Systemic Tumor Suppression via Macrophage-Driven Automated Homing of Metal-Phenolic-Gated Nanosponges for Metastatic Melanoma.

Cell-based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug-loading with high accumulations in solid tumors. Herein, a tumor-targeting cellular drug delivery system (MAGN) by surface engineering of tumor-homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron-tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the "ON-OFF" gating effect of the polyphenol-based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor-targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs.

Controlling burst and final drug release times from porous polylactide devices derived from co-continuous polymer blends.

This work has demonstrated that it is possible to exercise a wide range of control over both the initial burst release and the final drug release times from porous polylactide (PLA) devices derived from cocontinuous polymer blends. Two strategies were used: a layer-by-layer polyelectrolyte surface deposition approach on the porous PLA surface and the application of a partially closed-cell protocol. A PLA porous substrate with a pore size of 1.5 microm, derived from a blend of PLA and polystyrene (PS) via selective solvent extraction of the PS phase, was used as the drug delivery device. The surface area and pore dimensions were examined via BET nitrogen adsorption and image analysis. Porous PLA substrates with 0, 3, and 5 layers of polyelectrolytes and with open areas of 100, 12, and 2% were studied both separately and in combination. In vitro release tests were performed to study the release profile of bovine serum albumin (BSA) from the devices via UV spectrophotometry. It is shown that, while both are important, surface modification is more dominant in controlling the release rate than the partially closed cell approach. When a five layer surface modification of the PLA and a partially closed cell approach (2% open area) are combined, denoted as the L5C sample, the synergy is dramatic with a 5x reduction in the first two hour burst release amount and a total release time that is extended by 123x as compared to the 100% open cell, surface unmodified, reference sample. The L5C sample ultimately releases 89% of the total BSA loaded, demonstrating the high level of interconnectivity of the microchannels in the porous PLA. The mechanism of release in this system is clearly diffusion controlled with well-defined concentration gradients, as measured by X-ray photoelectron spectroscopy (XPS), observed in the direction of release. These results point toward a diffusion mechanism combined with a sorption/desorption interaction of the BSA with the modified PLA surface.