Multifunctional Biodegradable Zwitterionic Polymer-Drug Conjugates for Multidrug Co-Delivery

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Project Summary Critical technological challenges have significantly restricted the applicability of polymer-based drug delivery systems (DDSs). Aliphatic polyesters, such as polylactide (PLA) and poly(3-hydroxybutyrate) (P3HB), are biodegradable and biocompatible, but their hydrophobicity and lack of functionalities limit their biomedical applications. Polyethylene glycol (PEG) has been broadly used in DDSs, but can cause undesired immunogenicity. Zwitterionic polymers (ZPs) have emerged as promising alternatives of PEGs, but typical ZPs are non-biodegradable and may possibly result in severe in vivo side effects. Combination therapy has great clinical potentials; however, the lack of appropriate DDSs limits its applicability. Cyclic polymers have shown novel biointerface properties, but in-depth studies are needed to gain insights into their in vitro and in vivo behaviors. To address these challenges, we design multifunctional biodegradable zwitterionic polymer-drug conjugates (ZPDCs; with both open-chain and cyclic structures) as novel PEG-free DDSs. It is hypothesized that such ZPDCs can possess a broad range of favorable biomedically relevant properties for effective multidrug co-delivery. To examine the hypothesis, we propose to systematically investigate ZPDCs with three specific aims: 1) to synthesize multifunctional biodegradable multidrug-containing ZPDCs, 2) to understand their structure-dependent interactions with biochemical environments & cells, and 3) to understand their structure-dependent in vivo behaviors. We will synthesize a library of well-defined ZPDCs with PLA or P3HB-based backbones that carry sulfobetaine-based zwitterions, paclitaxel and gemcitabine as multidrug as combination therapy for pancreatic cancer, cyanine5.5 as imaging dye, and plectin-1 targeted peptide as targeting ligand. These ZPDCs will be prepared through living ring-opening polymerization of alkene/alkyne-functionalized cyclic esters, followed by alkyne-azide and thiol-ene dual Click functionalization. Comprehensive analytical approaches will be employed to characterize the ZPDCs to verify their well-controlled structures. To achieve insightful understanding on their structure-dependent biointerface properties, systematic biochemical, cellular and in vivo studies of ZPDCs will be performed. Research activities will include anti-biofouling analysis, drug release study, degradation assessment, cytotoxicity assay, evaluation of cellular uptake efficiency and mechanisms, the determination of blood circulation time, the measurements of pharmacokinetics and biodistribution, the examination of immune responses, and the evaluation of therapeutic efficacy in vivo. Together, the proposed R01 studies will establish the synthetic method for ZPDCs, provide key insights into their structure-dependent biointerface properties, and elucidate their design rules. These studies will lay a solid foundation for the development of ZPDCs as a new, PEG-free platform technology. The in-depth comparative studies of cyclic and open-chain ZPDCs will provide critical guideline on topological design of polymeric biomaterials. The outcomes of this project potentially may also benefit patients with pancreatic cancer.