Editorial :
Editorial The
treatment of multiple myeloma has been a real headache for a long time since the
disease is relatively resistant to traditional chemotherapy because the majority
of plasma cells do not divide, limiting the effectiveness of conventional
cytotoxic agents that affect overall to rapidly growing cells. However, since
the early 1980s the treatment of multiple
myeloma has evolved from the death after about two years of progressive
deterioration of quality of life, until more and more large asymptomatic periods
of complete remission by more advanced and targeted therapies like the high-dose
therapies supplemented with autologous stem-cell transplantation, and the use
of novel molecular-targeted agents (immunomodulatory drugs and proteasome inhibitors),
achieving survivals of more than ten years in some patients that continue with
their first complete remission. Note that the complete remission state is an important
prognostic factor for survival in myeloma patients and can be defined as an
absence of monoclonal
paraprotein in serum and urine, less than five percent of plasma
cells in bone marrow, no increase of lytic bone lesions, and disappearance of plasmacytomas. The
current treatment of multiple myeloma comprises supportive treatment and
initial induction chemotherapy courses, followed by single or double high dose therapy
supported with autologous transplant, and finished by a consolidation therapy that
prolongs significantly the survival of patients. Although the treatment with alkylating
compounds, like melphalan, bendamustine and cyclophosphamide, and corticosterioids
have been the traditional chemotherapeutic cocktail for the treatment of
multiple myeloma for decades, the understanding of the biology of multiple
myeloma has allowed the development of novel
biological agents that target myeloma cells and the
bone-marrow microenvironment, which has a fundamental role in multiple myeloma pathogenesis.
Note that survival of malignant myeloma cells is dependent on the bone marrow
microenvironment and the evasion of the anti-tumor immune responses. Among these
new agents should be noted the immunomodulatory
drugs (IMiDs), like thalidomide and derivatives (lenalidomide and pomalidomide)
and the proteasome inhibitors drugs, like bertezomib and carfilzomib (and
several new agents in phase II and III trials, like marizomib, ixazomib and
oprozomib). Although, the incorporation of IMiDs and proteasome
inhibitors in the treatment of multiple myeloma has improved long-term
outcome of patients, increasing their overall survival, many patients relapsed
or were refractory to these drugs because of myeloma cells increase the
secretion of survival factors and become unaffected to apoptotic signals, dying
as a result of disease or complications arising. Therefore, there are novel
agents under preclinical and clinical investigation, like histone deacetylase inhibitors
(vorinostat, panobinostat, belinostat y romidepsina), heat shock protein 90
inhibitors, arsenic trioxide, deubiquitylating enzymes inhibitors, monoclonal
antibodies (elotuzumab, daratumumab, lorvotuzumab, siltuximab, tabalumab,
denosumab, figitumumab, bavacizumab, mapatumumab, dacetuzumab, lucatumumab and
milatuzumab, among others), and inhibitors of different signaling pathways,
that explore new mechanisms to interfere with the interactions between the
malignant plasma cells and its microenvironment, achieving promising results in
the fight against relapsed/refractory multiple myeloma. However, despite all
efforts, multiple myeloma has no cure nowadays. To
provide a step forward in the treatment of multiple myeloma, the use of
targeted magnetic molecularly imprinted nanomedicines may avoid the traditional
treatments of this pathogenesis that involve a large deterioration in the
quality of life of the patients for long periods and are not always effective.
These novel magnetic nanomedicines
will be able to remotely destroy the plasma cells and prevent the cancer from
coming back again, attacking the bone-marrow microenvironment, decreasing
relapse or recurrence and resistance to available drugs. Although
exist a clear rationale for using magnetic hyperthermia (procedure that use
heat to kill cancerous cells with minimal damage to normal cells) in haematological
cancer treatment, it has been mainly used as adjunctive therapy with radiotherapy
and chemotherapy in solid tumors. In literature, there are numerous examples of
in vivo applications
of magnetic hyperthermia in the treatment of solid tumors, but there are only several
papers related to magnetic hyperthermia in hematologic cancers. Nowadays, the
more promising approach to generate a locally targeted hyperthermia is the
intracellular hyperthermia by means of intravenous administered nano-scale
magnetic particles that can generate heat, in the malignant cells of tumors,
under a high frequency alternating magnetic field (AMF) by magnetic hysteresis
loss for ferro- and ferri-magnetic materials, or Brownian and mostly Neel
relaxation pathways for superparamagnetic materials. Note that magnetic
hyperthermia based on magnetic
nanoparticles received regulatory approval as a new clinical cancer therapy,
the thermotherapy, in 2010. Molecular
imprinting is a promising technology that creates“intelligent materials” that
simulates the typical molecular recognition of biological systems. Molecular
imprinting polymers (MIPs) are cross-linked polymeric networks formed in the
presence of a template that creates a recognition site. The subsequent release of
the template allows the material to exhibit a selective “memory” with respect
to the template. This technology has been widely used to recognize small
molecules, like herbicides, metal ions or amino acids, in several applications,
such us chromatography,
sensor technology, separation processes and immune
sorbent assays (ELISA). However, researchers have faced many difficulties
in recognizing large molecular weight molecules, like peptides and proteins. sensor technology, chromatography, Molecular imprinting, haematological cancer, multiple myeloma.The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines
Abstract
Full-Text
Multiple
myeloma is the second more frequently haematological cancer in the western
world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers
cases and the 10-13% of hematologic diseases. The disease is caused by an
uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate
in different parts of the body, usually in the bone marrow, around some bones,
and rarely in other tissues, forming tumor deposits, called plasmocytomas. This
uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal
monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation
of the other antibodies produced by the normal plasma cells that are destroyed.
The anormal secretion of paraproteins unbalance the osteoblastosis
and osteoclastosis processes, leading to bone lesions that cause lytic bone
deposits and the release of calcium from bones (hypercalcemia) that may produce
renal failure. Regions affected by bone lesions are the skull, spine, ribs,
sternum, pelvis and bones that form part of the shoulders and hips. The
substitution of the healthy bone marrow by infiltrating malignant cells and the
inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia
and leukopenia. Multiple myeloma patients are immunosuppressed because of
leukopenia and the abnormal immunoglobulin production caused by the
uncontrolled clonal proliferation of plasma cells, being susceptible to
bacterial infections, like pneumonias and urinary tract infections. The
interaction of immunoglobulin with hemostatic mechanisms may lead to
haemorrhagic diathesis or thrombosis. Also, disorders of the central and
peripheral nervous system are part of the disease, being the more common
neurological manifestations the spinal cord compressions and the peripheral
neuropathies.Molecular
imprinting
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