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International Journal of Molecular... Mar 2024The advancement of exosome studies has positioned engineered exosomes as crucial biomaterials for the development of advanced drug delivery systems. This study focuses...
The advancement of exosome studies has positioned engineered exosomes as crucial biomaterials for the development of advanced drug delivery systems. This study focuses on developing a hybrid exosome system by fusing mesenchymal stem cells (MSCs) exosomes with folate-targeted liposomes. The aim was to improve the drug loading capacity and target modification of exosome nanocarriers for delivering the first-line chemotherapy drug paclitaxel (PTX) and its effectiveness was assessed through cellular uptake studies to evaluate its ability to deliver drugs to tumor cells in vitro. Additionally, in vivo experiments were conducted using a CT26 tumor-bearing mouse model to assess the therapeutic efficacy of hybrid exosomes loaded with PTX (ELP). Cellular uptake studies demonstrated that ELP exhibited superior drug delivery capabilities to tumor cells in vitro. Moreover, in vivo experiments revealed that ELP significantly suppressed tumor growth in the CT26 tumor-bearing mouse model. Notably, for the first time, we examined the tumor microenvironment following intratumoral administration of ELP. We observed that ELP treatment activated CD4 and CD8 T cells, reduced the expression of M2 type tumor-associated macrophages (TAMs), polarized TAMs towards the M1 type, and decreased regulatory T cells (Tregs). Our research highlights the considerable therapeutic efficacy of ELP and its promising potential for future application in cancer therapy. The development of hybrid exosomes presents an innovative approach to enhance drug delivery and modulate the tumor microenvironment, offering exciting prospects for effective cancer treatment strategies.
Topics: Animals; Mice; Exosomes; CD8-Positive T-Lymphocytes; Drug Delivery Systems; Biocompatible Materials; Disease Models, Animal; Paclitaxel; Neoplasms
PubMed: 38612457
DOI: 10.3390/ijms25073645 -
The European Physical Journal. E, Soft... Dec 2023Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development...
Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). To determine whether PTX solubility is governed by lipid membrane structure or by local intermolecular interactions, we used synchrotron small-angle X-ray scattering. To increase the signal/noise ratio, we used DNA to condense the lipid formulations into lipoplex pellets. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of liposomal carriers for PTX delivery.
Topics: Paclitaxel; Liposomes; Solubility; Antineoplastic Agents; Micelles; Neoplasms
PubMed: 38099960
DOI: 10.1140/epje/s10189-023-00388-2 -
Polymers Feb 2024Liposomes show promise for anti-cancer drug delivery and tumor-targeted therapy. However, complex tumor microenvironments and the performance limitations of traditional...
Liposomes show promise for anti-cancer drug delivery and tumor-targeted therapy. However, complex tumor microenvironments and the performance limitations of traditional liposomes restrict clinical translation. Hyaluronic acid (HA)-modified nanoliposomes effectively target CD44-overexpressing tumor cells. Combination therapy enhances treatment efficacy and delays drug resistance. Here, we developed paclitaxel (PTX) liposomes co-modified with ginsenoside compound K (CK) and HA using film dispersion. Compared to cholesterol (Ch), CK substantially improved encapsulation efficiency and stability. In vitro release studies revealed pH-responsive behavior, with slower release at pH 7.4 versus faster release at pH 5. In vitro cytotoxicity assays demonstrated that replacing Ch with CK in modified liposomes considerably decreased HCT-116 cell viability. Furthermore, flow cytometry and fluorescence microscopy showed a higher cellular uptake of PTX-CK-Lip-HA in CD44-high cells, reflected in the lower half maximal inhibitory concentrations. Overall, CK/HA-modified liposomes represent an innovative, targeted delivery system for enhanced tumor therapy via pH-triggered drug release and CD44 binding.
PubMed: 38337294
DOI: 10.3390/polym16030405 -
International Journal of Nanomedicine 2024The high mortality rate of malignant ovarian cancer is attributed to the absence of effective early diagnosis methods. The LHRH receptor is specifically overexpressed in...
INTRODUCTION
The high mortality rate of malignant ovarian cancer is attributed to the absence of effective early diagnosis methods. The LHRH receptor is specifically overexpressed in most ovarian cancers, and the integrin αvβ3 receptor is also overexpressed on the surface of ovarian cancer cells. In this study, we designed LHRH analogues (LHRHa)/RGD co-modified paclitaxel liposomes (LHRHa-RGD-LP-PTX) to target LHRH receptor-positive ovarian cancers more effectively and enhance the anti-ovarian cancer effects.
METHODS
LHRHa-RGD-LP-PTX liposomes were prepared using the thin film hydration method. The morphology, physicochemical properties, cellular uptake, and cell viability were assessed. Additionally, the cellular uptake mechanism of the modified liposomes was investigated using various endocytic inhibitors. The inhibitory effect of the formulations on tumor spheroids was observed under a microscope. The co-localization with lysosomes was visualized using confocal laser scanning microscopy (CLSM), and the in vivo tumor-targeting ability of the formulations was assessed using the IVIS fluorescent imaging system. Finally, the in vivo anti-tumor efficacy of the formulations was evaluated in the armpits of BALB/c nude mice.
RESULTS
The results indicated that LHRHa-RGD-LP-PTX significantly enhanced cellular uptake in A2780 cells, increased cytotoxicity, and hand a more potent inhibitory effect on tumor spheroids of A2780 cells. It also showed enhanced co-localization with endosomes or lysosome in A2780 cells, improved tumor-targeting capability, and demonstrated an enhanced anti-tumor effect in LHRHR-positive ovarian cancers.
CONCLUSION
The designed LHRHa-RGD-LP-PTX liposomes significantly enhanced the tumor-targeting ability and therapeutic efficacy for LHRH receptor-positive ovarian cancers.
Topics: Animals; Mice; Humans; Female; Ovarian Neoplasms; Liposomes; Receptors, LHRH; Integrin alphaVbeta3; Cell Line, Tumor; Mice, Nude; Paclitaxel; Oligopeptides
PubMed: 38562611
DOI: 10.2147/IJN.S442921 -
Infection and Drug Resistance 2024Kaposi sarcoma (KS) incidence has decreased since the initiation of combination antiretroviral therapy (cART), but it remains the most common cancer in people with...
INTRODUCTION
Kaposi sarcoma (KS) incidence has decreased since the initiation of combination antiretroviral therapy (cART), but it remains the most common cancer in people with HIV/AIDS (PWHA). PWHA with advanced immunosuppression who initiate antiretroviral therapy are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS).
CASE PRESENTATION
This report covers the case of a 25-year-old male with AIDS-related KS who relapsed after Liposomal Doxorubicin, but recovered well after administration of nab-paclitaxel (Nab-PTX).
CONCLUSION
This is a rare case in choosing Nab-PTX to treat relapsed AIDS-KS and get good feedback. We report the case to provide a possible solution to treat AIDS-KS.
PubMed: 38623529
DOI: 10.2147/IDR.S456286 -
Archiv Der Pharmazie Mar 2024It is well known that bone-related diseases are difficult to treat due to the relatively low blood flow. Therefore, targeting the delivery of drugs to bone may not only...
It is well known that bone-related diseases are difficult to treat due to the relatively low blood flow. Therefore, targeting the delivery of drugs to bone may not only improve the therapeutic effect but also reduce the dose. To prepare liposomes, a series of novel multivalent glutamic hexapeptide derivatives were designed and synthesized as liposome ligands, which can effectively deliver paclitaxel (PTX) to bone. The liposomes were prepared and their encapsulation efficiency, particle size, stability, zeta potential, hemolysis, and release behavior were characterized. The results indicated that the coated liposomes, PTX-Glu6 -Lip, PTX-Glu6 -Lip, PTX-Glu6 -Lip, and PTX-Glu6 -Lip, showed remarkable bone-targeting activity. Compared with the other coated liposomes, PTX-Glu6 -Lip showed prominent targeting ability and anti-bone metastasis activity on the basis of in vitro and in vivo evaluations. Our study may contribute to the field of design of bone-targeting drugs.
Topics: Liposomes; Structure-Activity Relationship; Drug Delivery Systems; Paclitaxel
PubMed: 38133558
DOI: 10.1002/ardp.202300620 -
Molecular Pharmaceutics Apr 2024Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19...
Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19 and the Phase III antitumor agent EndoTAG-1. However, the therapeutic potential of these positively charged liposomes is limited by dose-dependent toxicity. While an increased content of cationic lipids in the formulation can enhance the uptake and cytotoxicity toward tumor-associated cells, it is crucial to balance these advantages with the associated toxic side effects. In this work, we synthesized the cationic lipid HC-Y-2 and incorporated it into sialic acid (SA)-modified cationic liposomes loaded with paclitaxel to target tumor-associated immune cells efficiently. The SA-modified cationic liposomes exhibited enhanced binding affinity toward both RAW264.7 cells and 4T1 tumor cells due to the increased ratios of cationic HC-Y-2 content while effectively inhibiting 4T1 cell lung metastasis . By leveraging electrostatic forces and ligand-receptor interactions, the SA-modified cationic liposomes specifically target malignant tumor-associated immune cells such as tumor-associated macrophages (TAMs), reduce the proportion of cationic lipids in the formulation, and achieve dual objectives: high cellular uptake and potent antitumor efficacy. These findings highlight the potential advantages of this innovative approach utilizing cationic liposomes.
Topics: Humans; Female; Liposomes; N-Acetylneuraminic Acid; Breast Neoplasms; COVID-19 Vaccines; Paclitaxel; Lung Neoplasms; Lipids; Cations; Cell Line, Tumor
PubMed: 38403951
DOI: 10.1021/acs.molpharmaceut.3c00767 -
Clinical and Experimental Medicine Dec 2023To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women...
AIMS
To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months.
METHODS
The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years.
RESULTS
Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and, of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes.
CONCLUSIONS
The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.
Topics: Humans; Female; Aged; Breast Neoplasms; Stroke Volume; Ventricular Function, Left; Neoplasm Recurrence, Local; Doxorubicin; Cyclophosphamide; Polyethylene Glycols; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 37634231
DOI: 10.1007/s10238-023-01144-8 -
Acta Pharmaceutica Sinica. B Jan 2024Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer, although it is limited by the low tumor delivery efficacy of anticancer drugs....
Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer, although it is limited by the low tumor delivery efficacy of anticancer drugs. Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect; however, excessively generated immunogenicity will cause serious inflammatory response syndrome. Here, we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts (LP@BG@CCM) by layer-by-layer encapsulation for the treatment of metastatic lung cancer. The preparation processes were simple, only involving film formation, electroporation, and pore extrusion. LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells. In the 4T1 breast cancer metastatic lung cancer mouse models, the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance, the reduced lung weight, the clear lung tissue structure, and the enhanced cancer cell apoptosis compared to its precursors. Moreover, several major immune factors were improved after administration of LP@BG@CCM, including the CD4/CD8a T cells in the spleen and the TNF-, IFN-, and IL-4 in the lung. LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy, which is a promising medication for the treatment of metastatic lung cancer.
PubMed: 38261850
DOI: 10.1016/j.apsb.2023.08.012 -
Pancreatology : Official Journal of the... Jun 2024Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to...
BACKGROUND/OBJECTIVES
Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study.
METHODS
In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups.
RESULTS
The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02).
CONCLUSIONS
The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.
Topics: Humans; Pancreatic Neoplasms; Leucovorin; Middle Aged; Male; Female; Fluorouracil; Aged; Irinotecan; Tegafur; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Retrospective Studies; Oxonic Acid; Liposomes; Treatment Outcome; Neoplasm Metastasis; Adult; Paclitaxel
PubMed: 38565467
DOI: 10.1016/j.pan.2024.03.014