Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 350

In 1985, based on the above formulation design and
characterization, combined with acceptable toxicology (significantly
better than F-DOX), superior PK, BD, and therapeutic efficacy in small
rodents (compared with F-DOX), we started to plan and apply for a
phase I clinical trial approval at the Hadassah University Hospital.
IND application was submitted and was approved in 1985 by the
Hadassah University Hospital Helsinki Committee and the Israel
Ministry of Health (MOH).

12.2.7 Scale-Up

The preparation for the clinical trials required fabrication of the OLV-
DOX at liter-scale batches, concomitantly with the development of
quality control assays (Barenholz et al., 1989; Gabizon et al., 1989b;
Amselem et al., 1989-90, 1990, 1992, 1993a, 1993b; Gabizon et al.,
1991; Barenholz and Amselem, 1993; Barenholz and Crommelin,
1994).

12.3 OLV-DOX Clinical Trials

12.3.1 What Was Known in 1985 on “First in Man”

Studies and the Clinical Use of Liposomes as
Carriers of Drugs and Imaging Agents?

The first clinical use of liposomes dates back to 1974, when the
fate of radiolabeled liposomes was examined in three cancer
patients (Gregoriadis et al., 1974). This was followed by Gregoriadis
and coworkers' use of liposomes as a carrier for the enzyme
glucocerebroside (a beta-glucosidase) for enzyme replacement
therapy for Gaucher's disease treatment (Belchetz et al., 1977).
More extensive studies in humans with radiolabeled “fluid”-phase
sonicated liposomes indicated that the major tissues of liposome
uptake are the liver and spleen (Richardson et al., 1979). A similar
study in which the distribution of technetium-99m-labeled MLV in
patients with Hodgkin's disease was performed by Perez-Soler et al.
(1985). The earliest report in the literature on the therapeutic use
of liposomes as drug carriers given systemically to a sizable group
of patients described the experience gained after administration of
amphotericin-B in liposomes. It showed clear beneficial antifungal