Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(d,l-lactide) and poly(ethylene glycol) (PEG-Dlink_m-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink_m-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1 % in comparison to 47.8 % of the non-responsive control. Furthermore, PEG-Dlink_m-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.

Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(d,l-lactide) and poly(ethylene glycol) (PEG-Dlink_m-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink_m-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1 % in comparison to 47.8 % of the non-responsive control. Furthermore, PEG-Dlink_m-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.

Delivery of small interfering RNA (siRNA) by nanocarriers has shown promising therapeutic potential in cancer therapy. However, poor understanding of the correlation between the physicochemical properties of nanocarriers and their interactions with biological systems has significantly hindered its anticancer efficacy. Herein, in order to identify the optimal size of nanocarriers for siRNA delivery, different sized cationic micellar nanoparticles (MNPs) (40, 90, 130, and 180 nm) are developed that exhibit similar siRNA binding efficacies, shapes, surface charges, and surface chemistries (PEGylation) to ensure size is the only variable. Size-dependent biological effects are carefully and comprehensively evaluated through both in vitro and in vivo experiments. Among these nanocarriers, the 90 nm MNPs show the optimal balance of prolonged circulation and cellular uptake by tumor cells, which result in the highest retention in tumor cells. In contrast, larger MNPs are rapidly cleared from the circulation and smaller MNPs are inefficiently taken up by tumor cells. Accordingly, 90 nm MNPs carrying polo-like kinase 1 (Plk1)-specific siRNA (siPlk1) show superior antitumor efficacy, indicating that 90 nm could either be the optimal size for systemic delivery of siRNA or close to it. Our findings provide valuable information for rationally designing nanocarriers for siRNA-based cancer therapy in the future.

Polyphosphoesters with repeating phosphoester linkages in the backbone can be easily functionalized, are biodegradable and potentially biocompatible, and may be potential candidates as polymer carriers of drug conjugates. Here, the efficacy of a polyphosphoester drug conjugate as an anticancer agent in vivo is assessed for the first time. With controlled synthesis, doxorubicin conjugated to poly(ethylene glycol)-block-polyphosphoester (PPEH–DOX) via labile hydrazone bonds form spherical nanoparticles in aqueous solution with an average diameter of ≈60 nm. These nanoparticles are effectively internalized by MDA-MB-231 breast cancer cells and release the conjugated doxorubicin in response to the intracellular pH of endosomes and lysosomes, resulting in significant antiproliferative activity in cancer cells. Compared with free doxorubicin injection, PPEH–DOX injection exhibits much longer circulation behavior in the plasma of mice and leads to enhanced drug accumulation in tumor cells. In an MDA-MB-231 xenograft murine model, inhibition of tumor growth with systemic delivery of PPEH–DOX nanoparticles is more pronounced compared with free doxorubicin injection, suggesting the potential of polyphosphoesters as carriers of drug conjugates in cancer therapy.

Patients with Her2-overexpressing (Her2⁺) breast cancers generally have a poorer prognosis due to the high aggressiveness and chemoresistance of the disease. Small interfering RNA (siRNA) targeting the gene encoding polo-like kinase 1 (Plk1; siPlk1) has emerged as an efficient therapeutic agent for Her2⁺ breast cancers. Poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-PLA)-based nanoparticles for siRNA delivery were previously developed and optimized. In this study, for targeted delivery of siPlk1 to Her2⁺ breast cancer, anti-Her2 single-chain variable fragment antibody (ScFv_Her2)-decorated PEG-PLA-based nanoparticles with si Plk1 encapsulation (ScFv_Her2-NP_{si Plk1}) are developed. With the rationally designed conjugation site, ScFv_Her2-NP_siRNA can specifically bind to the Her2 antigen overexpressed on the surface of Her2⁺ breast cancer cells. Therefore, ScFv_Her2-NP_{si Plk1} exhibits improved cellular uptake, promoted Plk1 silencing efficiency, and induced enhanced tumor cell apoptosis in Her2⁺ breast cancer cells, when compared with nontargeted NP_{si Plk1}. More importantly, ScFv_Her2-NP_siRNA markedly enhances the accumulation of siRNA in Her2⁺ breast tumor tissue, and remarkably improves the efficacy of tumor suppression. Dose-dependent anti-tumor efficacy further demonstrates that ScFv_Her2-decorated PEG-PLA-based nanoparticles with siPlk1 encapsulation can significantly enhance the inhibition of Her2⁺ breast tumor growth and reduce the dose of injected siRNA. These results suggest that ScFv_Her2-decorated PEG-PLA-based nanoparticles show great potential for targeted RNA interference therapy of Her2⁺ breast tumor.

Inspired by the influence of chemical structure of end groups on the phase transition temperature of thermoresponsive polymers, we demonstrated a strategy to control the multi-responsiveness of polymer assemblies via subtle modification of end groups of thermoresponsive polymer segments and revealed its potential application for drug delivery. By developing polymer assemblies composed of poly(aliphatic ester) as the inner core and thermoresponsive polyphosphoester as the outer shell, we showed that end groups of thermoresponsive polyphosphoester segments controlled the surface property of assemblies and further determined the stimuli-responsive behavior. The phase-transition temperatures of the unmodified polymer assemblies are tightly controlled by their surface properties due to the hydrophilic to hydrophobic transitions of end groups in response to an environmental stimulus (e.g. pH or light irradiation). External control over these surface properties can by asserted by adjusting the chemical structure and composition of the terminal groups of the thermoresponsive polyphosphoesters.

We report a series of biocompatible and biodegradable block copolymers of poly(ε-caprolactone) with “clickable” polyphosphoester (PPE). The block copolymers are synthesized through controlled ring-opening polymerization of five-membered cyclic phosphoester monomer, propargyl ethylene phosphate (PAEP), initiated with poly(ε-caprolactone) macroinitiator. The polymerization followed first-order kinetics with living polymerization characteristics, thus the molecular weight and composition of copolymers are tunable by adjusting the feed ratio of PAEP monomer to macroinitiator. Azide-functionalized poly(ethylene glycol) has been grafted to the copolymer to demonstrate the reactive feasibility by Cu(I)-catalyzed “click” chemistry of azides and alkynes, generating “brush-coil” polymers. The mild conditions associated with the click reaction are shown to be compatible with poly(ε-caprolactone) and PPE backbones, rendering the click reaction a generally useful method for grafting numerous types of functionality onto the block copolymers. The block copolymers also show good biocompatibility to cells, suggesting their suitability for a range of biomaterial applications. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

Pluronic analogs based on block copolymers of poly(propylene oxide) and poly(ethyl ethylene phosphate) (PEEP-PPO-PEEP) were synthesized, and the thermoresponsive behavior, including aggregation at low concentration and gelation at high concentration were studied. At lower concentrations up to 10 wt %, thermo-induced aggregation of PEEP-PPO-PEEP was demonstrated by UV-vis absorbance measurements using 1,6-diphenyl-1,3,5-hexatriene as a probe. Microthermal analyzes showed symmetrically endothermic and exothermic thermograms during the thermo-induced aggregation and de-association processes, which was also associated with the dehydration and rehydration of PPO blocks, as revealed by the variable temperature NMR measurements. Thermo-induced aggregation with the increased temperatures was also observed by dynamic light scattering. At higher concentration from 20 to 40 wt %, the aqueous solution of PEEP-PPO-PEEP underwent thermo-induced phase transitions from a clear solution to a turbid solution, then to opaque gel and syneresis phases, depending on the molecular weights of PEEP blocks. Such a thermoresponsive hydrogel was used for doxorubicin incorporation. Sustained release of drug was achieved from the gel, demonstrating the polyphosphoester-based Pluronic analogs' potential for biomedical applications. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6168–6179, 2009

Aliphatic polyesters and polyphosphoesters (PPEs) have received much interest in medical applications due to their favorable biocompatibility and biodegradability. In this work, novel amphiphilic triblock copolymers of PPE and poly(L-lactic acid) (PLLA) with various compositions were synthesized and characterized. The blocky structure was confirmed by GPC analyses. These triblock copolymers formed micelles composed of hydrophobic PLLA core and hydrophilic PPE shell in aqueous solution. Critical micellization concentrations of these triblock copolymers were related to the polymer compositions. Incubation of micelles at neutral pH followed by GPC analyses revealed that these polymer micelles were hydrolysized and resulted in decreased molecular weights and small oligomers, whereas its degradation in basic and acid mediums was accelerated. MTT assay also demonstrated the biocompatibility against HEK293 cells. These biodegradable polymers are potential as drug carriers for biomedical application. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6425–6434, 2008