Therapeutic Regulation of Epigenetics in Cancer Treatment through Drug Delivery Systems
Time：2024/4/6 19:01:02 Views：51
In addition to genetic factors, epigenetic
factors are also strongly associated with cancer, especially its malignant
evolution. Although epigenetic-based cancer therapies have been used with some
efficacy in hematologic malignancies, they remain ineffective in a broader
range of solid tumors. This is partly due to the inherent physicochemical
properties of the drugs and their biological barriers in vivo. Meanwhile, as an upstream signaling strategy that broadly
affects drug resistance, metabolism, immunity, and other aspects of tumors, its
efficient combination with other antitumor therapies is also one of the answers
to the problem of efficacy in solid tumors. Therefore, we summarize how to
maximize the efficacy of epigenetic-based antitumor therapy by designing
on-demand drug delivery systems based on the characteristics of epigenetic
regulation of tumors and the effects of existing epigenetic drugs, and further
discuss the design and therapeutic potentials of matched intelligent
co-delivery systems based on the combination of epigenetic regulation with
multiple different therapies. The results were published online in Nano
Today (IF=17.4) under the title of Therapeutic Regulation of Epigenetics in
Cancer Treatment through Drug Delivery Systems.
Finding key factors that intervene in the
malignant evolution of tumors is crucial for antitumor therapy as tumors
continue to remodel themselves and remodel their surrounding microenvironment
as they progress to gain resistance to recurrence and further invasion and
metastasis in response to treatment. With the completion of large-scale genome
projects, more and more evidence is revealing the importance of chromatin
status rather than DNA sequence alterations in cancer development and
especially cancer progression, i.e., the critical role of epigenetic
alterations in the malignant evolution of cancer.
Epigenetic inheritance refers to the stable
heritable regulation of gene expression segments only without altering the
genome sequence. This process is more complex compared to gene mutation and is
determined by structural changes in chromatin, including mechanisms such as DNA
methylation, histone modification and remodeling of chromosomes or nucleosomes,
which are important for the organism to maintain normal cell growth and
differentiation into different functional cells. Unlike irreversible genetic
mutations, epigenetic regulation is a dynamic and reversible process because
epigenetic modifications can be labeled or removed on DNA or histones by
specific catalytic enzymes. In turn, these epigenetic marks are further bound
by enzymes containing specific recognition structural domains and initiate
downstream signaling. These key enzymes are therefore important drug targets
for intervening in epigenetic regulation, and many small molecule inhibitors
have been developed against different epigenetic enzymes. However, although a
few of them have been approved for marketing due to their effectiveness against
hematologic malignancies, the majority of epigenetic drugs are still in the
preclinical and clinical research phase, and there are virtually no drugs that
can be used as single agents for the treatment of solid tumors. Therefore,
addressing the question of how to extend the application of epigenetic drugs to
the treatment of solid tumors and in what way epigenetic drugs should play a
role in the treatment of solid tumors will make a great contribution to the
fight against cancer.
The fundamental reason for the significant
difference in efficacy of epigenetic drugs in hematologic malignancies and
solid tumors is that different disease models have different therapeutic
accessibility to the same drug, i.e., the effective drug exposure as determined
by the pharmacokinetic properties of the drug itself and its fate in vivo. In
addition, besides directly acting as proliferation-inhibiting antitumor agents,
an increasing number of studies have revealed the remarkable potential of
epigenetic drugs as a co-modulator in overcoming chemoresistance, reversing
immunosuppression, sensitizing radiotherapy, and synergizing other therapies.
Thus combination therapies based on epigenetic modulation would be attractive
for antitumor therapy. Whether it is optimizing the in vivo pharmacokinetic
behavior of epigenetic drugs or combining epigenetic drugs with other
therapeutic molecules, the key to solving the problem lies in effective drug
delivery. Rational on-demand design can confer outstanding advantages to drug
delivery systems to match the shortcomings of epigenetic drugs, while
circumventing the hindrances and dilemmas during in vivo therapeutic processes.
In addition, smart multifunctional and integrated co-delivery systems are
capable of optimizing synergistic effects according to the sequential logic or
spatio-temporal demands of combination therapy, and have the advantages of
controlled drug ratios, unified in vivo fate, and responsive triggered
localization of drug release, which have great potentials for application in
epigenetically modulated combination therapy-based strategies. In summary, we
first outlined the characteristics of tumor epigenetic regulation, from which
we summarized the therapeutic needs of epigenetic regulation, then explored how
to design a rational drug delivery system based on therapeutic needs to achieve
solid tumor application of epigenetic antitumor therapies, and further
summarized how to apply intelligently matched multifunctional co-delivery
systems to epigenetic regulation-based combination therapy strategies, and
discussed the current research frontiers as well as opportunities and potential
issues for future development.
Link to the original article: https://authors.elsevier.com/a/1itaK6DSyBHtud
