Liposomal drug delivery systems: from concept to clinical applications.

Doxil®--the first FDA-approved nano-drug: lessons learned.

Solid lipid nanoparticles: Production, characterization and applications

https://dash.harvard.edu/bitstream/handle/1/29293165/Cancer%20Nanotechnology.pdf?sequence=1

Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials (“theranostics”) and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date.

In preclinical studies, a doxorubicin liposome formulation containing polyethylene-glycol (Doxil) shows a long circulation time in plasma, enhanced accumulation in murine tumors, and a superior therapeutic activity over free (unencapsulated) doxorubicin (DOX). The purpose of this study was to characterize the pharmacokinetics of Doxil in cancer patients in comparison with free DOX and examine its accumulation in malignant effusions. The pharmacokinetics of doxorubicin and/or liposome-associated doxorubicin were analyzed in seven patients after injections of equivalent doses of free DOX and Doxil and in an additional group of nine patients after injection of Doxil only. Two dose levels were examined, 25 and 50 mg/m2. When possible, drug levels were also measured in malignant effusions. The plasma elimination of Doxil followed a biexponential curve with half-lives of 2 and 45 h (median values), most of the dose being cleared from plasma under the longer half-life. Nearly 100% of the drug detected in plasma after Doxil injection was in liposome-encapsulated form. A slow plasma clearance (0.1 liter/h for Doxil versus 45 liters/h for free DOX) and a small volume of distribution (4 liters for Doxil versus 254 liters for free DOX) are characteristic of Doxil. Doxorubicin metabolites were detected in the urine of Doxil-treated patients with a pattern similar to that reported for free DOX, although the overall urinary excretion of drug and metabolites was significantly reduced. Doxil treatment resulted in a 4- to 16-fold enhancement of drug levels in malignant effusions, peaking between 3 to 7 days after injection. Stomatitis related to Doxil occurred in 5 of 15 evaluable patients and appears to be the most significant side effect in heavily pretreated patients. The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier. The enhanced drug accumulation in malignant effusions is apparently related to liposome longevity in circulation. Further clinical investigation is needed to establish the relevance of these findings with regard to the ability of liposomes to modify the delivery of doxorubicin to solid tumors and its pattern of antitumor activity.

https://cancerres.aacrjournals.org/content/canres/54/4/987.full.pdf

Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes.

Background. The authors compared the therapeutic effects of doxorubicin in two formulations: free in saline suspension and encapsulated in sterically stabilized liposomes composed of hydrogenated soy phosphatidylcholine/2cholesterol/polyethylene glycol-distearoyl-phosphatidyl-ethanolamine (Doxil, Liposome Technology, Inc., Menlo Park, CA).



Results. Laser scan microscope and microfluoro-meter studies showed that the liposome-encapsulated drug entered the liver, the kidneys, and the tumor in greater quantity and remained in the liver and in the tumor longer than the free drug. The liposome formulation produced a 25-fold increase in doxorubicin at the disease site. Doxil was significantly more effective than the free drug in inhibiting growth and in effecting cures and had only minor and temporary systemic toxic effects.



Conclusions. The current study demonstrated the therapeutic efficacy of doxorubicin, encapsulated in sterically stabilized liposomes, against prostate carcinoma. Decreased systemic elimination, increased penetration into the tumor, and long liposome presence with slow drug release into the tumor probably accounted for the enhanced therapeutic effect of doxorubicin in sterically stabilized liposomes. Cancer 1994; 73:1478–84.



Method. The drug formulations were injected intravenously to treat human prostate carcinoma PC-3, implanted subcutaneously into nude Swiss mice. Confocal laser scan microscopy and microfluorometry were used to determine tissue distribution and to quantitate drug uptake.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819940301%2973%3A5%3C1478%3A%3AAID-CNCR2820730526%3E3.0.CO%3B2-1

Tissue distribution and therapeutic effect of intravenous free or encapsulated liposomal doxorubicin on human prostate carcinoma xenografts.

Background. This study compared the therapeutic effects of doxorubicin hydrochloride in saline and in sterically stabilized, long-circulating liposomes composed of hydrogenated soy phosphatidylcholine/cholesterol/polyethylene glycol-distearoyl-phosphatidyl-ethanolamine (Doxil).



Methods. The drug formulations were injected intravenously or intraperitoneally to treat the human ovarian carcinoma HEY, which was implanted subcutaneously or intraperitoneally into mature female Swiss nude mice.



Results. The long-circulating liposome formulation was significantly more effective than was the free drug in inhibiting tumor growth and in producing cure. The liposome formulation was significantly less toxic than was the free drug. This is the first demonstration of the therapeutic effectiveness of doxorubicin in sterically stabilized liposomes against human tumor xenografts.



Conclusions. The encapsulation of doxorubicin in long-circulating liposomes significantly enhanced the therapeutic efficacy of the drug against a human ovarian carcinoma.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819931215%2972%3A12%3C3671%3A%3AAID-CNCR2820721219%3E3.0.CO%3B2-U

Therapy of human ovarian carcinoma xenografts using doxorubicin encapsulated in sterically stabilized liposomes

Purpose: To examine the possibility that hyperthermia would accelerate drug release from long-circulating liposomes, and enhance their antitumor activity. Methods and Materials: Liposomes were prepared by thin film hydration technique. Hyperthermia was induced by ultrasound apparatus and a water bath heating system. The antitumor efficacy of treatment against RIF-1 tumor in C3H mice was evaluated by the tumor growth delay assay. Results: In vitro drug release experiments demonstrated that increase in temperature from 37°C to 41°C resulted in about a sixfold increase in doxorubicin (DOX) release in a 1-h period. Increasing the temperature to 43°C, resulted in only a modest additional drug release. Drug uptake studies showed that local hyperthermic treatment immediately following the drug administration dramatically enhanced Stealth liposome-encapsulated doxorubicin (S-DOX) uptake by tumors, but did not do so for free DOX. At 42°C and at a dose of 10 mg/kg, the accumulation of S-DOX was about 10-fold and 2.5-fold higher than that with free drug and S-DOX at 37°C, respectively. The antitumor efficacy study confirmed our hypothesis that the addition of hyperthermia to the treatment of RIF-I tumors with doxorubicin encapsulated in long-circulating liposomes would enhance antitumor effects. Two hyperthermia treatments given at 24-h intervals appeared to be the most promising method of combining heat and long-circulating liposomes. The increased antitumor activity was not accompanied by increased toxicity, as determined by the body weight of the mice. Conclusion: Local hyperthermic treatment is able to accelerate DOX release from long-circulating liposomes, increase tumor uptake, and enhance their antitumor efficacy. The combination of local hyperthermia and long-circulating liposomes appears to show considerable promise in the treatment of localized diseases.

Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy

Drugs that are entrapped in the interior of nanocarriers such as liposomes have no therapeutic activity, i.e. they are not bioavailable. In order to achieve therapeutic activity, drug release from the liposomes must occur at a rate sufficient to achieve therapeutic concentrations of drug at the cellular target. For ligand-targeted liposomes, directed against internalizing antigens, receptor-mediated internalization of the liposome package occurs and the entrapped drugs become active (bioavailable) upon their intracellular release from the lysosomal apparatus. We have examined, in a murine breast cancer model, the rate and the extent of bioavailability of doxorubicin (DXR) entrapped in liposomes targeted by a single-chain antibody fragment against the HER2/neu antigen, in comparison with free DXR and non-targeted liposomal DXR (DOXIL®). Breast cancer tumors contained the highest total levels of DXR and the highest levels of bioavailable DXR when anti-HER2/neu-targeted liposomes were used, and the targeted ...

Anthony Huang

Papers

Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes.

Tissue distribution and therapeutic effect of intravenous free or encapsulated liposomal doxorubicin on human prostate carcinoma xenografts.

Therapy of human ovarian carcinoma xenografts using doxorubicin encapsulated in sterically stabilized liposomes

Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy

Bioavailability and therapeutic efficacy of HER2 scFv-targeted liposomal doxorubicin in a murine model of HER2-overexpressing breast cancer.