Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 339

Functional and ultrastructural studies of liposomes injected
i.v. into inbred C57BL/6N mice were performed to determine
whether free liposomes can traverse capillaries . In the
liver and spleen, organs with discontinuous (sinusoidal)
capillaries, ultrastructural and cell fractionation studies
revealed that small (300 to 800 Å diameter), sonicated,
unilamellar liposomes were more efficient in penetrating liver
sinusoids to interact with hepatocytes than were large (0.5
to 10 μm) multilamellar liposomes. Ultrastructural studies
of the behavior of liposomes in the continuous capillaries of
the lungs revealed that circulating phagocytic cells engulf the
liposomes in the capillaries. Transcapillary migration of
free liposomes was not observed . We conclude that free
liposomes are unable to extravasate to reach the alveoli
for subsequent engulfment by alveolar macrophages.
Instead, liposomes in the lung capillaries are engulfed by
circulating blood phagocytes, which subsequently migrate
to the alveoli to become alveolar macrophages . Experiments
on the recruitment of blood monocytes into the lungs subjected
to whole- or partial-body X-radiation confirmed that transfer
of i.v.-injected liposomes to the alveolar compartment was
mediated by blood monocytes. The inability of liposomes to
escape from continuous capillaries and their rapid uptake
by circulating and fixed phagocytic cells calls into question
the feasibility of using liposomes to “target” drugs to cells
in extravascular tissues.
This and Poste's 1983 publication were “catastrophic” to the
medical application of liposomes as it led the scientific community
as well as the major grant agencies, the pharma industry, and the
venture capital community to lose interest in this field. It took 10
more years for the field to recover and gain back some trust that
enabled the development of more than 10 FDA-approved liposomal
drugs from 1995 to the present.
The above Poste et al. papers were published at the stage when we
were in the middle of the development of our liposomal doxorubicin
formulation and set the conditions for our selection of liver tumors
as the preferred tumor choice. Only very little help from very few
published papers was available to us in 1979. Very few relevant
papers were published till then, exemplified by Gregoriadis et al.
(1974) and Richardson et al. (1979). A few other groups all over the