Hyaluronidase (HAase) inhibitor-incorporated hyaluronic acid (HA) hydrogel cross-linked with 1,4-butanediol diglycidyl ether (BDDE) was designed to reduce the toxicity risk induced by BDDE and its biodegradation rate in subcutaneous tissue. The formulation composition of hydrogel and its preparation method were optimized to have a high swelling ratio and drug content. Quercetin (QCT) and quetiapine (QTP), as an HAase inhibitor and model drug, respectively, were incorporated into the cross-linked hydrogel using the antisolvent precipitation method for extending their release after subcutaneous injection. The cross-linked HA (cHA)-based hydrogels displayed appropriate viscoelasticity and injectability for subcutaneous injection. The incorporation of QCT (as an HAase inhibitor) in the cHA hydrogel formulation resulted in slower in vitro and in vivo degradation profiles compared to the hydrogel without QCT. Single dosing of optimized hydrogel injected via a subcutaneous route in rats did not induce any acute toxicities in the blood chemistry and histological staining studies. In the pharmacokinetic study of rats following subcutaneous injection, the cHA hydrogel with QCT exhibited a lower maximum QTP concentration and longer half-life and mean residence time values compared to the hydrogel without QCT. All of these results support the designed HAase inhibitor-incorporated cHA hydrogel being a biocompatible subcutaneous injection formulation for sustained drug delivery.

Although cyclodextrin (CD)-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their optimal designs for enhanced tumor retention and reduced off-target accumulation have rarely been proposed. Herein, we present a delicately tailored structure of a renal-clearable zwitterionic CD, hepatkis-(6-deoxy-6-((phenylboronic acid-tetraethyleneglycol-l-glutamic acid N α -sulfobetaine)-octaethyleneglycol-caproamide))-β-cyclodextrin (PBA-(ZW)-CD), for colorectal cancer (CRC)-selective drug delivery. Twenty CD derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting ve candidates are complexed with adamantyl sulfocyanine 7 and evaluated for biodistribution. PBA-(ZW)-CD, the optimized structure, displays a high tumor-to-background ratio of 3.7-4.1. PBA-(ZW)-CD inclusion complexes of doxorubicin and ulixertinib are fabricated, and their enhanced tumor accumulation (vs. free doxorubicin, 2.0-folds; vs. free ulixertinib, 2.1-folds), facilitated elimination (vs. free doxorubicin, 15.2 and 0.0% remaining in the heart and muscles, respectively; vs. free ulixertinib, 17.7 and 7.4% in the liver and kidneys, respectively), and tumor penetration comparable to those of free drugs are veri ed via mass-spectrometric quantitation and imaging. The improved antitumor e cacy of PBA-(ZW)-CD/drug combination therapy is demonstrated in heterotopic and orthotopic CRC models (vs. free drug combination, tumor size reduction by 52.0 and 76.2%, respectively), suggesting that PBA-(ZW)-CD can be used as a promising CRC-targeted nanoplatform.

PEGylated Eudragit L100 (ELP)-containing proliponiosomes (PLNs) were developed for improved oral delivery of celecoxib (CXB). The successful introduction of PEG 2000 or 5000 to Eudragit L100 (EL) was confirmed via proton nuclear magnetic resonance analysis of which calculated molar substitution ratio of PEG to EL was 36.0 or 36.7, respectively. CXB, ELP, phospholipid, and non-ionic surfactants were dissolved in dimethyl sulfoxide and lyophilized to produce CXB-loaded PLNs (CXB@PLNs). The physical state of CXB@PLNs was evaluated using differential scanning calorimetry and powder X-ray diffractometry, which revealed that crystalline CXB was transformed into amorphous form after the fabrication procedure. The reconstitution of CXB@PLNs in aqueous media generated CXB-loaded liponiosomes with nano-sized mean diameters and spherical morphology. CXB@PLNs displayed enhanced dissolution rate and permeability compared to CXB suspension. In vivo pharmacokinetic studies performed on rats demonstrated the improved oral bioavailability of CXB@PLNs compared to that of CXB suspension. No serious systemic toxicity was observed in the blood biochemistry tests performed on rats. These results suggest that the developed PLNs could be promising oral delivery systems for improving the bioavailability of poorly water-soluble drugs, such as CXB.

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Although cyclodextrin (CD)-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their optimal designs for enhanced tumor retention and reduced off-target accumulation have rarely been proposed. Herein, we present a delicately tailored structure of a renal-clearable zwitterionic CD, hepatkis-(6-deoxy-6-((phenylboronic acid-tetraethyleneglycol-l-glutamic acid Nα-sulfobetaine)-octaethyleneglycol-caproamide))-β-cyclodextrin (PBA-(ZW)-CD), for colorectal cancer (CRC)-selective drug delivery. Twenty CD derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are complexed with adamantyl sulfocyanine 7 and evaluated for biodistribution. PBA-(ZW)-CD, the optimized structure, displays a high tumor-to-background ratio of 3.7–4.1. PBA-(ZW)-CD inclusion complexes of doxorubicin and ulixertinib are fabricated, and their enhanced tumor accumulation (vs. free doxorubicin, 2.0-folds; vs. free ulixertinib, 2.1-folds), facilitated elimination (vs. free doxorubicin, 15.2 and 0.0% remaining in the heart and muscles, respectively; vs. free ulixertinib, 17.7 and 7.4% in the liver and kidneys, respectively), and tumor penetration comparable to those of free drugs are verified via mass-spectrometric quantitation and imaging. The improved antitumor efficacy of PBA-(ZW)-CD/drug combination therapy is demonstrated in heterotopic and orthotopic CRC models (vs. free drug combination, tumor size reduction by 52.0 and 76.2%, respectively), suggesting that PBA-(ZW)-CD can be used as a promising CRC-targeted nanoplatform.