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Abstract Bladder cancer is a leading cause of cancer‐related mortality, yet current intravesical drug delivery methods often suffer from poor retention times in the bladder. Gecko feet‐like nanomaterials offer the potential to overcome this challenge, however, conventional methods to fabricate high surface area nanomaterials for drug delivery involve complex and expensive manufacturing processes. In this work, a simple fluid flow templating method is reported for manufacturing soft dendritic particles (SDPs) composed of poly(lactic‐co‐glycolic acid) (PLGA) with a chitosan coating for enhanced adhesion to epithelial tissues via van der Waals interactions. The biodegradable SDPs encapsulate chemotherapeutic agents and are administered using an alginate hydrogel, enabling precise deposition by extrusion for sustained drug release. The results demonstrate that SDPs adhere to mouse and human cancer cells for several days. The SDPs effectively encapsulate and release several clinically utilized chemotherapeutic drugs such as gemcitabine, docetaxel, and methotrexate, exhibiting superior cancer cell killing in vitro. In murine models, gemcitabine‐loaded SDPs instilled into tumor‐bearing bladders elicited stronger CD45+ immune cell responses than control groups while maintaining minimal toxicity. This work presents a simple, biomimetic drug delivery platform with prolonged retention and controlled drug release, offering a versatile approach for enhancing therapeutic delivery in epithelial cancer models.
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This content will become publicly available on December 30, 2026
Peptomer Linkers Enable Kinetic Control over Co‐Delivery of Multiple Chemotherapeutics
ABSTRACT Combination cancer therapies offer to minimize toxicity and alleviate patient burden, but a key challenge is independent control over the release of multiple therapeutics, especially in systems with chemotherapeutic drugs of similar size and structure. Due to MMP upregulation in cancer microenvironments, matrix metalloproteinase (MMP)‐degradable linkers are often exploited for targeted release; however, their short substrates exhibit overlap with multiple proteases, which confounds kinetic control. Here, a library of MMP‐responsive “peptomer” drug linkers was developed to control release on fast and slow timescales. Peptomers are hybrid molecules of peptides and non‐natural peptoids (N‐substituted glycines), which hinder proteolytic susceptibility. Systematic variation of peptoid substitutions within a pan‐MMP‐cleavable peptide sequence yielded distinct degradation kinetics to multiple MMPs. Two chemotherapeutics, doxorubicin and geldanamycin, were conjugated to peptomer linkers and incorporated into polyethylene glycol (PEG)‐based hydrogels for sequential delivery. Fluorogenic and mass spectrometry‐based assays demonstrated decoupled release of each drug in response to MMP‐2 and MMP‐9. In vitro studies using MDA‐MB‐231 and A549 cells showed that cell death rates correlated with the order of drug release. These findings highlight peptomers as modular, biocompatible linkers capable of kinetic control over multiple therapeutic agents, providing a versatile platform for improving the precision of combination drug delivery systems.
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- Award ID(s):
- 2046746
- PAR ID:
- 10679823
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Advanced Healthcare Materials
- Volume:
- 15
- Issue:
- 11
- ISSN:
- 2192-2640
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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