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Abstract To date, the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration. Herein, a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared, denoted SMONs-HA-Cy5.5, and comparative studies between SMONs-HA-Cy5.5 (24.2 MPa) and stiff counterparts (79.2 MPa) are conducted. Results indicate that, apart from exhibiting a twofold increase in tumor cellular uptake, the soft nanoplatforms also display a remarkable pharmacokinetic advantage, resulting in considerably improved tumor accumulation. Moreover, SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration, achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts. Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels, diffuse farther in the dense extracellular matrix, and reach deeper tumor tissues compared to the stiff ones. Specifically, the soft nanoplatforms generate a 16-fold improvement (43 vs. 2.72 μm) in diffusion distance in tumor parenchyma. Based on the significantly improved blood circulation and tumor accumulation/penetration, a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5. The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones.

Highlights: Soft mesoporous organosilica nanoplatforms modified with hyaluronic acid and cyanine 5.5 are constructed. Therapeutic efficacy of the soft nanoplatforms on tumor is higher both in vitro and in vivo after loading photosensitizer chlorin e6 compared to that of stiff counterparts.To date, the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration. Herein, a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared, denoted SMONs-HA-Cy5.5, and comparative studies between SMONs-HA-Cy5.5 (24.2 MPa) and stiff counterparts (79.2 MPa) are conducted. Results indicate that, apart from exhibiting a twofold increase in tumor cellular uptake, the soft nanoplatforms also display a remarkable pharmacokinetic advantage, resulting in considerably improved tumor accumulation. Moreover, SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration, achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts. Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels, diffuse farther in the dense extracellular matrix, and reach deeper tumor tissues compared to the stiff ones. Specifically, the soft nanoplatforms generate a 16-fold improvement (43 vs. 2.72 μm) in diffusion distance in tumor parenchyma. Based on the significantly improved blood circulation and tumor accumulation/penetration, a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5. The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones. [ABSTRACT FROM AUTHOR]

Limited blood circulation and poor tumor penetration are two main obstacles hampering the clinical translation of conventional nanosized drug delivery systems (NDDS). Here, red-blood-cell (RBC)-mimetic nanoparticles (NPs) with long circulation and peptide-enhanced tumor penetration for treating metastatic breast cancer are reported. The RBC-mimetic NPs are composed of a paclitaxel (PTX)-loaded polymeric core and a hydrophilic RBC vesicle shell. The RBC-mimetic NPs display dramatically elongated blood circulation with an elimination half time of 32.8 h, 5.8-fold higher than that of the parental polymeric NPs (i.e., 5.6 h). Moreover, the experimental results demonstrate that the tumor penetration ability of the RBC-mimetic NPs can be significantly improved by coadministrating with a tumor-penetrating peptide iRGD. Antitumor studies using a metastatic 4T1 breast tumor model show that RBC-mimetic NPs in combination with iRGD significantly inhibit over 90% of the tumor growth and suppress 95% of the lung metastasis, much more efficient than PTX-loaded polymer NP alone or the combination of polymer NPs and iRGD. The results reveal the importance of both long circulation and tumor penetration of nanosized drugs for efficient cancer therapy, which can provide a new insight for NDDS design. [ABSTRACT FROM AUTHOR]