Phase IIa/IIb Clinical Trial of NC-6004 in Combination with Pembrolizumab in Subjects with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Have Failed Platinum or a Platinum-containing Regimen
A Phase 1b/2 Dose Escalation and Expansion Trial of NC-6004 (Nanoparticle Cisplatin) plus Gemcitabine in Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, Biliary Tract, and Bladder Cancer
Synthesis of doxorubicin-loaded peptosomes hybridized with gold nanorod for targeted drug delivery and CT imaging of metastatic breast cancer.
作者: Maliheh Hasannia ; Khalil Abnous ; Seyed Mohammad Taghdisi ; Sirous Nekooei ; Mohammad Ramezani ; Mona Alibolandi
Cancer nanomedicines based on synthetic polypeptides have attracted much attention due to their superior biocompatibility and biodegradability, stimuli responsive capability through secondary conformation change, adjustable functionalities for various cargos such as peptides, proteins, nucleic acids and small therapeutic molecules. Recently, a few nanoformulations based on polypeptides comprising NK105, NC6004, NK911, CT2103, have entered phase I-III clinical trials for advanced solid tumors therapy. In the current study, we prepared polypeptide-based vesicles called peptosome via self-assembly of amphiphilic polypeptide-based PEG-PBLG diblock copolymer.
In this regard, poly(γ-benzyl L-glutamate (PBLG) was synthesized via ring opening polymerization (ROP) of γ-benzyl L-glutamate-N-carboxyanhydride (BLG-NCA) using N-hexylamine as initiator. Then amine-terminated PBLG was covalently conjugated to heterofuctional maleimide PEG-carboxylic acid or methyl-PEG-carboxylic acid. The PEG-PBLG peptosomes were prepared through double emulsion method for the co-delivery of doxorubicin.HCl and gold nanorods as hydrophilic and hydrophobic agents in interior compartment and membrane of peptosomes, respectively (Pep@MUA.GNR-DOX) that DOX encapsulation efficiency and loading capacity were determined 42 ± 3.6 and 1.68 ± 3.6. Then, theranostic peptosomes were decorated with thiol-functionalized EpCAM aptamer throught thiol-maleimide reaction producing Apt-Pep@MUA.GNR-DOX for targeted delivery. The non-targeted and targeted peptosomes showed 165.5 ± 1.1 and 185 ± 4.7 nm diameters, respectively while providing sustained, controlled release of DOX. Furthermore, non-targeted and targeted peptosomes showed considerable serum stability. In vitro study on MCF-7 and 4T1 cells showed significantly higher cytotoxicity for Apt-Pep@MUA.GNR-DOX in comparison with Pep@MUA.GNR-DOX while both system did not show any difference in cytotoxicity against CHO cell line. Furthermore, Apt-Pep@MUA.GNR-DOX illustrated higher cellular uptake toward EpCAM-overexpressing 4T1 cells compared to Pep@MUA.GNR-DOX. In preclinical stage, therapeutic and diagnostic capability of the prepared Pep@MUA.GNR-DOX and Apt-Pep@MUA.GNR-DOX were investigated implementing subcutaneous 4T1 tumor model in BALB/c mice. The obtained data indicated highest therapeutic index for Apt-Pep@MUA.GNR-DOX compared to Pep@MUA.GNR-DOX and free DOX. Moreover, the prepared system showed capability of CT imaging of tumor tissue in 4T1 tumorized mice through tumor accumulation even 24 h post-administration.
In this regard, the synthesized theranostic peptosomes offer innovative hybrid multipurpose platform for fighting against breast cancer.
A multicenter, single-arm, basket design, phase II study of NC-6004 plus gemcitabine in patients with advanced unresectable lung, biliary tract, or bladder cancer.
作者: Simona Ruxandra Volovat ; Tudor-Eliade Ciuleanu ; Piotr Koralewski ; Juneko E Grilley Olson ; Adina Croitoru ; Krassimir Koynov ; Stefano Stabile ; Giulio Cerea ; Atsushi Osada ; Iulian Bobe ; Constantin Volovat
NC-6004 is a nanoparticle developed using micellar technology that can improve release of cisplatin, a standard treatment for many cancer types, and achieve selective distribution to tumors. Here, in the Phase II portion of this study, the activity, safety, tolerability, and effects on quality of life of NC-6004 in combination with gemcitabine was examined in 34 squamous non-small cell lung carcinoma (NSCLC) patients, 50 biliary tract cancer patients, and 13 bladder cancer patients. All patients received 135 mg/m2 NC-6004 on day one and 1,250 mg/m2 gemcitabine on days one and eight. The median progression-free survival was 3.9 months in NSCLC patients, 4.3 months in biliary tract cancer patients, and 6.8 months in bladder cancer patients fit for cisplatin treatment. The most frequently reported Grade 3 Treatment Emergent Adverse Events across all cohorts were nausea, anemia and neutropenia, and hyponatremia. Quality of life measures for patients who received the combined therapy were generally consistent with expectations for patients undergoing chemotherapy. Overall, combined NC-6004 and gemcitabine treatment resulted in long-lasting antitumor activity and had a favorable safety profile, suggesting that it should be investigated further as a therapy for various types of cancer.
2019-12-09·Biomacromolecules2区 · 化学
Cancer Nanomedicines Based on Synthetic Polypeptides
Nanomedicines are deemed as the most promising treatment modality for malignant cancers. Particularly, cancer nanomedicines based on synthetic polypeptides have gained interest because they possess excellent safety, unique hierarchical structure, and tailorable functionalities to suit for delivery of diverse drugs including synthetic drugs, peptides, proteins, and nucleic acids. A few polypeptide-based nanoformulations (e.g., NK105, NC6004, NK911, CT2103) are under phases I-III clinical investigation for treating patients with advanced solid tumors. In recent years, progress has been made in the development of robust and high drug loading, tumor-targeting, membrane-disrupting, and stimuli-sensitive nanomedicines from de novo functional polypeptides, which afford not only better safety and reduced adverse effects, but also further improved anticancer efficacy over clinical formulations. Moreover, virus-mimicking vehicles have been devised from polypeptides for efficient nonviral delivery of highly potent peptides, proteins, and nucleic acids, greatly advancing biotherapy for cancers. In this Perspective, we highlight the state-of-the-art design and fabrication of cancer nanomedicines based on synthetic polypeptides and, at the end, give our viewpoints on their future development for targeted cancer therapy and potential challenges for clinical translation.