Biomacromolecules

Thermoresponsive Hyaluronate-Based Nanogels for Enhanced Phenanthriplatin Delivery in Cisplatin-Resistant Ovarian Cancer

Stimuli-responsive hyaluronic acid carriers face limitations due to limited carboxyl groups, which are divided between drug conjugation and functional modifications. Thermoresponsive nanogels based on selectively oxidized hyaluronan (2,3-dicarboxy hyaluronate, DCH) grafted with poly(

Affibody-Functionalized Elastin-like Peptide–Drug Conjugate Nanomicelle for Targeted Ovarian Cancer Therapy

Recombinant elastin-like polypeptides (ELPs) have emerged as an attractive nanoplatform for drug delivery due to their tunable genetically encoded sequence, biocompatibility, and stimuli-responsive self-assembly behaviors. Here, we designed and biosynthesized an HER2 (human epidermal growth factor receptor 2)-targeted affibody-ELP fusion protein (Z-ELP), which was subsequently conjugated with monomethyl auristatin E (MMAE) to build a protein-drug conjugate (Z-ELP-M). Due to its thermal response, Z-ELP-M can immediately self-assemble into a nanomicelle at physiological temperature. Benefiting from its active targeting and nanomorphology, Z-ELP-M exhibits enhanced cellular internalization and deep tumor penetration

Carbosilane Glycodendrimers for Anticancer Drug Delivery: Synthetic Route, Characterization, and Biological Effect of Glycodendrimer–Doxorubicin Complexes

The complexity of drug delivery mechanisms calls for the development of new transport system designs. Here, we report a robust synthetic procedure toward stable glycodendrimer (glyco-DDM) series bearing glucose, galactose, and oligo(ethylene glycol)-modified galactose peripheral units. In vitro cytotoxicity assays showed exceptional biocompatibility of the glyco-DDMs. To demonstrate applicability in drug delivery, the anticancer agent doxorubicin (DOX) was encapsulated in the glyco-DDM structure. The anticancer activity of the resulting glyco-DDM/DOX complexes was evaluated on the noncancerous (BJ) and cancerous (MCF-7 and A2780) cell lines, revealing their promising generation- and concentration-dependent effect. The glyco-DDM/DOX complexes show gradual and pH-dependent DOX release profiles. Fluorescence spectra elucidated the encapsulation process. Confocal fluorescence microscopy demonstrated preferential cancer cell internalization of the glyco-DDM/DOX complexes. The conclusions were supported by computer modeling. Overall, our results are consistent with the assumption that novel glyco-DDMs and their drug complexes are very promising in drug delivery and related applications.

Cisplatin-Loaded Tobacco Mosaic Virus for Ovarian Cancer Treatment

Ovarian cancer is the foremost cause of gynecological cancer and a major cause of cancer death in women. Treatment for advanced stage is surgical debulking followed by chemotherapy; however, most patients relapse with more aggressive and therapy-resistant tumors. There is a need to develop drug delivery approaches to deliver platinum therapies to tumors to increase efficacy while maintaining safety. Toward this goal, we utilized the protein nanotubes from the plant virus, tobacco mosaic virus (TMV), as a drug carrier. Specifically, the nanochannel of TMV was loaded with the active dication form of cisplatin (cisPt

Nanocomposite Hydrogel Bioinks for 3D Bioprinting of Tumor Models

In vitro tumor models were successfully constructed by 3D bioprinting; however, bioinks with proper viscosity, good biocompatibility, and tunable biophysical and biochemical properties are highly desirable for tumor models that closely recapitulated the main features of native tumors. Here, we developed a nanocomposite hydrogel bioink that was used to construct ovarian and colon cancer models by 3D bioprinting. The nanocomposite bioink was composed of aldehyde-modified cellulose nanocrystals (aCNCs), aldehyde-modified hyaluronic acid (aHA), and gelatin. The hydrogels possessed tunable gelation time, mechanical properties, and printability by controlling the ratio between aCNCs and gelatin. In addition, ovarian and colorectal cancer cells embedded in hydrogels showed high survival rates and rapid growth. By the combination of 3D bioprinting, ovarian and colorectal tumor models were constructed in vitro and used for drug screening. The results showed that gemcitabine had therapeutic effects on ovarian tumor cells. However, the ovarian tumor model showed drug resistance for oxaliplatin treatment.

Biomimetic Chitosan Nanogels Codeliver Drug/Small Activating RNA for Metastasis-Inhibited Necroptosis Therapy of Ovarian Cancer

Ovarian cancer remains the leading cause of gynecologic malignancy-related deaths. Developing novel nanoplatforms to overcome the low efficacy of chemotherapy and advanced metastasis in ovarian cancer is crucial. Here, we report biomimetic chitosan nanogels (CH NGs) designed to codeliver gambogic acid (GA) and MAS1 small activating RNA (saMAS1). The formed CH NGs/GA/saMAS1 camouflaged with ovarian cancer cell membranes (CM) can release GA in a pH-responsive manner, target cancer cells, and induce the killing effects through GA-mediated necroptosis. Meanwhile, saMAS1 upregulates MAS1 expression, counteracting the activation of angiotensin II receptor type 1 (AGTR1) and thereby inhibiting the renin-angiotensin system (RAS) signaling pathway, subsequently impeding metastasis. The therapeutic efficacy of CH NGs/GA/saMAS1@CM NGs regarding primary tumor killing and metastasis inhibition was further confirmed using ovarian mouse models. These biocompatible CH NGs represent a promising advanced nanomedicine formulation to tackle ovarian cancer through metastasis-inhibited necroptosis following the codelivery of GA and saMAS1.

Nucleus-Localizing Coacervates Synergize with Chemotherapy for the Treatment of Drug-Resistant Ovarian Tumors

Tumor-targeting intracellular chemotherapy represents a precision therapy to overcome multidrug resistance (MDR) in ovarian cancers, yet efficient drug enrichment in resistant cells is difficult. Peptide-based coacervates have emerged as an intracellular reservoir for drug delivery; however, enhancing their antitumor efficacy requires precise control over the spatiotemporal distribution of drugs within tumor cells. To address this, we developed a nucleus-localizing coacervate system by complexing a cell-penetrating peptide with sodium alginate (SA), which enables efficient delivery of the DNA-binding drug doxorubicin (DOX) into the cell nucleus. Remarkably, the fluorescence partition coefficient of DOX in the nucleus of ovarian cancer cells increased by 4 ± 0.5-fold compared to coacervate-free controls, while nuclear drug retention was extended from approximately 4 to 36 h. This nucleus-localized drug delivery and sustained retention enhanced the killing efficacy of DNA-targeting medicine against MDR cells by 60 ± 5% at clinical doses, offering a promising therapeutic strategy for treating drug-resistant ovarian cancers. Keywords: complexed coacervates, intracellular drug delivery, ovarian cancer, multi-drug resistance, cell-penetrating peptide.