Multifunctional Chitosan/Porous Silicon@Au Nanocomposite Hydrogels for Long-Term and Repeatedly Localized Combinatorial Therapy of Cancer via a Single Injection

Abstract

Considering the future clinical applications of localized cancer therapy, it is of great importance to construct injectable biodegradable nanocomposite hydrogels with combinatorial therapeutic efficacy. Here, porous silicon nanoparticles (PSiNPs) as host matrix were chosen to fabricate PSiNPs@Au nanocomposites via in situ reductive synthesis of gold nanoparticles. Then PSiNPs@Au nanocomposites were further incorporated into thermosensitive chitosan (CS) hydrogels to construct CS/PSiNPs@Au nanocomposite hydrogels, which showed in situ gelation at physiological temperature, excellent biodegradability, and biocompatibility. Especially with the encapsulation of CS hydrogels, PSiNPs@Au nanocomposites had a long-term stable photothermal effect with higher local temperature under near-infrared (NIR) laser irradiation, whether in vitro or in vivo. Besides, assisted by NIR laser irradiation, CS/PSiNPs@Au nanocomposite hydrogels exhibited a long-term sustained release of anticancer drugs (doxorubicin hydrochloride, DOX) in acidic tumor environments. Finally, DOX/CS/PSiNPs@Au precursors were administrated into tumor-bearing mice via a single intratumoral injection, which presented a significant synergistic chemo-photothermal therapeutic efficacy under repeated NIR laser irradiation during long-term cancer treatments. Accordingly, we developed a novel strategy to prepare multifunctional CS/PSiNPs@Au nanocomposite hydrogels and also demonstrated their potential applications in localized cancer therapy in future clinics.

Multifunctional Hydrogel Nanocomposites for Biomedical Applications

“…On-demand delivery is a form of drug delivery where a stimulus, either generated in the body or administered externally, causes drug release [ 70 ]. Hydrogels can be tailored to respond to stimuli, and therefore are optimally suited for the localized delivery of drugs to more effectively target tumor cells or various pathogens [ 26 , 38 ]. However, without manipulation, many hydrogels may release drugs in an uncontrolled or unpredictable manner [ 25 , 26 ].…”

“…For instance, a nanocomposite hydrogel was developed for long-term drug delivery of biomacromolecular drugs in the inner ear by incorporating a protein drug into poly(lactic-co-glycolic acid) (PLGA) NPs, which improved mechanical properties of the hydrogel as well as extended the time of drug release 1.5- to 3-fold [ 48 ]. Nanoparticles may also enable the development of hydrogels to respond to a variety of in situ and external stimuli including electromagnetic radiation, thus allowing the simultaneous use of orthogonal delivery modalities [ 25 , 26 , 38 , 70 ].…”

“…Other researchers have developed on-demand delivery systems that respond to external stimuli such as electromagnetic radiation, which allows for more control over the timing and amount of drug released for localized and recurring dosage for the treatment of infections, post-surgery wounds, and cancers [ 38 , 70 ]. Ultraviolet (UV) radiation is often required to cause structural changes in hydrogels to deliver drugs; however, unlike near-infrared (NIR) radiation, UV cannot penetrate deep into the tissue and is carcinogenic [ 70 ].…”

“…However, with the addition of nanoparticles, like lanthanide-doped LiYF4 NPs, hydrogels can locally upconvert NIR to UV wavelengths, enabling drug delivery [ 70 ]. Others have leveraged the photothermal effects of nanoparticles in combination with chemical drug delivery to create “localized combinatorial therapy,” which is especially helpful in fighting cancer [ 38 ]. For example, Xia et al developed chitosan hydrogels containing silicon-gold NPs that exhibited photothermal effects under NIR for hyperthermia ablation of tumors and aided with the controlled release of anticancer drugs in the acidic environment of the tumor [ 38 ].…”

Inorganic Porous Nanoparticles for Drug Delivery in Antitumoral Therapy

“…PSi which contained gold nanoparticles (PSi@Au) were embedded within thermosensitive chitosan hydrogels which exhibited long term photothermal and drug release capacities. [ 37 ] This hydrogel suffered in situ gelation when was injected in the tumoral tissue inducing a potent antitumoral effect under NIR exposition due to the synergy between hyperthermia and chemotherapy.…”