Search

Purpose: A multivesicular liposome (MVL) is a liposomal vehicle designed to achieve sustained release characteristics for drugs with short half-lives. For example, a commercial MVL formulation of bupivacaine has been approved by the U.S. Food and Drug Administration for local and regional analgesia. For complex formulations like those containing MVLs, challenges in developing an in vitro release testing (IVRT) method may hinder generic development and regulatory approval. In this study, we developed an accelerated rotator-based IVRT method with the ability to discriminate bupivacaine MVLs with different quality attributes., Methods: Three IVRT experimental setups including mesh tube, horizontal shaker, and vertical rotator were screened to ensure that at least 50% of bupivacaine can release from MVLs in 24 h. Sample dilution factors, incubation temperature, and the release media pH were optimized for the IVRT. The reproducibility of the developed IVRT method was validated with commercial bupivacaine MVLs. The discriminative capacity was assessed via comparing commercial and compromised bupivacaine MVL formulations., Results: The rotator-based release setup was chosen due to the capability to obtain 70% of drug release within 24 h. The optimized testing conditions were chosen with a 50-fold dilution factor, a temperature of 37ºC, and a media pH of 7.4., Conclusions: An accelerated rotator-based IVRT method for bupivacaine MVLs was developed in this study, with the discriminatory ability to distinguish between formulations of different qualities. The developed IVRT method was a robust tool for generic development of MVL based formulations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Exparel is a bupivacaine multivesicular liposomes (MVLs) formulation developed based on the DepoFoam technology. The complex composition and the unique structure of MVLs pose challenges to the development and assessment of generic versions. In the present work, we developed a panel of analytical methods to characterize Exparel with respect to particle size, drug and lipid content, residual solvents, and pH. In addition, an accelerated in vitro drug release assay was developed using a rotator-facilitated, sample-and-separate experimental setup. The proposed method could achieve over 80% of bupivacaine release within 24 h, which could potentially be used for formulation comparison and quality control purposes. The batch-to-batch variability of Exparel was examined by the established analytical methods. Four different batches of Exparel showed good batch-to-batch consistency in drug content, particle size, pH, and in vitro drug release kinetics. However, slight variation in lipid contents were observed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anna Schwendeman reports financial support was provided by US Food and Drug Administration. Minzhi Yu reports financial support was provided by American Heart Association. Anna Schwendeman reports a relationship with EVOQ Therapeutics that includes: board membership, consulting or advisory, equity or stocks, and funding grants., (Copyright © 2023 Elsevier B.V. All rights reserved.)

To overcome multidrug resistance (MDR) in cancer chemotherapy with high efficiency and safety, a reduction-sensitive liposome (CL-R8-LP), which was co-modified with reduction-sensitive cleavable PEG and octaarginine (R8) to increase the tumor accumulation, cellular uptake and lysosome escape, was applied to co-encapsulate doxorubicin (DOX) and a P-glycoprotein (P-gp) inhibitor of verapamil (VER) in this study. The encapsulation efficiency (EE) of DOX and VER in the binary-drug loaded CL-R8-LP (DOX + VER) was about 95 and 70% (w/w), respectively. The uptake efficiencies, the cytotoxicity, and the apoptosis and necrosis-inducing efficiency of CL-R8-LP (DOX + VER) were much higher than those of DOX and the other control liposomes in MCF-7/ADR cells or tumor spheroids. Besides, CL-R8-LP (DOX + VER) was proven to be uptaken into MCF-7/ADR cells by clathrin-mediated and macropinocytosis-mediated endocytosis, followed by efficient lysosomal escape. In vivo, CL-R8-LP (DOX + VER) effectively inhibited the growth of MCF-7/ADR tumor and reduce the toxicity of DOX and VER, which could be ascribed to increased accumulation of drugs in drug-resistant tumor cells and reduced distribution in normal tissues. In summary, the co-delivery of chemotherapeutics and P-gp inhibitors by our reduction-sensitive liposome was a promising approach to overcome MDR, improve anti-tumor effect and reduce the toxicity of chemotherapy.

[D]-H6L9, as a pH-responsive anti-microbial peptide (AMP), has been evidenced by us to be an excellent choice in tumor microenvironment-responsive delivery as it could render liposomes responsive to the acidified tumor microenvironment. However, [D]-H6L9-modified liposomes could not actively target to tumor area. Therefore, integrin αvβ3-targeted peptide RGD was co-modified with [D]-H6L9 onto liposomes [(R + D)-Lip] for improved tumor delivery efficiency. Under pH 6.3, (R + D)-Lip could be taken up by C26 cells and C26 tumor spheroids (integrin αvβ3-positive) with significantly improved efficiency compared with other groups, which was contributed by both RGD and [D]-H6L9, while RGD did not increase the cellular uptake performance on MCF-7 cells (integrin αvβ3-negative). Results showed that RGD could decrease cellular uptake of (R + D)-Lip while [D]-H6L9 could increase it, implying the role of both RGD and [D]-H6L9 in cellular internalization of (R + D)-Lip. On the other hand, (R + D)-Lip could escape the entrapment of lysosomes. PTX-loaded (R + D)-Lip could further increase the cellular toxicity against C26 cells compared with liposomes modified only with RGD and [D]-H6L9 respectively, and achieve remarkable tumor inhibition effect on C26 tumor models.

The chemotherapy of aggressive glioma is usually accompanied by a poor prognosis because of the formation of vasculogenic mimicry (VM) and brain cancer stem cells (BCSCs). VM provided a transporting pathway for nutrients and blood to the extravascular regions of the tumor, and BCSCs were always related to drug resistance and the relapse of glioma. Thus, it is important to evaluate the inhibition effect of antiglioma drug delivery systems on both VM and BCSCs. In this study, paclitaxel-loaded liposomes modified with a multifunctional tandem peptide R8-c(RGD) (R8-c(RGD)-Lip) were used for the treatment of glioma. An in vitro cellular uptake study proved the strongest targeting ability to be that of R8-c(RGD)-Lip to glioma stem cells. Drug loaded R8-c(RGD)-Lip exhibited an efficient antiproliferation effect on BCSCs and could induce the destruction of VM channels in vitro. The following pharmacodynamics study demonstrated that R8-c(RGD)-modified drug-loaded liposomes achieved both anti-VM and anti-BCSC effects in vivo. Finally, no significant cytotoxicity of the blood system or major organs of the drug-loaded liposomes was observed under treatment dosage in the safety evaluation. In conclusion, all of the results proved that R8-c(RGD)-Lip was a safe and efficient antiglioma drug delivery system.

The development of highly efficient tumor-targeted delivery systems is crucial for successful tumor treatment. Previously, a novel cell-penetrating peptide TAT and cleavable polyethylene glycol (PEG) co-modified liposome delivery system (C-TAT-Lipo) showed enhanced accumulation in tumor regions. Under the control of cysteine (Cys), the liposomes were activated extracellularly and achieved increased delivery of their cargo into tumor cells efficiently. In this study, we developed an optimal formulation for the encapsulation of Doxorubicin (DOX) by this delivery system for tumor treatment. The in vitro study showed that the C-TAT-Lipo with Cys delivery system not only enhanced the amount of DOX delivered by at least 100% compared to other DOX-containing formulations, but also displayed high cytotoxicity against tumorigenic cell lines. Compared to other groups, the DOX-loaded C-TAT-Lipo formulation in the presence of cysteine enhanced treatment efficacy by lowering the IC50 (1.67 +/- 0.14 microM) and increasing the cancer cell apoptosis percentage (37.10%). Moreover, the in vivo antitumor activity also showed that DOX-loaded C-TAT-Lipo with injection of cysteine achieved the best tumor growth inhibition with a tumor growth rate of only 58.40 +/- 16.33% (% of initial volume/day), which was significant less than that achieved by other DOX formulations.

The treatment of glioma is a great challenge because of the existence of the blood-brain barrier (BBB). In order to reduce toxicity to the normal brain tissue and achieve efficient treatment, it is also important for drugs to specifically accumulate in the glioma foci and penetrate into the tumor core after entering into the brain. In this study, a specific ligand cyclic RGD peptide was conjugated to a cell penetrating peptide R8 to develop a multifunctional peptide R8-RGD. R8-RGD increased the cellular uptake of liposomes by 2-fold and nearly 30-fold compared to separate R8 and RGD respectively, and displayed effective penetration of three-dimensional glioma spheroids and BBB model in vitro. In vivo studies showed that R8-RGD-lipo could be efficiently delivered into the brain and selectively accumulated in the glioma foci after systemic administration in C6 glioma bearing mice. When paclitaxel (PTX) was loaded in liposomes, R8-RGD-lipo could induce the strongest inhibition and apoptosis against C6 cells and finally achieved the longest survival in intracranial C6 glioma bearing mice. In conclusion, all the results indicated that the tandem peptide R8-RGD was a promising ligand possessing multi functions including BBB transporting, glioma targeting and tumor penetrating. And R8-RGD-lipo was proved to be a potential anti-glioma drug delivery system., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tumor-oriented nanocarrier drug delivery approaches with pH-sensitivity have been drawing considerable attentions over the years. Here we described a liposomal delivery system modified with pH-responsive cell penetrating peptide TH (TH-Lip). Conventional cell penetrating peptide (CPP)-related drug delivery tactics sometimes seemed limited due to the extensive in vivo penetration and the lack of proper selectivity of conventional CPPs. In this study, TH (AGYLLGHINLHHLAHL(Aib)HHIL-NH₂), an engineered α-helical cell penetrating peptide originated from peptide TK (AGYLLGKINLKKLAKL(Aib)LLIL-NH₂), was endowed pH-responsiveness after complete replacement of all lysines in the sequence of TK into histidines, and was introduced onto the surface of liposomes. Accordingly, TH-Lip could benefit from the unique property of TH, as the cell penetrating capacity of TH was concealed during the blood circulation and in normal tissues because of the neutral pH under those conditions. However, when TH-Lip reached the tumor, and as pH declined, histidines in TH peptide protonated and the surface charge of TH-Lip converted from negative to positive, initiating activated cell penetrating capacity and leading to enhanced cellular and tumor spheroid uptake. The endocytosis inhibition assay demonstrated that the endocytosis of TH-Lip was influenced by the positively charged surface of the liposomes in acidic environment and was mediated by clathrin, and the intracellular trafficking study suggested that the liposomes were mainly accumulated in endoplasmic reticulum and Golgi apparatus. After systemic administration in mice, TH-Lip could be internalized into tumor cells efficaciously. When it comes to the delivery of paclitaxel (PTX), the pH-responsiveness of TH-Lip led to strong inhibition against tumor cell growth which occurred both in vitro (under pH 6.3) and in vivo, and the tumor inhibition rate reached 86.3% on C26 tumor-bearing mice for PTX-loaded TH-Lip. Therefore, TH-Lip proved itself to be a promising pH-responsive strategy for drug delivery within acidified tumor microenvironment., (© 2013 Published by Elsevier Ltd.)

Immune checkpoint blockade treatment is one of the most promising immunotherapies, which exhibits promising therapeutic effects on inhibition of metastasis. However, immunotherapy has little effect on pancreatic cancer, due to its extensive fibrotic matrix and immunosuppressive tumor microenvironment. Mild hyperthermia induced by photothermal therapy (PTT) has been proven to activate the immune responses in the tumor microenvironment. Herein, we designed a combine strategy of mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL), in which BMS-202 loaded small-sized albumin nanoparticle (HSA-BMS) was encapsulated. Mild hyperthermia reduced the tumor hypoxia, relieved the interstitial pressure and increased the recruitment of endogenous immune cells in tumors. In the meantime, small-sized HSA-BMS was released from large-sized HSA-BMS@CAP-ILTSL in response to fibroblast activation protein-α (FAP-α) and near-infrared (NIR) laser, and enhanced the immunological responses by recovering the activity of T lymphocytes, accompanied by secreting relevant cytokines (TNF-α and IFN-γ). The combined therapy (HSA-BMS@CAP-ILTSL) could not only significantly suppress the tumor growth in vivo , but also decrease the amounts of metastatic nodules in distant organs. These results suggested that size-adjustable nanoparticles had a great potential in the treatment of metastatic pancreatic cancer. The desmoplastic stroma and hypoperfusion of pancreatic cancer imposed physical barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We constructed size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL) with size around 120 nm, where small sized albumin nanoparticle (10 nm) of immune checkpoint inhibitor (HSA-BMS) were encapsulated inside. Mild hyperthermia not only contributed to release HSA-BMS for penetration (blocking the immunosuppressive signals deep in the tumor), but enhanced tumor blood perfusion for infiltration of endogenous immune cells. In the two-pronged treatment, the pancreatic cancer immunotherapy significantly enhanced and the risk of cancer metastasis was reduced. Overall, the strategy provides a promising approach to increase drug accumulation and improve the anti-tumor immune activity in pancreatic cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Liposomal Amphotericin B, known as AmBisome®, is a life-saving antifungal product that sold $407 million in 2019. AmBisome® has a rather complex physical structure in that Amphotericin B (AmpB) forms a stable ionic complex with the lipid bilayer to maintain AmBisome®'s low toxicity and high stability in systemic circulation. Failed attempts to reproduce AmBisome®'s precise structure has resulted in faster drug release and higher toxicity both in vitro and in vivo. In this study, we established several analytical methodologies to quantify liposomal AmpB components, characterize thermal properties of the liposome, and determine particle size distribution, AmpB aggregation state, and drug release kinetics. We applied these methodologies together with in vitro hemolytic potential and antifungal activity tests to characterize multiple lots of AmBisome® and two generic products approved in India, Phosome® and Amphonex®. We also used Fungizone®, a micellar AmpB formulation, and "leaky" AmpB liposomes as negative controls. Our results showed that Phosome® and Amphonex® were both similar to AmBisome®, while Fungizone® and 'leaky" liposomes exhibited differences in both thermal properties and AmpB aggregation state, leading to faster drug release and higher toxicity. Due to the increased interest of the pharmaceutical industry in making generic AmBisome® and the lack of standard analytical methods to characterize liposomal AmpB products, the methodologies described here are valuable for the development of generic liposomal AmpB products. [ABSTRACT FROM AUTHOR]

On one hand, the application of anti-microbial peptides (AMPs) in the construction of AMPs-mediated drug delivery system has not yet been fully exploited; on the other hand, its non-selectivityin vivohas also limited its clinical application. In this work, we chose one pH-responsive peptide, [D]-H6L9, and functionalized it onto the surface of liposomes (D-Lip). The protonation of histidines in the sequence of [D]-H6L9under pH 6.3 could switch the surface charge of D-Lip from negative (under pH 7.4) to positive (under pH 6.3), and the cellular uptake and tumor spheroids uptake were increased accordingly. Lysosome co-localization assay suggested that there was only little overlap of D-Lip with lysosomes in 12 h, which indicated that D-Lip could escape lysosomes effectively.In vivobiodistribution assay on C26 tumor-bearing BALB/C mice showed that DiR-labeled D-Lip could reach tumors as much as PEG-Lip, and both tumor slices and quantitative measurement of dispersed cells ofin vivotumors by flow cytometry demonstrated that D-Lip could be taken up by tumors more efficiently. Therefore, we have established an anti-microbial peptide-mediated liposomal delivery system for tumor delivery. [ABSTRACT FROM PUBLISHER]

Human chromosome 7 open reading frame 24 has been identified as a tumor-related protein, and later it was shown to be γ-glutamylcyclotransferase ( GGCT). This protein is upregulated in various types of cancer and is proved to be associated with cellular proliferation. RNA interference is an effective method to achieve highly specific gene regulation. In this study, the anti- GGCT si RNA was incorporated into a comprehensively evaluated polyethylene glycol-hyaluronic acid-modified liposomal si RNA delivery system ( PEG- HA- NP) for drug-resistant MCF-7 breast cancer therapy by systemic administration. The PEG- HA- NP had a diameter of 216 nm and a zeta potential of −17.4 mV. Transfection of anti- GGCT si RNA-loaded PEG- HA- NP could achieve effective GGCT downregulation and induce the subsequent cell cytotoxicity against MCF-7/ ADR cells. Systemic administration of PEG- HA- NP at 0.35 mg/kg si RNA could retard the tumor growth and induce necrosis of tumor tissue while showing no obvious toxicity to normal tissues. Therefore, systemic administration of anti- GGCT-loaded PEG- HA- NP was proved to be a promising strategy for drug-resistant MCF-7 breast cancer therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:476-484, 2015 [ABSTRACT FROM AUTHOR]

Tumor targeted drug delivery system with high efficiency of tumor accumulation, cell internalization and endosomal escape was considered ideal for cancer therapy. Herein, a cleavable polyethylene glycol (PEG) and octaarginines (R8) co-modified liposome (CL-R8-LP) was developed, in which the cholesterol was used as an alternative anchor to the commonest phospholipids for the diversified development of surface modification. The in vitro hemolysis assay and bio-distribution study demonstrated that CL-R8-LP improved biocompatibility and tumor accumulation compared with the single R8 modified liposomes (R8-LP), since the strong positive charges, toxicity and non-specificity of R8 were efficiently shielded by the outer cleavable PEG. And the cellular uptake, cytotoxicity and apoptosis of CL-R8-LP on C26 cells were much stronger than that of control liposomes in which R8 was not included or exposed. In addition, it was confirmed that CL-R8-LP entered cells via clathrin-mediated endocytosis and the macropinocytosis, and followed by a more efficient endosomal escape compared with R8-LP due to the topology change of R8. The enhanced in vivo delivery efficiency and anti-tumor efficacy were validated in C26 bearing mice. In conclusion, the results demonstrated that CL-R8-LP was a promising vehicle for enhancing the chemotherapy of solid cancers. [ABSTRACT FROM AUTHOR]

Purpose: Cell penetrating peptides (CPPs) were widely used as motifs for drug delivery to tumor. In former study, an RGD reverse sequence dGR was used to develop active-targeting liposome R8dGR-Lip, which showed well penetrating ability and treatment efficiency on glioma model. However, recurrence after tumor resection caused by post-operative residual cancer cells was a huge obstacle in tumor treatment. In consideration of the effective anti-cancer effect of PTX-R8dGR-Lip when treating glioma in former study, we decide to evaluate its pharmacodynamics on tumor resection models, which were more invasive and resistant.Method: In vitro, the effectiveness of PTX-R8dGR-Lip in reducing tumor initiating cell (TIC) was investigated using mammosphere formation. In vivo, the inhibition efficiency of PTX-R8dGR-Lip on C6 glioma recurrence and 4 T1 breast cancer recurrence model were evaluated, including tumor bioluminescence imaging, survival rate and immumohistochemical staining, etc..Results: C6 mammosphere formation rate of PTX-R8dGR-Lip group was 48.06 ± 2.72%, and 4 T1 mammosphere formation rate of PTX-R8dGR-Lip group was 39.51 ± 4.02% when PBS group was set as 100%. C6 and 4 T1 bioluminescent tumor resected model were established, then effectiveness of different PTX-loaded preparations were evaluated on these two models. PTX-R8dGR-Lip could obviously inhibit tumor recurrence, prolong survival rate and reduce tumor tissue invasion.Conclusion: PTX-R8dGR-Lip could reduce post-operative recurrence rate, prolong survival time, and decrease the proliferation of residual cancer cells through regulating the expression of recurrence-related cytokines. [ABSTRACT FROM AUTHOR]

Abstract: This study was mainly focused on developing a dual-ligand liposomal delivery system to enhance both targeting specificity and cellular uptake. The specific ligand transferrin (TF) and the cationic cell-penetrating peptide TAT were connected with cholesterol via a polyethylene glycol (PEG) spacer to prepare the dual-ligand liposomes (TAT/TF-PEG-LP). Then the in vitro cellular uptake by three kinds of cells that possessed different expressing levels of transferrin receptor (TFR) and the in vivo delivery efficiency were evaluated. Compared to the single-ligand TAT or TF modified liposomes (TAT-PEG-LP or TF-PEG-LP), TAT/TF-PEG-LP exhibited the enhanced cellular uptake and selectivity via the synergistic effect of both ligands in vitro. The ex vivo fluorescence imaging of tumors, the qualitative observation of tumor frozen section and the quantitative determination of cellular uptake in tumor tissues altogether showed the in vivo delivery efficiency of TAT/TF-PEG-LP was higher than that of other liposomes. In conclusion, the dual-ligand liposomes co-modified with TF and TAT possessed a strong capability for synergistic targeted delivery of payload into tumor cells both in vitro and in vivo. [Copyright &y& Elsevier]

Recurrence after tumor resection is mainly caused by post-operative inflammation and residual cancer cells, which is a serious obstacle to breast cancer treatment. Traditional nanoparticles rely primarily on the enhanced permeability and retention (EPR) effect in well-vascularized tumors. In this study, a macrophage-based carrier is designed to enhance the efficiency of targeting to recurrent tumors through a "dual-guide" strategy. After tumor resection, a burst of inflammatory factors occurs in the resection wound, which can recruit monocytes/macrophages rapidly. Combined with the tropism of monocyte chemoattractant protein, a large number of macrophage-mediated carriers will be recruited to surgical recurrence sites. Octaarginine (RRRRRRRR , R 8)-modified liposomes in macrophages contain two agents with different pharmacological mechanisms, paclitaxel (PTX) and resveratrol (Res), which have enhanced therapeutic effects. In vitro study demonstrated that macrophage-mediated carriers approach 4 T1 cells through an inflammatory gradient and reach recurrence tumors through a "dual-guide" strategy. Then, membrane fusion and inflammation-triggered release deliver the drug into the recurrent tumor cells. In vivo experiments show that macrophage-based carriers exhibit effective tumor-targeting ability, especially in post-operation situations. More importantly, macrophage-mediated liposomes encapsulated with PTX and Res inhibit tumor recurrence in both ectopic and orthotopic 4 T1 post-operative recurrence models. Unlabelled Image • Enhanced tumor targeting in postoperative resection model by dual response and the inflammatory tropism of macrophages. • Macrophage-based carrier facilitates the internalization of liposomes via multiple mechanisms including microcatheters. • A combination of paclitaxel and resveratrol to suppress tumor proliferation while inhibiting postoperative inflammation. [ABSTRACT FROM AUTHOR]

The use of pH-responsive cell-penetrating peptides (CPPs) is an attractive strategy for drug delivery in vivo, however, they still could not actively target to the desired sites. Here, we designed a pH-responsive CPP (TR) with the ability of active targeting to integrin α v β 3 , which was a tandem peptide consisted of active targeting ligand peptide (c(RGDfK)) and pH-responsive CPP (TH). The targeting efficiency of TR with integrin was evaluated by molecular simulation and docking studies. The affinity assays of TR peptide modified liposomes (TR-Lip) at pH 7.4 and pH 6.5 demonstrated adequately the pH-responsive binding efficacy of TR-Lip with integrin α v β 3 . The cellular uptake of CFPE-labeled TR-Lip on integrin α v β 3 -overexpressing B16F10 cells was 41.67-, 30.67-, and 11.90-fold higher than that of CFPE-labeled PEG-, RGD-, and TH-modified liposomes at pH 6.5, respectively, suggesting that TR-Lip could not only actively target to α v β 3 -overexpressing cells compared to TH-Lip, but also significantly increased cellular uptake compared to RGD-Lip. At the concentration of 20 μg/mL paclitaxel (PTX), the killing activity of PTX-loaded TR-Lip (PTX-TR-Lip) against B16F10 cells was 1.80-, 1.45-, 1.30-, 1.15-time higher than that of PTX-loaded PEG-, RGD-, TH-modified liposomes and free PTX at pH 6.5, respectively. In vivo imaging displayed the maximum accumulation of DiD-labeled TR-Lip at tumor sites compared to the other groups. Tumor inhibition rate of B16F10 tumor-bearing mice treated with PTX-TR-Lip was 85.04%, relative to that of PBS. In B16F10 tumor-bearing mice, PTX-TR-Lip showed significantly higher survival rate compared with the other groups. Collectively, all the results in vitro and in vivo suggested that TR-Lip would be a potential delivery system for PTX to treat integrin α v β 3 -overexpressing tumor-bearing mice. [ABSTRACT FROM AUTHOR]

Abstract: Though PEGylation has been widely used to enhance the accumulation of liposomes in tumor tissues through enhanced permeability and retention (EPR) effects, it still inhibits cellular uptake and affects intracellular trafficking of carriers. Active targeting molecules displayed better cell selectivity but were shadowed by the poor tumor penetration effect. Cell penetrating peptides could increase the uptake of the carriers but were limited by their non-specificity. Dual-ligand system may possess a synergistic effect and create a more ideal drug delivery effect. Based on the above factors, we designed a multistage liposome system co-modified with RGD, TAT and cleavable PEG, which combined the advantages of PEG, specific ligand and penetrating peptide. The cleavable PEG could increase the stability and circulation time of liposomes during circulation. After the passive extravasation to tumor tissues, the previously hidden dual ligands on the liposomes were exposed in a controlled manner at the tumor site through exogenous administration of a safe reducing agent l-cysteine. The RGD specifically recognized the integrins overexpressed on various malignant tumors and mediated efficient internalization in the synergistic effect of the RGD and TAT. In vitro cellular uptake and 3D tumor spheroids penetration studies demonstrated that the system could not only be selectively and efficiently taken up by cells overexpress ingintegrins but also penetrate the tumor cells to reach the depths of the avascular tumor spheroids. In vivo imaging and fluorescent images of tumor section further demonstrated that this system achieved profoundly improved distribution within tumor tissues, and the RGD and TAT ligands on C-R/T liposomes produced a strong synergistic effect that promoted the uptake of liposomes into cells after the systemic administration of l-cysteine. The results of this study demonstrated a tremendous potential of this multistage liposomes for efficient delivery to tumor tissue and selective internalization into tumor cells. [Copyright &y& Elsevier]

[Display omitted] Surgery combined with postoperative treatment is a widely accepted therapeutic strategy against breast cancer. Macrophage-based carriers have been proved to be an effective postoperative drug delivery system due to their inflammatory tendency. However, the slow and incomplete release of the cargo and the postoperative inflammation remain to be solved. Here, we described a macrophage-mediated photothermal therapy combined with anti-inflammatory strategy to inhibit breast cancer postoperative relapse. The anti-inflammatory resveratrol and photothermal agent indocyanine green (ICG) were loaded in octaarginine (R8)-modified liposomes, then ingested by macrophages to form the macrophage-based drug delivery system (Res/ICG-R8-Lip@MP). Res/ICG-R8-Lip@MP showed effective tumor-targeting ability via inflammatory tropism of macrophages and excellent near-infrared (NIR) photothermal performance. In vitro experiments showed that the carrier could not only trigger drug release though inflammation, but also utilize the photothermal conversion property to destroy the macrophage-based carrier at the local tumor to maximize drug release. In vivo experiments indicated that Res/ICG-R8-Lip@MP ablated residual tumor tissues and reduced the postoperative inflammation, and at the same time achieved significant effect of inhibiting tumor postoperative relapse. This synergistic photothermal and anti-inflammatory strategy has great potential in postoperative treatment of breast cancer. [ABSTRACT FROM AUTHOR]