximately 35 to 60 degrees C). The mutual interactions among the components (PAAc backbone and PNIPAAm and mPEG grafts) of the copolymer were shown to play a crucial role in the evolution of the ultimate assembly structure. A molecular packing model was proposed to illustrate the mechanisms of the thermally induced structural transformation processes for the amphiphilic graft copolymer in water.

Hsin-Hung Chen,1 Wen-Chia Huang,2 Wen-Hsuan Chiang,2 Te-I Liu,2 Ming-Yin Shen,2,3 Yuan-Hung Hsu,4 Sung-Chyr Lin,1 Hsin-Cheng Chiu2 1Department of Chemical Engineering, National Chung Hsing University, Taichung, 2Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 3Department of Surgery, National Taiwan University Hospital-Hsinchu Branch, 4Pharmaceutical Optimization Technology Division, Biomedical Technology and Device Research Laboratory, Industrial Technology Research Institute, Hsinchu, Taiwan Abstract: In this study, a novel pH-responsive cholesterol-PEG adduct-coated solid lipid nanoparticles (C-PEG-SLNs) carrying doxorubicin (DOX) capable of overcoming multidrug resistance (MDR) breast cancer cells is presented. The DOX-loaded SLNs have a mean hydrodynamic diameter of ~100nm and a low polydispersity index (under 0.20) with a high drug-loading efficiency ranging from 80.8% to 90.6%. The in vitro drug release profiles show that the DOX-loaded SLNs exhibit a pH-controlled drug release behavior with the maximum and minimum unloading percentages of 63.4% at pH 4.7 and 25.2% at pH 7.4, respectively. The DOX-loaded C-PEG-SLNs displayed a superior ability in inhibiting the proliferation of MCF-7/MDR cells. At a DOX concentration of 80 µM, the cell viabilities treated with C-PEG-SLNs were approximately one-third of the group treated with free DOX. The inhibition activity of C-PEG-SLNs could be attributed to the transport of C-PEG to cell membrane, leading to the change of the composition of the cell membrane and thus the inhibition of permeability glycoprotein activity. This hypothesis is supported by the confocal images showing the accumulation of DOX in the nuclei of cancer cells and the localization of C-PEG on the cell membranes. The results of in vivo study further demonstrated that the DOX delivered by the SLNs accumulates predominantly in tumor via enhanced permeability and retention effect, the enhanced passive tumor accumulation due to the loose intercellular junctions of endothelial cells lining inside blood vessels at tumor site, and the lack of lymphatic drainage. The growth of MCF-7/MDR xenografted tumor on Balb/c nude mice was inhibited to ~400mm3 in volume as compared with the free DOX treatment group, 1,140mm3, and the group treated with 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] solid lipid nanoparticles, 820mm3. Analysis of the body weight of nude mice and the histology of organs and tumor after the administration of DOX-loaded SLNs show that the SLNs have no observable side effects. These results indicate that the C-PEG-SLN is a promising platform for the delivery of therapeutic agents for MDR cancer chemotherapy. Keywords: pH-responsive, solid lipid nanoparticles, multidrug resistance, permeability glycoprotein