Dipole Orientation Matters: Longer-Circulating Choline Phosphate than Phosphocholine Liposomes for Enhanced Tumor Targeting

Zwitterionic phosphocholine (PC) liposomes are widely used in drug delivery because of their high biocompatibility and long blood circulation time. We herein report that by flipping the direction of the PC dipole, the resulting choline phosphate (CPe) liposomes have an even longer circulation time, as confirmed at both cellular and animal-model levels. Even when 33% cholesterol was included in the lipid formulation with a poly­(ethylene glycol) layer, the CPe liposome still had a longer blood circulation time. Isothermal titration calorimetry indicates a lack of protein adsorption or PC membrane attachment for the CPe liposomes. This is different from the previously reported adhesion of CP polymers to PC lipid membranes, which may be attributed to the different ways of displaying the CP headgroup. With a longer blood circulation time, the CPe liposomes accumulated in tumors more easily than PC liposomes, which is likely due to the enhanced permeation and retention effect and tumor cell uptake. This study provides key insights into zwitterionic biointerfaces for biomedical, analytical, and materials applications

Understanding the Capsanthin Tails in Regulating the Hydrophilic–Lipophilic Balance of Carbon Dots for a Rapid Crossing Cell Membrane

Here we use natural Chinese paprika to prepare a new kind of amphiphilic carbon dot (A-Dot) that exhibits bright, multicolored fluorescence and contains hydrophilic groups as well as lipophilic capsanthin tails on the surface. It is found that the capsanthin tails in a phospholipid-like structure can promote cell internalization of the A-Dots via crossing cell membranes rapidly in an energy-independent fashion. Compared to highly hydrophilic carbon dots (H-Dots), a control sample prepared from the microwave thermolysis of citric acid and ethyl­ene­di­amine, our synthesized A-Dots can be taken up by CHO, HeLa, and HFF cells more easily. More importantly, we develop a method to calibrate the hydrophilic–lipophilic balance (HLB) values of various kinds of carbon dots (C-Dots). HLB values of A-Dots and H-Dots are determined to be 6.4 and 18.4, respectively. Moreover, we discover that the cellular uptake efficiency of C-Dots is closely related to their HLBs, and the C-Dots with an HLB value of around 6.4 cross the cell membrane easier and faster. As we regulate the HLB value of the A-Dots from 6.4 to 15.3 by removing the capsanthin tails from their surfaces via alkali refluxing, it is found that the refluxed A-Dots can hardly cross HeLa cell membranes. Our work is an essential step toward understanding the importance of regulating the HLB values as well as the surface polarity of the C-Dots for their practical use in bioimaging and also provides a simple but effective way to judge whether the C-Dots in hand are appropriate for cell imaging

Enzyme Degradable Hyperbranched Polyphosphoester Micellar Nanomedicines for NIR Imaging-Guided Chemo-Photothermal Therapy of Drug-Resistant Cancers

Multidrug resistance (MDR) is the major cause for chemotherapy failure, which constitutes a formidable challenge in the field of cancer therapy. The synergistic chemo-photothermal treatment has been reported to be a potential strategy to overcome MDR. In this work, rationally designed enzyme-degradable, hyperbranched polyphosphoester nanomedicines were developed for reversing MDR via the codelivery of doxorubicin and IR-780 (hPPE_DOX&IR) as combined chemo-photothermal therapy. The amphiphilic hyperbranched polyphosphoesters with phosphate bond as the branching point were synthesized via a simple but robust one-step polycondensation reaction. The self-assembled hPPE_DOX&IR exhibited good serum stability, sustained release, preferable tumor accumulation, and enhanced drug influx of doxorubicin in resistant MCF-7/ADR cells. Moreover, the degradation of hPPE_DOX&IR was accelerated in the presence of alkaline phosphatase, which was overexpressed in various cancers, resulting in the fast release of encapsulated doxorubicin. The enzyme-degradable polymer generated synergistic chemo-photothermal cytotoxicity against MCF-7/ADR cells and, thus, the efficient ablation of DOX-resistant tumor without regrowth. This delivery system may open a new avenue for codelivery of chemo- and photothermal therapeutics for MDR tumor therapy