Haotian Sun

Polymers in the Co-delivery of siRNA and Anticancer Drugs for the Treatment of Drug-resistant Cancers

Recently, co-delivery of siRNA and anticancer drugs has drawn much attention in the treatment of drug-resistant cancers. Drug resistance is exhibited by cancer cells, which limits the efficacy of chemotherapy. When siRNA and anticancer drugs are delivered into cancer cells simultaneously, the siRNA is expected to silence the genes related to drug resistance, decreasing the drug efflux pumps and activating the cell’s apoptosis pathways. In a timeframe following the release of siRNA, the accumulation of the co-delivered anti-cancer drug inside of the cancer cells will increase, resulting in promoted chemotherapeutic effects. Several classes of nanocarriers have been designed based on polymers for co-delivery, including surface-modified polymer nanoparticles (NPs), polymer micelles, dendrimers, polymer nanocapsules, polymer-modified liposomes, and polymer-modified silica and gold NPs. Compared with separate delivery, co-delivery showed significant advantages in the treatment of drug-resistant cancers. This review focuses on polymers in the co-delivery of siRNA and anticancer drugs, and summarizes key advances in the recent several years.

Biodegradable zwitterionic sulfobetaine polymer and its conjugate with paclitaxel for sustained drug delivery

A fully biodegradable zwitterionic polymer and the corresponding conjugate with paclitaxel (PTX) were synthesized as promising biomaterials. Allyl-functionalized polylactide (PLA) was employed as the precursor of polymer backbones. UV-induced thiol-ene reaction was conducted to conjugate thiol-functionalized sulfobetaine (SB) with the PLA-based backbone. The resulting zwitterionic polymer did not exhibit considerable cytotoxicity. A polymer-drug conjugate was also obtained by thiol-ene reaction of both thiol-functionalized SB and PTX with allyl-functionalized PLA. The conjugate could readily form narrowly-dispersed nanoparticles in aqueous solutions with a volume-average hydrodynamic diameter (Dh,V) of 19.3 ± 0.2 nm. Such a polymer-drug conjugate-based drug delivery system showed full degradability, well-suppressed non-specific interaction with biomolecules, and sustained drug release. In vitro assessments also confirmed the significant anti-cancer efficacy of the conjugate. After 72 h incubation with PLA-SB/PTX containing 10 µg/mL of PTX, the cell viabilities of A549, MCF7, and PaCa-2 cells were as low as 20.0 ± 2.5%, 1.7 ± 1.7%, and 14.8 ± 0.9%, respectively. Both flow cytometry and confocal microscopy suggested that the conjugates could be easily uptaken by A549 cells before the major release of PTX moieties. Overall, this work elucidates promising potentials of biodegradable zwitterionic polymer-based materials in biomedical applications. STATEMENT OF SIGNIFICANCE The applicability of FDA-approved biodegradable aliphatic polyesters has been significantly restricted because they are hydrophobic and lack functionalities. Recently zwitterionic polymers have emerged as promising hydrophilic biomaterials, but most of the reported zwitterionic polymers are non-biodegradable. This study reports a novel aliphatic polyester-based zwitterionic polymer and the corresponding polymer-drug conjugate. Their aliphatic polyester and zwitterionic components provide them with high enzymatic degradability and low nonspecific interactions with biomolecules, respectively. While the zwitterionic polymer did not show noticeable cytotoxicity, the corresponding polymer-anticancer drug conjugate exhibited acid-sensitive sustained drug release, remarkable effectiveness in killing cancer cells, as well as the ready cellular internalization. This work lays a foundation for the further development of synthetic biodegradable zwitterionic polymer-based materials which potentially may have broad and significant biomedical applications.

A degradable brush polymer-drug conjugate for pH-responsive release of doxorubicin

To achieve high precision and efficacy in disease treatment, biodegradability and environmental responsivity are highly desired in drug delivery systems. Having a polylactide (PLA)-based biodegradable scaffold conjugated with doxorubicin (DOX) moieties via pH-responsive linkages, a brush polymer–drug conjugate (BPDC) was synthesized and studied. The biodegradable scaffold, PLA-graft-aldehyde/polyethylene glycol (PLA-g-ALD/PEG), was prepared via a copper-catalyzed alkyne–azide click reaction. Subsequently, the BPDC was obtained by conjugating doxorubicin with the scaffold through an acid-sensitive Schiff base linkage. The well-controlled structures of the resulting BPDC and its precursors were verified by proton nuclear magnetic resonance and gel permeation chromatography characterization. As revealed by dynamic light scattering and transmission electron microscopy, the BPDC had a well-defined nanostructure with the size of 10–30 nm. A drug release study of the BPDC demonstrated a much faster release of DOX at the pH of 5.5 than at the pH of 7.4. Both cell internalization and cytotoxicity studies of the BPDC in MCF-7 breast cancer cells indicated its significant potential for application as a novel anticancer nanomedicine.

Brush polymer-based nanostructures for drug delivery

Abstract Polymeric nanostructures have been broadly investigated for applications in drug delivery. As compared with other types of polymers, brush polymers (BPs) can possess not only unimolecular but also intermolecularly assembled nanostructures with versatile properties, and therefore drug delivery via BP-based scaffolds has attracted drastically increasing interest. A broad variety of BPs with diverse structural features and properties have been integrated with drugs via either physical encapsulation or chemical conjugation to construct BP-based drug-delivery systems. Besides drugs, various biomedical functionalities, including targeting ligands, imaging elements, and other biologically related moieties, can also be incorporated into these drug-delivery systems to further improve their therapeutic performance. In this chapter, an overview on BP-based drug-delivery systems is presented. Following a general discussion on structural design of BP-based scaffolds, BP-based drug-encapsulated, drug-conjugated, and multifunctional systems are discussed. The future research directions of BP-based drug-delivery systems are highlighted.