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Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Daniel Bobo, Kye J. Robinson, Jiaul Islam, Kristofer J. Thurecht, Simon R. Corrie
In terms of intravenous delivery, classical liposomes typically exhibit short circulating half-lives due to rapid clearance. In general, the lipid bilayer structure of liposomes results in recognition by the immune system and subsequent clearance from circulation by macrophages. Clearance has been minimized by PEGylation of the liposome surface. PEGylated liposomal doxorubicin (Doxil®), the first example of a liposomal nanoparticle drug, was proven effective in the reduction of cardiotoxic side effects of doxorubicin treatment. Doxil® has been approved for Karposi’s sarcoma, ovarian cancer, and multiple myeloma, as well as for metastatic breast cancer [51]. In comparison to free doxorubicin (DOX), the PEGylated liposome resulted in 4 to 16 fold enhancement of drug levels in malignancies [52]. The PEGylated liposomal carrier was quickly adopted for the delivery of other drugs such as Ambisome®, an amphotericin B to treat fungal infections, and Visudyne®, delivering verteporphin for wet macular degeneration [53, 54]. These and many of the other approved liposomes rely strictly on passive targeting which successfully increases distribution to diseased tissue.
Therapy with Oncolytic Clostridium novyi-NT: From Mice to Men
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
One such approach exploits the so-called enhanced permeability and retention (EPR) effect, a biological phenomenon associated with the aberrant tumor vasculature [11, 12]. The histological basis for the EPR effect includes fenestrations on the vessel wall, defects generated during the development of tumor vessels, and the lack of a functional lymphatic system. These defects in the tumor vascular system allow increased permeation and retention of the macromolecular drugs or nanoparticles within an appropriate size range in the tumor parenchyma [13–16]. In contrast, the macromolecular and nanosized drug formulations are less likely to accumulate in normal tissues with a well-developed vascular system. The development of Doxil® exemplifies a successful clinical application of the EPR concept. Doxil is a PEGylated liposomal formulation of doxorubicin that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of AIDS-related Kaposi’s sarcoma, recurrent ovarian cancer, metastatic breast cancer, and multiple myeloma [17]. However, the EPR effect can be highly variable among individual tumors because of the heterogeneity associated with the tumor vasculature [18], limiting the application of the macromolecular and nanosized drug formulations to a relatively small patient population.
Nanotechnology: Regulatory Perspective for Drug Development in Cancer Therapeutics
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Another early nanomedicine, liposomal encapsulated doxorubicin (Doxil®), is regulated by the FDA and has been available in the clinic for treatment of various cancers since 1995. Drug incorporation inside the hydrophilic core or within the hydrophobic phospholipid bilayer coat of liposomes, has been shown to improve drug solubility, enhance drug transfer into cells and tissues, facilitate organ avoidance, and modify drug release profiles, minimizing toxicity.91 The liposomal formulation of the popular anthracyline, doxorubicin, which is commonly used to treat metastatic breast and ovarian cancer, is reported to have diminished cardiotoxicity and enhanced therapeutic efficacy compared to the free form of the drug.15–17 This increased efficacy is most likely due to the passive targeting of solid tumors through the enhanced permeability and retention effect inherent to tumor vasculature and aberrant tumor morphology.17 The approximate diameter of the doxorubicin–liposomal product is reported to be 100 nm, near the size limits described in the FDA definition of a nanomedicine.
Transferrin receptor-mediated liposomal drug delivery: recent trends in targeted therapy of cancer
Published in Expert Opinion on Drug Delivery, 2022
Solmaz Mojarad-Jabali, Somayeh Mahdinloo, Masoud Farshbaf, Muhammad Sarfraz, Yousef Fatahi, Fatemeh Atyabi, Hadi Valizadeh
Doxil® has been previously reported for ovarian cancer treatment. Although it has reduced the toxic effects of DOX in normal tissues, Doxil® still suffers from poor tumor tissue penetration and specific targeting to ovarian cancer. Thus, the development of more specific DDSs to guide the intended cargo to the tumor tissue and promote its intracellular delivery is still in great demand [197]. In this regard, DOX-loaded liposomes modified with R8 and Tf exhibited enhanced in vitro cytotoxicity in A2780 cells (an ovarian cancer cell line) and effectively controlled the tumor growth in ovarian xenografts than non-modified liposomes [198]. Nevertheless, the TfR targeting through cisplatin-loaded holo-Tf-functionalized PEGylated liposomes did not significantly increase the cisplatin concentration in cisplatin-resistant ovarian cancer cells compared to non-targeted formulations [199].
Delivery of anti-cancer drugs using microbubble-assisted ultrasound in digestive oncology: from preclinical to clinical studies
Published in Expert Opinion on Drug Delivery, 2022
Jean-Michel Escoffre, Najib Sekkat, Edward Oujagir, Sylvie Bodard, Coralie Mousset, Antoine Presset, Romain Chautard, Jean Ayoub, Thierry Lecomte, Ayache Bouakaz
Thus, Zhu et al. investigated the efficacy of MB-assisted US to deliver the Doxil® in hepatocellular carcinoma (H22) mouse model [55]. Four days after tumor transplantation, mice received an i.v. injection of Doxil® (10 mg/kg), then an i.v. injection of MBs (200 μL at 4 × 109 MB/mL). The tumors were insonified with US pulses (lab-made US device: 1.1 MHz, 50% DC, 2.06 W/cm2) for a total exposure time of 150 s. This treatment induced a significant tumor inhibition (79.7% vs 62.4%) and hence a lower tumor volume growth (9.7% vs 26.1%) than Doxil® alone. The acoustically mediated Doxil® delivery significantly increased the i.t. concentration of DOX compared with tumors treated with Doxil® on its own. These data clearly demonstrated a positive correlation between the acoustically mediated enhancement of i.t. DOX bioavailability and the increase in its therapeutic effectiveness. Despite an increase in the i.t. DOX concentration after MB-assisted US, the DOX concentration in normal tissues has not decreased. Nevertheless, the assessment of liver function by dosing of alanine and aspartate aminotransferases showed that the acoustically mediated enhancement of DOX concentration in the liver tissue did not induce hepatic side effects. In addition, the acoustically mediated Doxil® delivery significantly increased the mouse survival rate in comparison with Doxil® alone (30 days versus 26 days). This preclinical study clearly demonstrated that MB-assisted US improved the therapeutic effectiveness of Doxil®.
Research progress in strategies to improve the efficacy and safety of doxorubicin for cancer chemotherapy
Published in Expert Review of Anticancer Therapy, 2021
Muhammad Sohail, Zheng Sun, Yanli Li, Xuejing Gu, Hui Xu
Two distinct mechanisms have been suggested for how DOX in the form of Doxil® enter into malignant cells in vivo. Doxil liposomes are taken up by cancer cells, and the drug is released intracellularly. Or the Doxil liposomes are released first into the tumor interstitial area, from which it reaches into cells as a vacant drug [71]. In comparison to traditional DOX treatment, fewer trials have shown that Doxil reduces systemic toxicity and improves patient survival rates [72,73]. The approval of Doxil® was the first step toward the commercialization of other nanopharmaceuticals. Following Doxil®, numerous other lipid-based nanocarriers were created, some of which were based on liposomes loaded with drugs or stealth liposomes with a cocktail of drug loadings and targeted moieties conjugated at the surface of the nanoparticle.