Caina Xu

Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment.

PLGA porous microspheres loaded with doxorubicin (DOX) and paclitaxel (PTX) were developed for in situ treatment of metastatic lung cancer. The synergistic effect of the combined drugs was investigated against B16F10 cells to obtain the optimal prescription for in vivo studies. The combination therapy showed great synergism when DOX was the majority in the combination therapy, while they showed moderate antagonism when PTX is in major. The combination of DOX and PTX at a molar ratio of 5/1 showed the best synergistic therapeutic effect in the free form. However, the drugs exhibited more synergism in the PLGA microspheres at a molar ratio of 2/1, due to the difference in drug release rate. The in vivo study verified the synergism of DOX and PTX at the optimal molar ratio. These results suggested that dual encapsulation of DOX and PTX in porous PLGA microspheres would be a promising technology for long effective lung cancer treatment.

Pulmonary Codelivery of Doxorubicin and siRNA by pH‐Sensitive Nanoparticles for Therapy of Metastatic Lung Cancer

A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis-aconitic anhydride (CA, a pH-sensitive linker) to obtain PEI-CA-DOX conjugates. The PEI-CA-DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI-CA-DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI-CA-DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma-bearing mice, the PEI-CA-DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long-term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI-CA-DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.

Polylysine-modified polyethylenimines as siRNA carriers for effective tumor treatment

Polyethylenimine-poly(L-lysine) (PEI-PLL) copolymer was synthesized via ring-opening polymerization of L-lysine N-carboxyanhydride (Lys(Z)-NCA) initiated by PEI. The complexation of PEI-PLL with siRNA was studied by particle size and zeta potential measurements. The flow cytometric analysis and confocal imaging showed its excellent intracellular trafficking ability. PEI-PLL displayed higher gene silencing efficiency and lower cytotoxicity than commercial PEI-25k in vitro. In the antitumor study, PEI-PLL was further combined with siVEGF and showed obviously tumor inhibition effect for the treatment of CT26 tumor model. Therefore, PEI-PLL is a promising siRNA carrier candidate for further antitumor treatment in vivo.

The suppression of metastatic lung cancer by pulmonary administration of polymer nanoparticles for co-delivery of doxorubicin and Survivin siRNA.

A pH-sensitive co-delivery system was designed for the treatment of metastatic lung cancers by pulmonary delivery of doxorubicin (DOX) and Survivin siRNA. Conjugates PEI-BMPH-DOX (PMD) of polyethylenimine (PEI) with DOX were developed via a pH-sensitive hydrazine bond (3-maleimidopropionic acid hydrazide, BMPH). Furthermore, the PMD/Survivin siRNA complex nanoparticles were prepared by electrostatic interaction between cationic PMD and anionic Survivin siRNA. The drug release of DOX from PMD conjugates increased with decreasing pH values. The DOX and Survivin siRNA could be effectively delivered into the same cells and enhanced the cytotoxicity in B16F10 cells. In the B16F10 tumor-bearing mice models, local delivery of PMD/siRNA complex nanoparticles by pulmonary delivery resulted in the preferential accumulation of DOX and siRNA in the lungs, and a considerable amount of DOX and siRNA accumulated in tumor tissues of the lungs, but limited DOX and siRNA were observed in normal lung tissues. Moreover, the PMD/Survivin siRNA complex nanoparticles showed enhanced antitumor efficacy compared with the mono-delivery of DOX or Survivin siRNA. Taken together, our findings offer an effective local delivery strategy by pulmonary administration for the treatment of metastatic lung cancer.

A pH sensitive co-delivery system of siRNA and doxorubicin for pulmonary administration to B16F10 metastatic lung cancer

Pulmonary co-delivery to the lungs offers a potential therapy for pulmonary diseases. In this study, doxorubicin was conjugated to polyethyleneimine by hydrazone bonds to form a pH sensitive conjugate (PEI-HZ-DOX). A co-delivery carrier was constructed by complexing Bcl2 siRNA with PEI-HZ-DOX. The complex particles could be used by pulmonary administration for metastatic lung cancer treatment. DOX release from the PEI-HZ-DOX conjugate was in a pH-dependent pattern and accelerated by decreasing pH. The cell uptake of DOX and siRNA from PEI-HZ-DOX/siRNA and efficient intracellular release of DOX from PEI-HZ-DOX in B16F10 cells were further confirmed. Cell apoptosis and antitumor effects of the combined therapy were evaluated in vitro, the results showed that co-delivery of DOX and siRNA had better antitumor efficacy than mono-delivery of DOX or siRNA. Furthermore, the biodistribution results showed that pulmonary administration could improve the deposition amounts of DOX and siRNA in the lungs and prolong the retention time compared with systemic administration, which demonstrated that the present delivery system is suitable for pulmonary co-delivery. Overall, pH sensitive PEI-HZ-DOX/siRNA complex nanoparticles exhibit great potential for clinical combination therapy of lung cancer by pulmonary administration in local delivery strategies.

Recent progress in cationic polymeric gene carriers for cancer therapy

In recent years, various carriers for gene delivery have been developed for biomedical applications. Among all kinds of gene carriers, cationic polymeric carriers for delivery therapeutic gene as non-viral carriers have received growing interests due to their improved high transfection efficiency with the relative safety. In particular, the advancement of novel polymeric gene carriers has gained much progress in the development of effective anticancer therapy. Herein, this review focused on the development of cationic polymeric carriers for cancer therapy, including polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimers, polylysine (PLL), chitosan and modified cationic polymers. And recent progresses in the development of novel polymeric carriers for gene delivery, such as targeted gene carriers, responsive gene carriers and multifunctional gene carriers, were summarized. Finally, the future perspectives in the development of novel polymeric carriers for delivery gene were presented.

Doxorubicin-loaded PLGA microparticles with internal pores for long-acting release in pulmonary tumor inhalation treatment

Doxorubicin (DOX) loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with internal pores (MP-D) were developed for long-acting release in pulmonary inhalation treatment. The PLGA microparticles exhibited favorable aerodynamic properties for pulmonary delivery. In vitro drug release profile suggested that MP-D have the advantage of long-term maintenance of drug concentrations. MTT assay demonstrated the in vitro anti-tumor efficiency of the DOX loaded PLGA microparticles. Furthermore, melanoma lung metastasis model was established to determine the in vivo antitumor efficiency. The mice treated with MP-D showed significantly fewer lesions than the untreated ones. The survival analysis indicated that MP-D prolonged the survival time of tumor-bearing mice. These results suggested that DOX loaded PLGA microparticles with internal pores have the potential to be used as long-acting release carriers in clinical lung cancer treatment.

Multifunctional Theranostic Nanoparticles Derived from Fruit-Extracted Anthocyanins with Dynamic Disassembly and Elimination Abilities

Low toxic theranostic nanoparticles that can simultaneously achieve effective tumor accumulation and rapid renal clearance are highly desired for imaging contrast agents and photothermal therapy (PTT) in tumor diagnosis and therapy. Herein, we report a one-pot method for preparing multifunctional nanoparticles (FeAP-NPs) based on the coordination interaction of natural polyphenols (anthocyanins) extracted from fruits, FeIII ions, and poly(l-glutamic acid)- g-methoxy poly(ethylene glycol) copolymers. The FeAP-NPs possess the following favorable advantages: (1) The components of FeAP-NPs originate from natural products, an endogenous element, and poly(amino acid) derivatives, guaranteeing their safety for in vivo application. (2) FeAP-NPs exhibit excellent dual photoacoustic (PA)/magnetic resonance (MR) imaging capacity and high photothermal efficiency. (3) FeAP-NPs can overcome the intractable dilemma of the enhanced permeability and retention (EPR) effect and renal clearance for nanomedicine through the dynamic disassembling ability, which induces a switch of the elimination pathway. Complete tumor ablation is realized by PTT in MCF-7-bearing nude mice under the precise guide of PA and MR imaging. The detailed evaluation of the safety, biodistribution, and elimination behaviors of FeAP-NPs is conducted in vitro or in vivo. This work provides a promising comprehensive solution for nanomedicine clinical application.