Empowering hydrophobic anticancer drugs by ultrashort peptides: General Co-assembly strategy for improved solubility, targeted efficacy, and clinical application

Article

Author: Liu, Shihao ; Zhang, Feng ; Zhang, Yi ; Guo, Jun ; Wang, Liping ; Gao, Feng

The current state of drug delivery systems allows for the resolution of specific issues like inadequate solubility, limited targeting capabilities, and complex preparation processes, requiring tailored designs for different drugs. Yet, the major challenge in clinical application lies in surmounting these obstacles with a universal carrier that is effective for a variety of anticancer drugs. Herein, with the help of computer simulation, we rationally design ultrashort peptides GY and CCYRGD, which can co-assemble with hydrophobic anticancer drugs into nanoparticles with enhanced solubility, targeting ability and anticancer efficacy. Taking 7-ethyl-10-hydroxy camptothecin (SN38) as a model anticancer drug, the co-assembled SN38-GY-CCYRGD nanoparticles significantly enhance the water solubility of SN38 by more than three orders of magnitude. The as-prepared nanoparticles can effectively kill cancer cells, e.g., human small cell lung cancer (A549) cells with a notable cell mortality rate of 71%. Mice experimental results demonstrate the nanoparticles' efficient targeting capability, marked reducing the toxicity to normal tissues while improving antitumor efficacy. This work presents a novel drug delivery method, integrating effective, targeted, and safe strategies into a comprehensive carrier system, designed for the administration of hydrophobic anticancer drugs.

01 Sep 2023·Cancers

Discovery of VIP236, an αvβ3-Targeted Small-Molecule-Drug Conjugate with Neutrophil Elastase-Mediated Activation of 7-Ethyl Camptothecin Payload for Treatment of Solid Tumors.

Article

Author: Heroult, Melanie ; Wong, Harvey ; Lerchen, Hans-Georg ; Johnson, Amy J ; Zubov, Dmitry ; Izumi, Raquel ; Stelte-Ludwig, Beatrix ; Hamdy, Ahmed ; Gericke, Kersten Matthias ; Frigault, Melanie M

The emerging field of small-molecule-drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvβ3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor. Pharmacokinetics studies of VIP236 in tumor-bearing mice demonstrated high stability of the SMDC in plasma and high tumor accumulation of the cleaved payload. Studies in bile-duct-cannulated rats showed that biliary excretion of the unmodified conjugate is the primary route of elimination. Treatment- and time-dependent phosphorylation of H2AX, a marker of DNA damage downstream of topoisomerase 1 inhibition, verified the on-target activity of the payload cleaved from VIP236 in vivo. Treatment with VIP236 resulted in long-lasting tumor regression in subcutaneous patient-derived xenograft (PDX) models from patients with non-small-cell lung, colon, and renal cancer as well as in two orthotopic metastatic triple-negative breast cancer PDX models. In these models, a significant reduction of brain and lung metastases also was observed.

01 Jul 2023·Cardiovascular and interventional radiology

Prospective Series of Transarterial Chemoembolization of Metastatic Colorectal Cancer to the Liver with 30-60 μm Microspheres Loaded with Irinotecan.

Article

Author: Panagiotou, Ir ; Filippiadis, D K ; Alevisopoulos, N ; Kelekis, N ; Kiakidis, Th ; Psarros, G ; Pellerin, O ; Moschouris, H ; Delicha, E ; Malagari, K ; Glantzounis, G ; Charokopakis, A ; Kartsouni, V ; Tsavaris, N ; Vergadis, C ; Emmanouil, E

PURPOSETo describe safety and clinical outcomes among patients with metastatic colorectal cancer (mCRC) to the liver treated with transarterial chemoembolization with HepaSphere™ Microspheres 30-60 μm loaded with irinotecan (ΙRI-HEP-TACE).MATERIAL AND METHODSIn this prospective study (NCT04866290), 100 adults with confirmed mCRC to the liver who were ineligible for resection were enrolled and followed up to 24 months or death. Study outcomes among Salvage (patients not tolerating more cycles of chemotherapy) and Non-salvage patients included overall survival (OS), progression-free survival (PFS), objective response (OR), objective response rate (ORR), best tumor response (BTR), adverse events (AEs), and pharmacokinetics of irinotecan and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38).RESULTSThe median age was 66 years (range: 31-89). Median OS was 15.08 months (95% confidence interval [CI]: 12.33-17.25). PFS was 8.52 months (95% CI: 6.0-9.0; p < 0.001). ORR was 42.2% (95% CI: 31.57-53.50) and 35.9% (95% CI: 25.57-47.62) based on modified RECIST (Response Evaluation Criteria in Solid Tumors) and RECIST 1.1 criteria. BTR was not significantly different between mRECIST and RECIST (p = 0.745). The Non-salvage group had a statistically significant difference in median OS relative to the Salvage group (15.3 vs. 3 months; p < 0.001). Pharmacokinetic analyses demonstrated no correlation of OS with plasma concentration of irinotecan and SN38 (all p > 0.05). Most AEs were Grade 2 (257/279), the most common AE was right upper abdominal pain (180/279). One major AE (tumor rupture) was reported.CONCLUSIONIRI-HEP-TACE is an alternative treatment for patients with Non-salvage mCRC to the liver.

100 Deals associated with BACPTDP

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	DEKK-TEC, Inc.	09 May 2018

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

BACPTDP

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation