Combination radiofrequency thermal ablation and adjuvant IV liposomal doxorubicin increases tissue coagulation and intratumoural drug accumulation

There has been marked interest in minimally-invasive, image-guided radiofrequency (RF) tumour ablation (i.e. coagulating tumour using short duration heating (<15?min) by directly applying temperatures >50°C via needle electrodes) to treat focal liver, renal, breast, bone and lung tumours. In spite of advances in RF technology and improved understanding of tumour biophysiology that now enable experimental treatment of tumours up to 5?cm, investigators have been unable to achieve complete ablation in many cases, particularly at the tumour margins and adjacent to blood vessels. One strategy for overcoming these limitations has been to take advantage of complementary interactions between RF thermal ablation and chemotherapy, particularly liposomal doxorubicin preparations, to attempt more complete tumour destruction. This paper will review published laboratory investigations demonstrating that this combined treatment paradigm has the unique potential both to potentiate preferential delivery of cytotoxic agents in liposome vehicles and to maximize the completeness of ablation of a treated tumour. New confirmatory data describing increased tumour destruction with RF ablation combined with different liposome preparations, documenting increased lipid peroxidation and expanding on previously published tumour growth studies is presented. Additionally, early clinical data including a randomized, pilot clinical study on 10 patients with primary and metastatic liver tumours, in which a non-optimized combination of RF ablation and IV liposomal doxorubicin (Doxil) increased the volume of tumour destruction 25–30% compared to RF alone, will also be described in detail.     

Utilizing Edible Agar as a Carrier for Dual Functional Doxorubicin-Fe3O4 Nanotherapy Drugs

The purpose of this study was to use agar as a multifunctional encapsulating material to allow drug and ferromagnetism to be jointly delivered in one nanoparticle. We successfully encapsulated both Fe₃O₄ and doxorubicin (DOX) with agar as the drug carrier to obtain DOX-Fe₃O₄@agar. The iron oxide nanoparticles encapsulated in the carrier maintained good saturation of magnetization (41.9 emu/g) and had superparamagnetism. The heating capacity test showed that the specific absorption rate (SAR) value was 18.9 ± 0.5 W/g, indicating that the ferromagnetic nanoparticles encapsulated in the gel still maintained good heating capacity. Moreover, the magnetocaloric temperature could reach 43 °C in a short period of five minutes. In addition, DOX-Fe₃O₄@agar reached a maximum release rate of 85% ± 3% in 56 min under a neutral pH 7.0 to simulate the intestinal environment. We found using fluorescent microscopy that DOX entered HT-29 human colon cancer cells and reduced cell viability by 66%. When hyperthermia was induced with an auxiliary external magnetic field, cancer cells could be further killed, with a viability of only 15.4%. These results show that agar is an efficient multiple-drug carrier, and allows controlled drug release. Thus, this synergic treatment has potential application value for biopharmaceutical carrier materials.     

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

Bacterial ghosts as a novel advanced targeting system for drug and DNA delivery

Although there are powerful drugs against infectious diseases and cancer on the market, delivery systems are needed to decrease serious toxic and noncurative side effects. In order to enhance compliance, several delivery systems such as polymeric micro- and nanoparticles, liposomal systems and erythrocyte ghosts have been developed. Bacterial ghosts representing novel advanced delivery and targeting vehicles suitable for the delivery of hydrophobic or water-soluble drugs, are the main focus of this review. They are useful nonliving carriers, as they can carry different active substances in more than one cellular location separately and simultaneously. Bacterial ghosts combine excellent natural or engineered adhesion properties with versatile carrier functions for drugs, proteins and DNA plasmids or DNA minicircles. The simplicity of both bacterial ghost production and packaging of drugs and/or DNA makes them particularly suitable for the use as a delivery system. Further advantages of bacterial ghost delivery vehicles include high bioavailability and a long shelf life without the need of cold-chain storage due to the possibility to freeze-dry the material.     

Nanomedicine for acute respiratory distress syndrome: The latest application,targeting strategy,and rational design

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air–blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.     

Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours

Purpose: In previous reports, laboratory-made lysolecithin-containing thermosensitive liposome encapsulating doxorubicin (LTSL-DOX) showed potent anticancer effects in FaDu human squamous cell carcinoma. To further study the spectrum of LTSL-DOX activity, the efficacy of its commercial formulation was re-examined in FaDu and compared in HCT116, PC3, SKOV-3 and 4T07 cancer cell lines. Factors that may influence differences in HT-LTSL-DOX efficacy were also examined.

Methods: Anticancer effect was measured using standard growth delay methods. We measured doubling time and clonogenic survival after doxorubicin exposure in vitro, and interstitial pH and drug concentrations in vivo.

Results: In all five tumour types, HT-LTSL-DOX increased median tumour growth time compared with untreated controls (p < 0.0006) and HT alone (p < 0.01), and compared with LTSL-DOX alone in FaDu, PC-3 and HCT-116 (p < 0.0006). HT-LTSL-DOX yielded significantly higher drug concentrations than LTSL-DOX (p < 0.0001). FaDu was most sensitive (p < 0.0014) to doxorubicin (IC₅₀ = 90 nM) in vitro, compared to the other cell lines (IC₅₀ = 129–168 nM). Of the parameters tested for correlation with efficacy, only the correlation of in vitro doubling time and in vivo median growth time was significant (Pearson r = 0.98, p = 0.0035). Slower-growing SKOV-3 and PC-3 had the greatest numbers of complete regressions and longest tumour growth delays, which are clinically important parameters.

Conclusions: These results strongly suggest that variations in anti-tumour effect of HT-LTSL-DOX are primarily related to in vitro doubling time. In the clinic, the rate of tumour progression must be considered in design of treatment regimens involving HT-LTSL-DOX.     

Efficacy and safety of pegylated liposomal doxorubicin in primary cutaneous B‐cell lymphomas and comparison with the commonly used therapies

Objectives: The therapy of advanced, relapsed or refractory primary cutaneous lymphomas is often unsatisfactory. Recent data indicate a favourable pharmacokynetic, pharmacodynamic and toxicity profile of pegylated liposomal doxorubicin (Peg‐Doxo) in primary cutaneous T‐cell lymphomas, while in primary cutaneous B‐cell lymphomas (PCBCLs), the drug efficacy has never been assessed so far. Methods: We performed a prospective phase II pilot clinical trial of Peg‐Doxo monotherapy (20 mg/m²) in PCBCLs. One patient had a marginal zone B‐cell lymphoma and four were affected by diffuse large B‐cell lymphoma‐leg type, all with widespread nodular lesions. Results: All the patients achieved a complete response (CR = 100%) in a short period of time (median 3 months), even when pretreated with radio‐chemotherapy. Two experienced a relapse. At follow‐up, one patient died for progressive disease; four are in CR after 5, 52, 63 and 69 months. As concerning the toxicity profile, the treatment was well‐tolerated, no one decreased or delayed the dose. The haematological toxicity was mild with only one case of grade III neutropenia; a patient showed a grade I neurotoxicity. Dermatological toxicity, in particular the palmar–plantar erythrodysesthesia, did not occurred, probably because of both the low dosages of Peg‐Doxo monotherapy and the oral prophylaxis with pyridoxine. Conclusions: In spite of the small number of patients, it emerges that monochemotherapy with Peg‐Doxo has a significantly high clinical activity and a good safety profile in PCBCLs, even in aggressive forms, compared with other therapeutic regimens, which are completely reviewed. It suggests the need of further investigations in this field.     

An update on chemotherapy for osteosarcoma

Introduction: In the early seventies chemotherapy significantly improved survival in osteosarcoma. Since then minor innovations have occurred although recent years have offered insights of clinical and scientific relevance.Areas covered: This review focuses on the most recent results of phase 3 and 2 studies. Published data or presentations at International meetings are discussed. A specific section discusses recent insights from studies supporting the hypothesis of a possible personalized chemotherapy approach.Expert opinion: Osteosarcoma is a rare tumor and any effort should be made to improve the level of International collaboration. The MAP (methotrexate, doxorubicin and cisplatin) regimen has become the treatment of choice. Poor pathological response to primary chemotherapy is confirmed as a predictive factor of survival and, presently with the available drugs, it is not recommended to intensify or change post-operative treatment on the basis of pathological response to primary chemotherapy. The genomic complexity and the heterogeneity of osteosarcoma makes active and effective molecularly targeted therapies unlikely to be available in the near future. A relation between pharmacogenetic profile and chemotherapy toxicity and prognosis has been reported. The new frontier for clinical research in osteosarcoma is to optimize the use of the active drugs available by personalizing chemotherapy treatment.