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Review
. 2021 Sep;8(18):e2101454.
doi: 10.1002/advs.202101454. Epub 2021 Jul 29.

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

Yuezhou Zhang  1   2 , Huaguang Cui  1   2 , Ruiqi Zhang  1   2 , Hongbo Zhang  3   4 , Wei Huang  1   2
Affiliations
Review

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

Yuezhou Zhang et al. Adv Sci (Weinh). 2021 Sep.

Abstract

This article provides a broad spectrum about the nanoprodrug fabrication advances co-driven by prodrug and nanotechnology development to potentiate cancer treatment. The nanoprodrug inherits the features of both prodrug concept and nanomedicine know-how, attempts to solve underexploited challenge in cancer treatment cooperatively. Prodrugs can release bioactive drugs on-demand at specific sites to reduce systemic toxicity, this is done by using the special properties of the tumor microenvironment, such as pH value, glutathione concentration, and specific overexpressed enzymes; or by using exogenous stimulation, such as light, heat, and ultrasound. The nanotechnology, manipulating the matter within nanoscale, has high relevance to certain biological conditions, and has been widely utilized in cancer therapy. Together, the marriage of prodrug strategy which shield the side effects of parent drug and nanotechnology with pinpoint delivery capability has conceived highly camouflaged Trojan horse to maneuver cancerous threats.

Keywords: cancer therapy; endogenous/exogenous stimuli; nanoprodrug; on-demand release; polyprodrug.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Schematic of the different forms of prodrug conjugates, respectively, and their potential as building blocks to fabricate nanoprodurg as newly emerging cancer therapy formulations under different endogenous/exogenous stimuli, drug connective patterns and biocompatibility.
Figure 1
Figure 1
Molecular structures of A) PTX, B) PTX‐VE, and D) PTX‐S‐S‐VE and individual SEM/TEM images after dispersion in water. Reproduced with permission.[ 24 ] Copyright 2014, American Chemical Society. C) Self‐_targeting all‐in‐one platinum (IV) amphiphiles for multimodal theranostic precise nanomedcine. Reproduced with permission.[ 21 ] Copyright 2018, American Chemical Society. E) Schematic illustration of the design of the probe‐inspired nanoprodrug. Reproduced with permission.[ 26 ] Copyright 2015, American Chemical Society. F) Schematic illustration of the action of FRRG‐DOX NPs as new carrier‐free NPs for cancer _targeting treatment. Reproduced with permission.[ 27 ] Copyright 2019, Elsevier. G) Illustration of the co‐assembly of peptide‐DOX and P‐gp inhibitor into an acid‐responsive nanogel for controllable drug release to overcome cancer drug resistance. Reproduced with permission.[ 31 ] Copyright 2017, Wiley‐VCH.
Figure 2
Figure 2
A) Chemical Structures of the Disulfide‐Bond‐Bridged PTX‐CIT Prodrugs: α‐PTX‐S‐S‐CIT, β‐PTX‐S‐S‐CIT, and γ‐PTX‐SS‐CIT; B) In vitro redox dual‐responsive drug release of prodrug nanoassemblies in the presence of various concentrations of DTT or H2O2 (n = 3). Reproduced with permission.[ 46 ] Copyright 2018, American Chemical Society. C) Sulfur/selenium/carbon bond‐bridged PTX‐CIT prodrug. D) Images of tumors after in vivo antitumor treatment using different types of prodrug nanoassemblies. Adapted with permission.[ 48 ] Copyright 2019, Nature Publishing Group. E) Result of attempted water dispersion of paclitaxel with a panel of excipients. Reproduced with permission.[ 54 ] Copyright 2018, Nature Publishing Group.
Figure 3
Figure 3
A) Plasmas were isolated at each blood collection, and then analyzed for CAB concentrations by UPLC/MS/MS. Horizontal dotted and dashed lines represent 1  ×  and 4  ×  PA‐IC90, respectively. B) Tissues were collected at each sacrifice day and then analyzed for CAB concentrations by UPLC/MS/MS. LN: lymph node. Reproduced with permission.[ 58 ] Copyright 2018, Elsevier. C) CAB was chemically modified with 14‐, 18‐ and 22‐carbon fatty acid chains to develop MCAB, M2CAB, and M3CAB, respectively. D) Morphological assessment of NCAB, NMCAB, NM2CAB, and NM3CAB by SEM. Reproduced with permission.[ 59 ] Copyright 2020, Nature Publishing Group. E) Layered arrangement of bexarotene prodrug after self‐assembling into a gas‐filled bubble followed by its rupture upon US exposure and interacts favorably with the cancer cell membrane to get inserted and eventually be cleaved enzymatically, releasing the active pharmaceutical ingredient. Reproduced with permission.[ 60 ] Copyright 2015, American Chemical Society.
Figure 4
Figure 4
A) Overall Synthetic Scheme for Sb‐cyclodextrin(CD)‐DOX‐ZAISe/ZnS@FA NPD by “Host–Guest” Assembly and Electrostatic Interaction Strategy. Reproduced with permission.[ 65 ] Copyright 2018, American Chemical Society. B) Schematic illustration for the preparation of charge‐convertible CDs‐based drug nanocarrier CDs‐Pt(IV)@PEG‐(PAH/DMMA) and the drug delivery process of CDs‐Pt(IV)@PEG‐(PAH/DMMA) Reproduced with permission.[ 66 ] Copyright 2016, American Chemical Society.
Figure 5
Figure 5
A) Synthesis of PTX2 and Self‐assembly of PTX2 in aqueous solution. Reproduced with permission.[ 69 ] Copyright 2017, Elsevier. B) MD simulations of tetrameric PTX‐S‐S‐PTX in water. Reproduced with permission.[ 70 ] Copyright 2016, American Chemical Society. C) Schematic diagram of amphiphilic drug–drug conjugate from fabrication, self‐assembly to self‐delivery. Reproduced with permission.[ 73 ] Copyright 2014, American Chemical Society. D) Preparation and characterization of DOX homodimeric prodrug nanoassemblies. Reproduced with permission.[ 80 ] Copyright 2020, AAAS.
Figure 6
Figure 6
A) Self‐assembly process diagram of the Rh hydrogel. Reproduced with permission.[ 83 ] Copyright 2019, Nature Publishing Group. B) TEM images of HCPT/Ce6 hybrid nanostructures with different ratios and whole body fluorescence images of 4T1 tumor‐bearing mice at different time points after being treated with HCPT/Ce6 NRs via intravenous injection. Reproduced with permission.[ 84 ] Copyright 2017, Royal Society of Chemistry. C) Natural self‐assembling mode between berberine (BBR) and flavonoid glycosides (BA, WOG) and their modified antibacterial application. Reproduced with permission.[ 86 ] Copyright 2019, American Chemical Society. D) Antibacterial mechanism: (top) Interaction between CA‐BBR NPs and MRSA. Inset shows HPLC‐HRMS/MS analysis of BBR in MRSA. (middle) FESEM images of MRSA treated without or with BBR and CA‐BBR NPs. (bottom) TEM images of MRSA treated without or with BBR and CA‐BBR NPs. Reproduced with permission.[ 87 ] Copyright 2020, American Chemical Society. E) Schematic illustration of the design and prepared DOX‐dopamine‐gossypol NPs with ultralong blood circulation and enhanced tumor penetration for efficient synergistic chemotherapy. Reproduced with permission.[ 89 ] Copyright 2019, Wiley‐VCH. F) Confocal fluorescence images of cancer‐derived NPs after 6 h co‐incubation with cells. Reproduced with permission.[ 92 ] Copyright 2021, Elsevier.
Figure 7
Figure 7
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Figure 8
Figure 8
A) Illustration of acetal‐linked polymer‐CUR conjugate micelle and its endocytosis. Reproduced with permission.[ 104 ] Copyright 2016, Elsevier. B) Schematic illustration of SCNs/Pt as a robust nanoplatform to overcome biological barriers to in vivo drug delivery in poorly permeably pancreatic tumor models. Reproduced with permission.[ 105 ] Copyright 2018, Elsevier. C) Schematic illustration of SCNs/Pt as a robust nanoplatform to overcome biological barriers to in vivo drug delivery in poorly permeably pancreatic tumor models. Reproduced with permission.[ 111 ] Copyright 2016, American Chemical Society. D) Schematic illustration showing the mechanism of spatial delivery of BLZ‐945 and Pt‐prodrug to TAMs and tumor cells. Reproduced with permission.[ 114 ] Copyright 2017, American Chemical Society. E) Schematic illustration of CT/UCL dual‐modal imaging and NIR photon improved cancer therapy process for UCNs‐Pt(IV)@PEG‐PAH‐DMMA. Reproduced with permission.[ 116 ] Copyright 2017, Elsevier. F) Structural formula of the mussel‐derived cancer‐cell‐_targeting peptide and the dynamic conjugation of antitumor drug BTZ with pH‐responsiveness. Reproduced with permission.[ 122 ] Copyright 2019, American Chemical Society.
Figure 9
Figure 9
A) In vitro cytotoxicity and apoptosis of cells treated with cisplatin, CP5 NPs, or cisplatin + control NPs. Reproduced with permission.[ 128 ] Copyright 2018, American Chemical Society. B) Histogram of particle‐size distribution of P6 NPs obtained by DLS and TEM morphologies of P6 NPs stored in water. Reproduced with permission.[ 129 ] Copyright 2019, American Chemical Society. C) Diagram showing the Preparation Process and Mechanisms Underlying the Effects of X‐PDT with LiLuF4:Ce@SiO2@Ag3PO4@Pt(IV) NPs. Reproduced with permission.[ 133 ] Copyright 2018, American Chemical Society. D) In vivo bioluminescence images of mice bearing luciferase PC3 cell xenograft tumors post 10 d treatment with different groups. And resected luciferase‐expressing PC3 tumors from experimental groups at the 21st day. Reproduced with permission.[ 134 ] Copyright 2017, Wiley‐VCH. E) Schematic illustration of the preparation of amphiphilic PCCO prodrug. Reproduced with permission.[ 135 ] Copyright 2018, Elsevier. F) Schematic illustration of TrxR‐responsive DDS for ROS‐mediated chemosensitization and anti‐recurrence/metastasis therapy based on TrxR activity inhibition. Reproduced with permission.[ 144 ] Copyright 2020, Elsevier. G) H&E staining images for major organs of MCF‐7 tumor‐bearing nude mice after different treatments for 15 days. Reproduced with permission.[ 149 ] Copyright 2019, American Chemical Society. H) ROS responsive polymer‐drug conjugates in vitro In vivo antitumor efficacy and body weigh after intravenous injection of different drug formulations (with POD‐equivalent dose of 2.5, 5, and 10 mg kg−1, respectively). Reproduced with permission.[ 150 ] Copyright 2019, Royal Society of Chemistry. I) Self‐assembly of MPP NPs and the ROS generation process. Reproduced with permission.[ 155 ] Copyright 2020, Elsevier.
Figure 10
Figure 10
A) Schematic representation of GGT‐triggered transcytosis of the dendrimer‐camptothecin conjugate for PDA therapy. Reproduced with permission.[ 161 ] Copyright 2020, American Chemical Society. B) Schematic showing the nanoclustered cascaded enzymes for _targeted tumor starvation and deoxygenation‐activated chemotherapy without causing systemic toxicity. Reproduced with permission.[ 163 ] Copyright 2019, American Chemical Society. C) Illustration of cooperative cancer treatment by combining CA4 nanodrug plus MMP9‐activated DOX prodrug nanomedicine. Reproduced with permission.[ 167 ] Copyright 2019, Wiley‐VCH.
Figure 11
Figure 11
A) Schematic illustration of the photoactivatable Pt(IV) prodrug‐backboned polymeric nanoparticle system (CNPPtCP/si(c‐fos)) for light‐controlled efficient gene delivery and synergistic PACT and RNAi on platinum‐resistant ovarian cancer. Reproduced with permission.[ 171 ] Copyright 2020, American Chemical Society. B) Schematic illustration of dual drug backboned shattering polymeric theranostic nanomedicine (DDBSP) for synergistic eradication of patient‐derived lung cancer. Reproduced with permission.[ 174 ] Copyright 2018, Wiley‐VCH. C) Synthetic routes and scheme of degradable PEG integrated by platinum for cancer treatment. Reproduced with permission.[ 175 ] Copyright 2019, Elsevier. D) Schematic of SPNpd for hypoxia‐activated synergistic PDT and chemotherapy. Reproduced with permission.[ 177 ] Copyright 2019, Wiley‐VCH.
Figure 12
Figure 12
A) The mechanisms of ultrasound‐triggered imaging and delivery of CAD. Reproduced with permission.[ 179 ] Copyright 2019, Elsevier. B) Activity of combination therapeutic nanoparticle in combination with radiation) TEM images of as‐prepared micelle, Scale bar = 100 nm. Reproduced with permission.[ 181 ] Copyright 2018, Elsevier. C) TEM images of worm‐like polymeric micelles. Scale bar = 100 nm. Reproduced with permission.[ 183 ] Copyright 2018, American Chemical Society. D) Working protocol of activatable nano prodrug. Reproduced with permission.[ 184 ] Copyright 2017, American Chemical Society. E) DOX prodrug being converted by Pd into uncaged DOX through allylcarbamate cleavage and Pd‐NP cotreatment enhances the concentration of proDOX causing 50% reduction in cell count. Reproduced with permission.[ 187 ] Copyright 2017, Nature Publishing Group. F) Overview of modular prodrug design strategy: a self‐immolative linker (gray) bridges three modular functional aspects of an inactive nontoxic prodrug. Reproducedunder the terms of the Creative Commons CC‐BY license.[ 188 ] Copyright 2018, American Chemical Society. G) Construction of self‐sacrificing iron oxide NPs with cisplatin(IV) prodrug (FePt‐NP2) circumvents the endocytosis of cisplatin into the cells. Reproduced with permission.[ 189 ] Copyright 2017, American Chemical Society. H) Schematic illustration of multistage assembly method for construction of the FeCO‐TPP@MSN@HA nanomedicine. Reproduced with permission.[ 190 ] Copyright 2020, American Association for the Advancement of Science.
Figure 13
Figure 13
A) pH/redox responsive polymeric prodrug and fabrication of shell cross‐linked prodrug micelles for antitumor drug transportation. Reproduced with permission.[ 192 ] Copyright 2018, American Chemical Society. B) Illustration of size‐shrinkable and charge‐reversal system for tumor chemo‐immunotherapy in vivo. Reproduced with permission.[ 194 ] Copyright 2020, Elsevier. C) Construction of Boolean logic nanoplatform for combination immunotherapy of cancer. Reproduced with permission.[ 195 ] Copyright 2020, Wiley‐VCH. D) Schematic illustration of the synthesis, upconversion luminescence magnetic resonance imaging, intracellular chemotherapy, and photothermal therapy (PTT) of UCNPs@Au‐DOX nanocomposites. Reproduced with permission.[ 196 ] Copyright 2017, Royal Society of Chemistry. E) Schematic illustration of constructing bifunctional supramolecular prodrug NPs and their application in cancer therapy. Reproduced with permission.[ 197 ] Copyright 2020, Royal Society of Chemistry. F) Schematic illustrations of molecular and supramolecular engineering on tumor‐specific multiple stimuli‐activated dendrimeric nanoassemblies with metabolic blockade and their synergistic effects for overcoming physiological barriers and cellular factors of chemotherapy resistance. Reproduced with permission.[ 199 ] Copyright 2017, American Chemical Society.
Figure 14
Figure 14
A) Scheme of hyaluronan‐PTX prodrugs multilayers construction through layer‐by‐layer approach and drug release mechanism. Reproduced with permission.[ 201 ] Copyright 2005, American Chemical Society. B) Schematic illustration of HNP preparation and intended mechanism for metastatic breast cancer treatment. Reproduced with permission.[ 204 ] Copyright 2018, American Chemical Society. C) A schematic illustration of the procedure for preparing nano‐chrysalis. Reproduced with permission.[ 206 ] Copyright 2017, Elsevier. D) Preparation and single‐stimulus (Light) dual‐drug sensitivity of Cur@DPNs and schematic representation of the intracellular action after endocytosis of Cur@DPNs for combinational photoactivated therapy. Reproduced with permission.[ 209 ] Copyright 2016, American Chemical Society. E) Release mechanism of 5‐Fluorouracil from the LMWC‐5 FU conjugate prodrug upon irradiating with λ  =  365 nm light. Reproduced with permission.[ 217 ] Copyright 2019, Elsevier.
Figure 15
Figure 15
A) C26 tumor volumes after injection with saline, PLG‐CA4 and CA4P on days 1, 5, and 9; Images of C26 tumors on day 11, mice on the left were treated with CA4P and mice on the right were treated with PLG‐CA4. Reproduced with permission.[ 225 ] Copyright 2017, Elsevier. B) siBec1@PPN effectively suppressed Pt‐resistant tumor growth. Reproduced with permission.[ 228 ] Copyright 2019, American Chemical Society. C) A schematic illustration to show the formation of HAS‐ICG‐PTX NPs by self‐assembly between HSA, PTX, and ICG. Reproduced with permission.[ 235 ] Copyright 2015, Wiley‐VCH. D) Schematic illustration of the programmed assembly strategy for the preparation of HSA‐ICG NPs and synergetic phototherapy. Reproduced with permission.[ 236 ] Copyright 2014, American Chemical Society. E) Efficacy and survival in HT‐1080 fibrosarcoma model (n = 8 per group). Reproduced with permission.[ 237 ] Copyright 2019, American Chemical Society.
Figure 16
Figure 16
A) Schematics of the DNA–Drug Nanostructures Assembled from Photolabile DNA‐Drug Amphiphiles. Reproduced with permission.[ 240 ] Copyright 2015, American Chemical Society. B) Growth curves of tumors treated with a dose of nanoplex; Reproduced with permission.[ 242 ] Copyright 2010, American Chemical Society. C) qRT‐PCR confirmation of REV1 and REV3L gene suppression in LNCaP cells that were harvested from a xenograft tumor and isolated by GFP sorting 2 or 3 d after injection of NP (siREV1, siREV3L). Reproduced with permission.[ 243 ] Copyright 2013, The National Academy of Sciences. D) Schematics of DNA‐graft‐PTX conjugate synthesis, and the self‐assembly of multifunctional PTX‐SNAs. Reproduced with permission.[ 246 ] Copyright 2019, Wiley‐VCH.
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