Dual Stimuli-Responsive Nanoparticle-Incorporated Hydrogels as an Oral Insulin Carrier for Intestine-Targeted Delivery and Enhanced Paracellular Permeation

For enhanced oral insulin delivery, a strategy of acid-resistant and enteric hydrogels encapsulating insulin-loaded nanoparticles was developed. The nanoparticles were prepared by the formation of an anionic insulin/heparin sodium (Ins/HS) aggregate, followed by coating of chitosan (CS) on the surface. The nanoparticles, tagged as CS/Ins/HS NPs, exhibited excellent mucosa affinity, effective protease inhibition, and marked paracellular permeation enhancement. Moreover, to improve the acid-stability of CS/Ins/HS NPs and impart the capacity of intestine-targeted delivery, a pH- and amylase-responsive hydrogel was synthesized via free radical copolymerization, using methacrylic acid as the monomer and acrylate-<i>grafted</i>-carboxymethyl starch as the cross-linker. The resulting hydrogel exhibited sharp pH-sensitivity in the gastrointestinal tract and rapid enteric behavior under intestinal amylase. The additional protection for insulin in artificial gastric fluid was confirmed by packaging CS/Ins/HS NPs into the hydrogel. The obtained nanoparticle-incorporated hydrogel was named as NPs@Gel-2. The release of insulin from NPs@Gel-2 was evidently accelerated in artificial intestinal fluid containing α-amylase. Furthermore, the hypoglycemic effects were evaluated with type-1 diabetic rats. Compared to subcutaneous injection of insulin solution, the relative pharmacological availability (rPA) for oral intake of NPs@Gel-2 (30 IU/kg) was determined to be 8.6%, along with rPA of 4.6% for oral administration of unpackaged CS/Ins/HS NPs (30 IU/kg). Finally, the two-week therapeutic outcomes in diabetic rats were displayed after twice-daily treatments by oral intake of NPs@Gel-2, showing the relief of diabetic symptoms and suppression of weight loss in the rats. Therefore, this dual stimuli-responsive nanoparticle-incorporated hydrogel system could be a promising platform for oral insulin delivery

Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment

Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the “browning” at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes <i>in vivo</i> in a diet-induced obesity mouse model

Intracellular pH-Sensitive PEG-<i>block</i>-Acetalated-Dextrans as Efficient Drug Delivery Platforms

Intracellular pH-sensitive micelles of PEG-<i>block</i>-acetalated-dextran (PEG-<i>b</i>-AC-Dex) were prepared and used for acid-triggered intracellular release of anticancer drug. The hydrodynamic radii (<i>R</i>_h) of PEG-<i>b</i>-AC-Dex micelles could increase after incubation in PBS solution at pH 5.5. Based on the pH-responsive <i>R</i>_h variation behavior, it was expected that the PEG-<i>b</i>-AC-Dex micelles should be interesting for intracellular drug delivery. Thus, doxorubicin (DOX), a wide-spectrum anticancer drug, was loaded into the micelles and the pH-dependent release of the payload DOX was tested <i>in vitro</i>. The <i>in vitro</i> drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at pH 7.4, while up to about 90% of the loaded DOX could be quickly released in PBS solution at pH 5.5. Compared to pH-insensitive PEG-PLA micelles, the PEG-<i>b</i>-AC-Dex micelles displayed a faster drug release behavior in tumor cells. Moreover, higher cellular proliferation inhibition efficacy was achieved toward tumor cells. These features suggested that DOX could be efficiently loaded and delivered into tumor cells <i>in vitro</i> by the intracelluar pH-sensitive micelles, leading to enhanced inhibition of tumor cell proliferation. Therefore, the pH-sensitive micelles may provide a promising carrier for acid-triggered drug release for cancer therapy

pH-Responsive Poly(ethylene glycol)/Poly(l‑lactide) Supramolecular Micelles Based on Host–Guest Interaction

pH-responsive supramolecular amphiphilic micelles based on benzimidazole-terminated poly­(ethylene glycol) (PEG-BM) and β-cyclodextrin-modified poly­(l-lactide) (CD-PLLA) were developed by exploiting the host–guest interaction between benzimidazole (BM) and β-cyclodextrin (β-CD). The dissociation of the supramolecular micelles was triggered in acidic environments. An antineoplastic drug, doxorubicin (DOX), was loaded into the supramolecular micelles as a model drug. The release of DOX from the supramolecular micelles was clearly accelerated as the pH was reduced from 7.4 to 5.5. The DOX-loaded PEG-BM/CD-PLLA supramolecular micelles displayed an enhanced intracellular drug-release rate in HepG2 cells compared to the pH-insensitive DOX-loaded PEG-<i>b</i>-PLLA counterpart. After intravenous injection into nude mice bearing HepG2 xenografts by the tail vein, the DOX-loaded supramolecular micelles exhibited significantly higher tumor inhibition efficacy and reduced systemic toxicity compared to free DOX. Furthermore, the DOX-loaded supramolecular micelles showed a blood clearance rate markedly lower than that of free DOX and comparable to that of the DOX-loaded PEG-<i>b</i>-PLLA micelles after intravenous injection into rats. Therefore, the pH-responsive PEG-BM/CD-PLLA supramolecular micelles hold potential as a smart nanocarrier for anticancer drug delivery

Enhanced Endosomal Escape by Light-Fueled Liquid-Metal Transformer

Effective endosomal escape remains as the “holy grail” for endocytosis-based intracellular drug delivery. To date, most of the endosomal escape strategies rely on small molecules, cationic polymers, or pore-forming proteins, which are often limited by the systemic toxicity and lack of specificity. We describe here a light-fueled liquid-metal transformer for effective endosomal escape-facilitated cargo delivery via a chemical-mechanical process. The nanoscale transformer can be prepared by a simple approach of sonicating a low-toxicity liquid-metal. When coated with graphene quantum dots (GQDs), the resulting nanospheres demonstrate the ability to absorb and convert photoenergy to drive the simultaneous phase separation and morphological transformation of the inner liquid-metal core. The morphological transformation from nanospheres to hollow nanorods with a remarkable change of aspect ratio can physically disrupt the endosomal membrane to promote endosomal escape of payloads. This metal-based nanotransformer equipped with GQDs provides a new strategy for facilitating effective endosomal escape to achieve spatiotemporally controlled drug delivery with enhanced efficacy

Self-Assembly of Cricoid Proteins Induced by “Soft Nanoparticles”: An Approach To Design Multienzyme-Cooperative Antioxidative Systems

A strategy to construct high-ordered protein nanowires by electrostatic assembly of cricoid proteins and “soft nanoparticles” was developed. Poly(amido amine) (PAMAM) dendrimers on high generation that have been shown to be near-globular macromolecules with all of the amino groups distributing throughout the surface were ideal electropositive “soft nanoparticles” to induce electrostatic assembly of electronegative cricoid proteins. Atomic force microscopy and transmission electron microscopy all showed that one “soft nanoparticle” (generation 5 PAMAM, PD5) could electrostatically interact with two cricoid proteins (stable protein one, SP1) in an opposite orientation to form sandwich structure, further leading to self-assembled protein nanowires. The designed nanostructures could act as versatile scaffolds to develop multienzyme-cooperative antioxidative systems. By means of inducing catalytic selenocysteine and manganese porphyrin to SP1 and PD5, respectively, we successfully designed antioxidative protein nanowires with both excellent glutathione peroxidase and superoxide dismutase activities. Also, the introduction of selenocysteine and manganese porphyrin did not affect the assembly morphologies. Moreover, this multienzyme-cooperative antioxidative system exhibited excellent biological effect and low cell cytotoxicity