Intracellular Nanoparticle Formation and Hydroxychloroquine Release for Autophagy‐Inhibited Mild‐Temperature Photothermal Therapy for Tumors

Abstract

Mild‐temperature photothermal therapy (PTT) of tumors has been intensively explored and adopted in preclinical/clinical trials in recent years. Nevertheless, tumor thermoresistance significantly compromises the therapeutic efficacy of mild‐temperature PTT, and therefore, the extra addition of anti‐thermoresistance agent is needed. Herein, by rational design of a peptide‐hydroxychloroquine (HCQ) conjugate Cypate‐Phe‐Phe‐Lys(SA‐HCQ)‐Tyr(H2PO3)‐OH (Cyp‐HCQ‐Yp), a “smart” strategy of enzyme‐triggered simultaneously intracellular photothermal nanoparticle formation and HCQ release is proposed for autophagy‐inhibited mild‐temperature PTT of tumor. In vitro results show that, under sequential catalysis of enzymes alkaline phosphatase and carboxylesterase, Cyp‐HCQ‐Yp is converted to Cypate‐Phe‐Phe‐Lys(SA)‐Tyr‐OH (Cyp‐Y) which self‐assembles into its nanoparticle Cyp‐NP and HCQ is released from Cyp‐HCQ‐Yp. By comparing with two control agents, it is validated that the exceptional therapeutic effect of Cyp‐HCQ‐Yp on tumor in vivo is achieved by its dual‐enzyme‐controlled intracellular nanoparticle formation and autophagy inhibition in tumors.

Molecular Engineering of Peptide–Drug Conjugates for Therapeutics

“…FFKY itself is also a brilliant assembly unit. After the enzymatic catalyzation by ALP, the compound Cyp-HCQ-Y can self-assemble to form nanoparticles with a size range of 95.1 to 169.7 nm [62]. The formed nanoparticles can be uptaken by tumor cells through endocytosis.…”

“…HCQ can connect to well-designed peptides and certain special dyes to self-assemble to form nanostructures and be used for the photothermal treatment (PTT) of cancer cells. In comparison with the conventional PTT strategy, peptide-modified materials show minimized damage toward healthy tissues caused by local hyperthermia (about 50 • C) [62]. Recently, Liang et al, designed a peptide derivative FFKYp (Yp) that covalently connects with HCQ and cypate (Cyp) via a succinate acid linker and an amide bond, respectively [62].…”

“…In comparison with the conventional PTT strategy, peptide-modified materials show minimized damage toward healthy tissues caused by local hyperthermia (about 50 • C) [62]. Recently, Liang et al, designed a peptide derivative FFKYp (Yp) that covalently connects with HCQ and cypate (Cyp) via a succinate acid linker and an amide bond, respectively [62]. Cyp-HCQ-Yp can be used for the PTT of some cancers with overexpression of both ALP and carboxylesterase (CES) (Figure 4).…”

“…Cyptate is a NIR dye that has been applied in preclinical therapy, normally as a probe. In Liang's work, cypate had the function of harvesting light energy and transferring it to thermal energy in order to inhibit tumor cell proliferation [62]. The researchers used the dual-enzyme-controlled self-assembly system, and HCQ was used as the factor to lower the temperature requirements for PTT so as to alleviate the side effects.…”

“…The researchers used the dual-enzyme-controlled self-assembly system, and HCQ was used as the factor to lower the temperature requirements for PTT so as to alleviate the side effects. Basing on the results of cell assays and animal trials, PDC-Cyp has a fascinating anti-cancer ability for HpG2 cells (human liver carcinoma cells), with almost neglectable side effects compared to Cyp-Y and HCQ [62]. PTT for anti-cancer therapy has received a lot of attention in the last ten years, and Liang was one of the first researchers to combine PTT with PDC and to obtain satisfactory results.…”