A thermo-responsive chemically crosslinked long-term-release chitosan hydrogel system increases the efficiency of synergy chemo-immunotherapy in treating brain tumors.

Glioblastoma multiforme (GBM) is an aggressive and common brain tumor. The blood-brain barrier prevents several treatments from reaching the tumor. This study proposes a Chemo-Immunotherapy synergy treatment chemically crosslinked hydrogel system that is injected into the tumor to treat GBM. The strategy uses doxorubicin and BMS-1 with a thermo-responsive and chemically crosslinked hydrogel for extended drug release into the affected area. The hydrogels are produced by mixing with Chitosan (Chi), modified Pluronic F-127 (PF-127) with aldehyde end group and doxorubicin and then chemically crosslinking the aldehyde and amine bonds to increase the drug retention time. PF-127-CHO/Chi, which gels at body temperatures and chemically crosslinks between PF-127-CHO and Chitosan, increases the time that the drug remains in the affected area and prevents the hydrogel from swelling and compressing surrounding tissue. The drug is released from the chemically crosslinked hydrogels, prevents tumor progression and increases survival for subjects with GBM tumors. The Synergy Chemo-Immunotherapy also allows more efficient treatment of GBM than chemotherapy. The PF-127-CHO/Chi DOX and BMS-1 group have a tumor that is 43 times smaller than the untreated group. These results show that the proposed chemically crosslinking hydrogel is an efficient intratumoral delivery platform for the treatment of tumors.

Engineering Nano- and Microparticles as Oral Delivery Vehicles to Promote Intestinal Lymphatic Drug Transport.

Targeted oral delivery of a drug via the intestinal lymphatic system (ILS) has the advantages of protecting against hepatic first-pass metabolism of the drug and improving its pharmacokinetic performance. It is also a promising route for the oral delivery of vaccines and therapeutic agents to induce mucosal immune responses and treat lymphatic diseases, respectively. This article describes the anatomical structures and physiological characteristics of the ILS, with an emphasis on enterocytes and microfold (M) cells, which are the main gateways for the transport of particulate delivery vehicles across the intestinal epithelium into the lymphatics. A comprehensive overview of recent advances in the rational engineering of particulate vehicles, along with the challenges and opportunities that they present for improving ILS drug delivery, is provided, and the mechanisms by which such vehicles target and transport through enterocytes or M cells are discussed. The use of naturally sourced materials, such as yeast microcapsules and their derived polymeric ß-glucans, as novel ILS-targeting delivery vehicles is also reviewed. Such use is the focus of an emerging field of research. Their potential use in the oral delivery of nucleic acids, such as mRNA vaccines, is proposed.

Preparation of thermosensitive PNIPAm-based copolymer coated cytodex 3 microcarriers for efficient nonenzymatic cell harvesting during 3D culturing.

Enzymatic detachment of cells might damage important features and functions of cells and could affect subsequent cell-based applications. Therefore, nonenzymatic cell detachment using thermosensitive polymer matrix is necessary for maintaining cell quality after harvesting. In this study, we prepared thermosensitive PNIPAm-co-AAc-b-PS and PNIPAm-co-AAm-b-PS copolymers and low critical solution temperature (LCST) was tuned near to body temperature. Then, spin coated polymer films were prepared for cell adhesion and thermal-induced cell detachment. The alpha-step analysis and scanning electron microscope image of the films suggested that the thickness of the films depends on the molecular weight and concentration which ranged from 206 to 1330 nm for PNIPAm-co-AAc-b-PS and 97.5-497 nm for PNIPAm-co-AAm-b-PS. The contact angles of the films verified that the polymer surface was moderately hydrophilic at 37°C. Importantly, RAW264.7 cells were convincingly proliferated on the films to a confluent of >80% within 48 h and abled to detach by reducing the temperature. However, relatively more cells were grown on PNIPAm-co-AAm-b-PS (5%w/v) films and thermal-induced cell detachment was more abundant in this formulation. As a result, PNIPAm-co-AAm-b-PS (5%w/v) was further used to coat commercial cytodex 3 microcarriers for 3D cell culturing and interestingly enhanced cell detachment with preserved potential of recovery was observed at a temperature of below LCST. Thus, surface modification of microcarriers with thermosensitive PNIPAm-co-AAm-b-PS could be vital strategy for nonenzymatic cell detachment and to achieve adequate number of cells with maximum cell viability and functionality.

Preparation of Immunotherapy Liposomal-Loaded Thermal-Responsive Hydrogel Carrier in the Local Treatment of Breast Cancer.

To reduce the side effects of immune drugs and the sustainable release of immune drugs on local parts, we have designed an injectable thermal-sensitive hydrogel containing an imiquimod-loaded liposome system. In the extracellular environment of tumor tissues (pH 6.4), 50% of the drug was released from the carrier, which could be a result of the morphological changes of the liposomal microstructure in the acidic environment. According to the results in animals, the drug-containing liposomes combined with hydrogel can be effectively applied in breast cancer therapy to delay the growth of tumors as well as to dramatically reduce the death rate of mice.

Thermosensitive double network of zwitterionic polymers for controlled mechanical strength of hydrogels.

Zwitterionic hydrogels have promising potential as a result of their anti-fouling and biocompatible properties, but they have recently also gained further attention due to their controllable stimuli responses. We successfully synthesized two zwitterionic polymers, poly(2-methacryloyloxyethyl phosphorylcholine) (poly-MPC) and poly(2-(methacryloyloxy)ethyl dimethyl-(3-sulfopropyl)ammonium hydroxide) (poly-DMAPS), which have complementary ionic sequences in their respective zwitterionic side groups and likely form an interpenetrating double network to improve their mechanical strength. The synthesized poly-MPC was blended in a poly-DMAPS matrix (MD gel) and showed high viscosity, while poly-DMAPS was blended in a poly-MPC hydrogel (DM gel) and revealed UCST behavior as the temperature increased. In addition, cross-section images of the MD hydrogel exhibited its compact and uniform structure, while the DM gel was found to exhibit a porous micro-structure with clear boundaries. The results explained the low viscosity of the DM gel, which was also confirmed via 3D Raman mapping. To sum up, the preliminary data demonstrated that binary zwitterionic hydrogels have thermosensitive mechanical properties, promoting further bio-applications in the future, such as in wound healing.