Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy:From intrinsic physicochemical properties to external modification

The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability,simple preparation method,and offering“all-in-one”functional platform features.However,the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey,which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment.In this review,we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy,including optimizing the intrinsic physicochemical properties and external modification.Finally,the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented.We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.

Mitochondria-acting carrier-free nanoplatform self-assembled by a-tocopheryl succinate carrying cisplatin for combinational tumor therapy

Unsatisfactory drug loading capability,potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy.To address the above obstacles,a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function.In this nanoplatform,the mitochondria-targeting small-molecular drug,a-tocopheryl succinate(TOS),firstly self-assembled into nanoparticles,which then were used as the carrier to conjugate cisplatin(CDDP).Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments,as well as pH-sensitive drug release and efficient cellular uptake.Due to the combined effects of reactive oxygen species(ROS)generation by TOS and DNA damage by CDDP,the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis,resulting in highly efficient anti-tumor outcomes in vitro.Collectively,the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.

High-drug-loading capacity of redox-activated biodegradable nanoplatform for active targeted delivery of chemotherapeutic drugs

Challenges associated with low-drug-loading capacity,lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy.Herein,we constructed active-targeting,redox-activated polymeric micelles(HPGssML)selfassembled aptamer-decorated,amphiphilic biodegradable poly(benzyl malolactonate-co-e-caprolactone)copolymer with disulfide linkage and p-conjugated moieties.HPGssML with a homogenous spherical shape and nanosized diameter(-150 nm)formed a low critical micellar concentration(10^-3mg/mL),suggesting good stability of polymeric micelles.The anticancer drug,doxorubicin(DOX),can be efficiently loaded into the core of micelles with high-drug-loading content via strong π-π interaction,which was verified by a decrease in fluorescence intensity and redshift in UV adsorption of DOX in micelles.The redox sensitivity of polymeric micelles was confirmed by size change and in vitro drug release in a reducing environment.Confocal microscopy and flow cytometry assay demonstrated that conjugating aptamers could enhance specific uptake of HPGssML by cancer cells.An in vitro cytotoxicity study showed that the half-maximal inhibitory concentration(IC50)of DOX-loaded HPGssML was two times lower than that of the control group,demonstrating improved antitumor efficacy.Therefore,the multifunctional biodegradable polymeric micelles can be exploited as a desirable drug carrier for effective cancer treatment.