Bingjun Sun

Prodrug-based nanoparticulate drug delivery strategies for cancer therapy

Despite the rapid developments in nanotechnology and biomaterials, the efficient delivery of chemotherapeutic agents is still challenging. Prodrug-based nanoassemblies have many advantages as a potent platform for anticancer drug delivery, such as improved drug availability, high drug loading efficiency, resistance to recrystallization upon encapsulation, and spatially and temporally controllable drug release. In this review, we discuss prodrug-based nanocarriers for cancer therapy, including nanosystems based on polymer-drug conjugates, self-assembling small molecular weight prodrugs and prodrug-encapsulated nanoparticles (NPs). In addition, we discuss new trends in the field of prodrug-based nanoassemblies that enhance the delivery efficiency of anticancer drugs, with special emphasis on smart stimuli-triggered drug release, hybrid nanoassemblies, and combination drug therapy.

Self-Assembled Redox Dual-Responsive Prodrug-Nanosystem Formed by Single Thioether-Bridged Paclitaxel-Fatty Acid Conjugate for Cancer Chemotherapy

Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug-based nanoplatform self-assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox-responsive prodrug-nanosystem demonstrates multiple therapeutic advantages, including one-step facile fabrication, high drug-loading efficiency (56%, w/w), on-demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug-nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.

Core-matched encapsulation of an oleate prodrug into nanostructured lipid carriers with high drug loading capability to facilitate the oral delivery of docetaxel.

Nanostructured lipid carriers (NLC) have been considered as promising vehicles for oral delivery of taxanes, such as docetaxel (DTX). However, the low drug loading capability (∼5%, w/w) has greatly limited their clinical application. In response to this challenge, a novel lipophilic oleate prodrug of DTX (DTX-OA) was synthesized and efficiently encapsulated in NLC using core-match technology, in which liquid lipid (OA) was used as core matrix to enhance compatibility with DTX-OA. DTX-OA-NLC showed uniform particle size of about 100nm with markedly high drug loading capability (∼23% of DTX, w/w) compared with DTX-NLC (∼5%, w/w). Besides, DTX-OA-NLC showed better colloidal stability and slower drug release property compared with DTX-NLC. The prepared NLC could be accumulated more easily in MDCK cells than drug solution, and clathrin-mediated endocytosis was the main endocytosis pathway. In situ single-pass intestinal perfusion (SPIP) and intestinal biodistribution studies demonstrated the improved membrane permeability and intestinal wall bioadhesion of NLCs. The bioavailability of DTX-OA-NLC showed 4.04-fold and 2.06-fold higher than DTX solution and DTX-NLC, respectively. These results suggest that the core-matched prodrug-NLC is a promising platform to facilitate the oral delivery of DTX.

Chemotherapy agent-unsaturated fatty acid prodrugs and prodrug-nanoplatforms for cancer chemotherapy

&NA; Unsaturated fatty acids (UFAs), with the distinct advantages of good biocompatibility and innate tumor‐targeting effect, have been widely investigated for the rational design of chemotherapy agent‐unsaturated fatty acid (CA‐UFA) prodrugs in cancer therapy. Among them, several CA‐UFA prodrugs have successfully entered clinical trials and are promising prospects for potential clinical applications. In addition, CA‐UFA prodrug‐based nanoparticulate drug delivery systems (nano‐DDS), which integrate the advantages of CA‐UFA prodrugs and nano‐DDS, have been emerging as versatile nano‐carriers for the efficient delivery of chemotherapeutics. In this paper, we review the advanced drug delivery strategies based on UFA conjugates and focus on the recent advances in CA‐UFA prodrugs and the emerging CA‐UFA prodrug‐based nano‐DDS. First, we discuss the rational design of CA‐UFA prodrugs in response to the multiple obstacles in chemotherapy, with particular emphasis on the latest progress in both preclinical studies and clinical trials. Moreover, the emerging CA‐UFA prodrug‐based nano‐DDS are also addressed. Finally, the prospects and potential challenges of CA‐UFA prodrug‐based drug delivery strategies in chemotherapy are highlighted. Graphical abstract Chemotherapy agent‐unsaturated fatty acid (CA‐UFA) prodrugs‐based drug delivery strategies show distinct advantages in cancer chemotherapy. Figure. No caption available.

Self-delivering prodrug-nanoassemblies fabricated by disulfide bond bridged oleate prodrug of docetaxel for breast cancer therapy

Abstract Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. In vivo, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.

Development of novel self-assembled ES-PLGA hybrid nanoparticles for improving oral absorption of doxorubicin hydrochloride by P-gp inhibition: In vitro and in vivo evaluation

Abstract To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium‐PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X‐ray diffraction (XRD) results revealed that the DOX‐ES complex was in an amorphous form. An in vitro release (pH 6.8 PBS) study showed the excellent sustained‐release characteristics of DOX‐loaded EPNs (DOX‐EPNs). In addition, in situ intestinal perfusion and intestinal biodistribution experiments demonstrated the improved membrane permeability and intestinal wall bioadhesion of DOX‐EPNs, and caveolin‐ and clathrin‐mediated endocytosis pathways were the main mechanisms responsible. The cytotoxicity of DOX was significantly increased by EPNs in Caco‐2 cells, compared with DOX‐Sol. Confocal laser scanning microscope (CLSM) images confirmed that the amount of DOX‐EPNs internalized by Caco‐2 cells was higher than that of DOX‐Sol showing that P‐glycoprotein‐mediated drug efflux was reduced by the introduction of EPNs. The qualitative detection of transcytosis demonstrated the ability of the nanoparticles (NPs) to cross Caco‐2 cell monolayers. An in vivo toxicity experiment demonstrated that DOX‐EPNs reduced cardiac and renal toxic effects and were biocompatible. An in vivo pharmacokinetics study showed that the AUC(0‐t) and t1/2 of DOX‐EPNs were increased to 3.63–fold and 2.47–fold in comparison with DOX solution (DOX‐Sol), respectively. All these results indicated that the novel EPNs were an excellent platform to improve the encapsulation efficiency of an aqueous solution of this antitumor drug and its oral bioavailability.

Disulfide Bond-Driven Oxidation- and Reduction-Responsive Prodrug Nanoassemblies for Cancer Therapy

Disulfide bonds have been widely used to develop reduction-responsive drug-delivery systems (DDS) for cancer therapy. We propose that disulfide bonds might be also used as an oxidation-responsive linkage just like thioether bonds, which can be oxidized to hydrophilic sulfoxide or sulphone in the presence of oxidation stimuli. To test our hypothesis, we design three novel paclitaxel-citronellol conjugates linked via different lengths of disulfide-bond-containing carbon chain. The prodrugs can self-assemble into uniform-size nanoparticles with impressively high drug loading (>55%). As expected, the disulfide-bond-bridged prodrug nanoparticles show redox dual-responsive drug release. More interestingly, the position of disulfide bonds in the carbon chain linkage has profound impacts on the redox dual responsiveness, thereby affecting the drug release, cytotoxicity, pharmacokinetics, biodistribution, and in vivo antitumor efficacy of prodrug nanoassemblies. The redox dual-responsive mechanism is elucidated, and how the position of disulfide bonds in the carbon chain affects the redox dual responsiveness and antitumor efficiency of prodrug nanoassemblies is also clarified. Our findings give new insight into the stimuli responsiveness of disulfide bonds and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.

Reduction-sensitive Paclitaxel Prodrug Self-assembled Nanoparticles with Tetrandrine Effectively Promote Synergistic Therapy Against Drug-sensitive and Multidrug-resistant Breast Cancer

Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitro simulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines.

Star-shape paclitaxel prodrug self-assembled nanomedicine: combining high drug loading and enhanced cytotoxicity

Conventional nanoparticulate drug delivery systems of paclitaxel (PTX) are challenged with low drug loading efficiency and potential biomaterials-induced toxicity. In this work, novel star-shape PTX prodrugs modified by vitamin E succinate with a load of double PTX molecules via carbonate (PC) or succinate (PE) as the linkers at the 2′ position of PTX were synthesized, which were capable of self-assembling into nanoparticles (NPs) with high loading efficiency despite their remarkably hydrophobic character. The in vitro studies revealed that the prodrugs in the form of nanoparticles with high physical stability were little hydrolyzed in rat plasma. In addition, the carbonate bond in PC was more susceptible to hydrolysis than the ester bond in PE in PBS. Compared with PENPs, PCNPs exhibited comparably higher in vitro cytotoxicity against MCF-7 cells and A549 cells due to more conversion of PC to PTX. The in vivo fluorescence imaging demonstrated that PCNPs could passively accumulate in tumors by EPR effect. These results suggested that compared with the succinate conjugate of PTX, the self-assembled NPs of the double PTX loaded carbonate conjugate with extracellular stability can be a more suitable candidate for treatment of cancers after being internalized by cancer cells for its stronger cytotoxicity, and the carbonate linkage is more feasible to be linked with PTX molecules for the design of such type of prodrugs. Overall, the self-assembled nanotechnology of novel star-shape prodrugs with a load of double PTX molecules opens new perspectives for the development of nanomedicines with high loading efficiency and enhanced cytotoxicity.